PROTOCOL GOG-0241
A GCIG INTERGROUP MULTICENTRE PHASE III TRIAL OF OPEN LABEL CARBOPLATIN
AND PACLITAXEL +/- BEVACIZUMAB COMPARED WITH OXALIPLATIN AND
CAPECITABINE +/- BEVACIZUMAB AS FIRST LINE CHEMOTHERAPY IN PATIENTS WITH
MUCINOUS EPITHELIAL OVARIAN CANCER (MEOC)
POINTS:
PER CAPITA MEMBERSHIP -
STUDY CHAIR
DAVID M. GERSHENSON, M.D.
M.D. ANDERSON CANCER CTR
DEPARTMENT OF GYN/ONC
1515 HOLCOMBE BLVD., BOX 440
HOUSTON, TX 77030-4009
(713) 792-2455
FAX: (713) 792-7586
E-MAIL: dgershen@mdanderson.org
STUDY CO-CHAIR
RICHARD T. PENSON, M.D.
MASSACHUSETTS GENERAL HOSPITAL
55 FRUIT STREET,
YAWKEY 9066
BOSTON, MA 02114-2617
(617) 726-5867
FAX: (617) 724-6898
EMAIL: rpenson@partners.org
NURSE CONTACT
JACALYN GANO
M.D. ANDERSON CANCER CTR
DEPARTMENT OF GYN/ONC
P.O. BOX 301439
HOUSTON, TX 77230-1439
(713) 794-1422
FAX: (713) 792-7586
E-MAIL: jgano@mdanderson.org
PATHOLOGIST
RICHARD ZAINO, M.D.
(SEE GOG WEBSITE DIRECTORY)
TRANSLATIONAL CO-CHAIR
JEFF BOYD, Ph.D.
(SEE GOG WEBSITE DIRECTORY)
TRANSLATIONAL CO-CHAIR
ANIL SOOD, M.D.
(SEE GOG WEBSITE DIRECTORY)
PATHOLOGIST
KAREN E. STREHLOW, M.D.
(SEE GOG WEBSITE DIRECTORY)
QUALITY OF LIFE CO-CHAIR
MICHAEL FRUMOVITZ, M.D.
(SEE GOG WEBSITE DIRECTORY)
STATISTICIAN
WILLIAM E. BRADY, M.S.
(SEE GOG WEB SITE DIRECTORY)
TRANSLATIONAL RES. SCIENTIST
ZOE MINER, PH.D.
(SEE GOG WEB SITE DIRECTORY)
Draft: July 9, 2009
This protocol was designed and developed by the Gynecologic Oncology Group (GOG). It is intended to be used
only in conjunction with institution-specific IRB approval for study entry. No other use or reproduction is authorized
by GOG nor does GOG assume any responsibility for unauthorized use of this protocol.
PROTOCOL GOG-0241
A GCIG INTERGROUP MULTICENTRE TRIAL OF OPEN LABEL CARBOPLATIN AND
PACLITAXEL +/- BEVACIZUMAB COMPARED WITH OXALIPLATIN AND CAPECITABINE
+/- BEVACIZUMAB AS FIRST LINE CHEMOTHERAPY IN PATIENTS WITH MUCINOUS
EPITHELIAL OVARIAN CANCER (MEOC)
Schema
mEOC
Eligible patients aged 18 or over with
newly diagnosed advanced mucinous ovarian carcinoma
FIGO stage II – IV OR recurrent stage I
Randomize
N=322¶
Carboplatin AUC 6
Paclitaxel 175mg/m2
6 cycles†
Each cycle =21 days
N=83
Oxaliplatin 130 mg/m2
Capecitabine 850mg/m2 bd
6 cycles†
Each cycle =21 days†
N=83
Clinical assessments every 3 months for 36 weeks
Telephone assessments every 3 weeks for 36 weeks
Treatment to start within 14 days
of randomization for all arms
Carboplatin AUC 6
Paclitaxel 175mg/m2
Bevacizumab 15 mg/kg
6 cycles†‡
Each cycle =21 days†
N=83
Oxaliplatin 130 mg/m2
Capecitabine 850mg/m2 bd
Bevacizumab 15 mg/kg
6 cycles†‡
Each cycle =21 days
N=83
Bevacizumab 15 mg/kg
12 cycles†
Each cycle= 21 days
Clinical assessments every 6 weeks for 36
weeks (i.e., the twelve 21-day cycles)
Follow-up:
 Every 3 months for 2 years
 Every 6 months for years 3-5
¶ Approximately 60 (or about 20%) of the patients are expected to be enrolled by GOG sites.
† Or until progression of disease or adverse effects prohibit further therapy.
‡ Bevacizumab can be omitted from the first cycle if chemotherapy must be started within 4 weeks of surgery. Please
refer to Section 5 for further details.
TABLE OF CONTENTS
PAGE
1.0
OBJECTIVES
1
2.0
BACKGROUND AND RATIONALE
2
3.0
PATIENT ELIGIBILITY AND EXCLUSIONS
4
4.0
STUDY MODALITIES
7
5.0
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE
21
6.0
TREATMENT MODIFICATIONS
30
7.0
STUDY PARAMETERS
39
8.0
EVALUATION CRITERIA
44
9.0
DURATION OF STUDY
52
10.0
STUDY MONITORING AND REPORTING PROCEDURES
53
11.0
STATISTICAL CONSIDERATIONS
58
12.0
BIBLIOGRAPHY
64
SUGGESTED PATIENT INFORMATION/INFORMED CONSENT
APPENDIX I -
Clinical Staging (FIGO)
APPENDIX II -
New York Heart Association Criteria
APPENDIX III-
Peripheral Vascular Disease
APPENDIX IV-
Anaphylaxis Precautions
APPENDIX V -
Patient Pill Calendar
APPENDIX VI-
Blood Pressure Check Calendar
-11.0
GOG-0241
OBJECTIVES
1.1
1.2
1.3
Primary Objective
1.11
To determine if capecitabine and oxaliplatin reduces the death rate compared to
carboplatin and paclitaxel in women with mucinous adenocarcinoma of the
ovary or fallopian tube.
1.12
To determine if bevacizumab reduces the death rate compared to no
bevacizumab in women with mucinous adenocarcinoma of the ovary or
fallopian tube.
Secondary Objectives
1.21
To determine if capecitabine and oxaliplatin increases the duration of
progression-free survival (PFS) compared to carboplatin and paclitaxel in
women with mucinous adenocarcinoma of the ovary or fallopian tube.
1.22
To determine if bevacizumab increases the duration of PFS compared to no
bevacizumab in women with mucinous adenocarcinoma of the ovary or
fallopian tube.
1.23
To compare the response rates for capecitabine and oxaliplatin versus
carboplatin and paclitaxel in patients with mucinous adenocarcinoma of the
ovary or fallopian tube with measurable disease after initial tumor reductive
surgery.
1.24
To compare the response rates for bevacizumab versus no bevacizumab in
patients with mucinous adenocarcinoma of the ovary or fallopian tube with
measurable disease after initial tumor reductive surgery.
1.25
To determine the nature and degree of toxicity of capecitabine and oxaliplatin
compared with that of carboplatin and paclitaxel in this cohort of patients.
1.26
To determine the nature and degree of toxicity of bevacizumab in this cohort of
patients.
1.27
To compare capecitabine and oxaliplatin versus carboplatin and paclitaxel with
respect to changes in patient reported neurotoxicity.
1.28
To determine the impact on Quality of Life (QOL, as measured by the FACT-O
TOI) following treatment with the above regimens
Exploratory Objectives
1.31
To identify expression of VEGF ligand, receptor, and activated receptor via
immunohistochemistry in mucinous adenocarcinoma of the ovary.
1.32
To identify expression of EGF ligand, receptor, and activated receptor via
immunohistochemistry in mucinous adenocarcinoma of the ovary.
-2-
1.33
2.0
GOG-0241
To assess the mutational status of the KRAS oncogene in primary mucinous
ovarian carcinomas obtained prior to treatment with oxaliplatin/capecitabine and
then to determine whether there exists evidence for a correlation between the
presence of KRAS mutation and response to therapy in this group of ovarian
cancer patients.
BACKGROUND AND RATIONALE
There will be an estimated 20,180 new cases of ovarian cancer in the United States in 2006, but
only 9% of these will have mucinous histology.1,2 Overall, survival of women with mucinous
adenocarcinoma of the ovary is better than its serous counterpart, but this is likely owing to the
fact that at diagnosis, mucinous carcinomas are often confined to the ovary, while serous
carcinomas are usually metastatic. In fact, over half of mucinous adenocarcinomas are localized
to the ovary at surgery, whereas over 80% of serous adenocarcinomas have distant spread.3
However, women with advanced-stage mucinous carcinomas of the ovary have a much shorter
progression-free and overall survival than those with advanced-stage serous carcinomas and are
more likely to fail adjuvant platinum-based chemotherapy regimens.4
In addition to differences in clinical behavior, laboratory data support molecular differences
between the different epithelial subtypes of ovarian cancer. When gene expression arrays were
performed on the subtypes of epithelial ovarian cancers, mucinous cancers grouped separately
from serous, endometrioid, and clear-cell tumors on dendrograms.5 In addition, KRAS more
often overexpressed in mucinous tumors when compared to serous, endometrioid, or clear-cell
tumors.6 The Ras family of proteins consists of three isoforms (H-, K-, and N-Ras) that play a
critical role in controlling normal and malignant cell growth7. KRAS mutation is one of the
most common abnormal genetic events in human cancer, with the highest incidence in
pancreatic carcinomas (90%) and colorectal tumors (50%).8 Mitogen-activated protein kinases
(MAPKs) are the best-characterized signal pathways in transduction and regulation of Ras
activity and cellular proliferation. Phosphorylation of its membrane-anchoring domain by
protein kinase-C (PKC) drives KRAS off the plasma membrane and onto the outer
mitochondrial membrane where it induces cell death.
Traditionally, women with all ovarian epithelial carcinomas have been treated similarly, with
upfront tumor debulking surgery followed by platinum-based adjuvant chemotherapy. Support
for this approach comes from Gynecologic Oncology Group (GOG) collaborative trials,9,10 as
well as studies in Europe and Canada.11 These studies showed platinum/taxane-based therapies
to have an advantage in women with advanced-stage epithelial ovarian cancers. However, only
3 to 4% of patients in each of those studies had mucinous histologies and, owing to small
numbers, subset analysis of these women has not been possible.
Unlike the 26% response rate reported for platinum-based chemotherapy regimens in patients
with mucinous ovarian carcinomas,4 combination therapy with a fluorouracil and either CPT-11
(irinotecan) or oxaliplatin have response rates of 50% in patients with advanced-stage
colorectal cancers.12,13 In one study of patients with advanced mucinous colorectal cancer,
subjects treated with a combination of 5-FU and oxaliplatin (FOLFOX) had a better response
rate, longer overall survival, and fewer chemotherapy-related side effects than those treated
either with CPT-11/5-FU or CPT-11/oxaliplatin combination therapies.14 More recently, Phase
I/II studies of the combination of capecitabine (Xeloda) and oxaliplatin (XELOX) as first-line
therapy have shown this combination to be as effective as the FOLFOX regimen.15,16 The GOG
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GOG-0241
has evaluated oxaliplatin alone in platinum-resistant epithelial tumors of the ovary, with
minimal activity shown.17 However, of the 23 evaluable patients, none had mucinous histology.
Mucinous ovarian carcinomas seem to have a clinical course that is more similar to mucinous
gastrointestinal carcinomas than to serous ovarian carcinomas.
We hypothesize that multimodality therapy with capecitabine and oxaliplatin (XELOX) will
offer a better response, longer progression-free survival, and longer overall survival than
current platinum/taxane strategies in patients with mucinous ovarian cancers.
This trial will help determine if oxaliplatin and capecitabine +/- bevacizumab improves OS and
PFS when compared to carboplatin and paclitaxel +/- bevacizumab in women with advanced
stage mucinous ovarian cancer. Acute and chronic toxicities from carboplatin and taxol and
their effect on QOL in women with gynecologic cancers is well-documented. 18-20 The effects
on QOL by the addition of bevacizumab to this regimen for women with gynecologic
malignancies is largely unknown. The effects on QOL with the oxaliplatin and capecitabine +/bevacizumab regimen in women with ovarian cancer has never been explored. Although data
on QOL with these regimens exist for patients with colorectal cancer, 21-22 a direct comparison
of QOL in patients receiving oxaliplatin and capecitabine vs oxaliplatin, capecitabine and
bevacizumab, however, does not exist.
Although high-quality, comparative QOL data for these regimens do not exist, we do have a
number of studies from which we might examine regimen toxicities. GOG 182-ICON 5
enrolled over 4300 women into a 5-arm, randomized study with carboplatin (AUC 6) and
paclitaxel (175 mg/m2) given every three weeks as one of the regimens. In this study, 864
evaluable patients received this combination. In this cohort, 24% had grade 2-4 peripheral
neuropathy. 23 Peripheral neuropathy, whose symptoms include parasthesias of the hands and
feet, can be severe with the carboplatin and paclitaxel combination and often is the dose
limiting toxicity of the regimen. Paclitaxel is the main source of neuropathy in women
receiving this regimen and its effects are cumulative. Most women have some resolution of
symptoms after discontinuation of therapy but significant peripheral neuropathy, often
described as “stocking/glove distribution” may be permanent in a small percentage of patients.
Myelosuppression was a more significant toxicity as 59% had grade 4 neutropenia and 22%
had a grade 3 or 4 thrombocytopenia.23 In this study, however, subjects received 8 cycles of
the carboplatin/paclitaxel regimen. A phase II study of capectibine and oxaliplatin in advanced
or metastatic colorectal cancer revealed significant (grade 3 or 4) diarrhea in 35% of the
patients who had not been pretreated. 24 In this study, however, diarrhea was greatly reduced to
< 15% when the capecitabine was reduced by 25% after the first episode of grade 3 or 4
diarrhea. In addition, 16% had “sensitive” neuropathy, 5% had nausea and vomiting, and 12%
had thrombocytopenia.24 In a recent study of oxaliplatin, capecitabine and bevacizumab in
patients with metastatic colorectal cancer, 73% of patients experienced grade 3 or 4 toxicity22.
This included hand-foot reaction (19%), diarrhea (19%), hypertension (14%) fatigue (13%),
sensory neuropathy (10%), nausea/vomiting (8%), and venous thromboembolic disease (7%).
In this study, however, the capecitabine was administered at 100 mg/m2 BID which is higher
than in the current protocol. The neurotoxicity most often reported from this combination is
secondary to administration of the oxaliplatin. Oxaliplatin neuropathies may be either acutely
with drug administration or chronic from cumulative effects of multiple doses. The acute
syndrome typically consists of burning, numbness and/or tingling in the oropharyngeal cavity.
This acute phase is almost always transient with resolution within hours or days after drug
administration. The chronic neuropathy is similar to that of paclitaxel presenting as parasthesia
of the hands and feet.25 Similar to the peripheral neuropathy experienced after paclitaxel
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GOG-0241
administration, most women with parasthesia from oxaliplatin will have resolution of
symptoms when the chemotherapy is discontinued although some might have chronic,
debilitating neuropathy.
In the current trial, QOL will be assessed using the Trial Outcome Index of the Functional
Assessment of Cancer Therapy-Ovary (FACT-O TOI).26,27 This 26-item summary score
captures the FACT-G QOL dimensions of Physical Well-Being (7 items), Functional WellBeing (7 items), and the Ovarian Cancer Subscale (12 item). By combining these three
subscales, one is assured of capturing the full range of physical aspects of QOL in advanced
ovarian cancer, including pain, fatigue, abdominal symptoms and functional status. By
combining questions GP4, O1, and O3, which assess abdominal pain, swelling and cramps
respectively, a comprehensive patient reported assessment of disease related abdominal
symptoms including ascites can be evaluated.
The neuropathic side effects of therapy will be measured by patient reported neurotoxicity,
using: (1) FACT-GOG/NTX4, which is a 4-item scale that reliably and validly assesses
platinum/paclitaxel-induced peripheral neuropathy, with Cronbach’s alpha ranging from 0.80 to
0.8528 and includes questions regarding numbness and tingling in hands and feet and
discomfort in hands and feet; and (2) a question regarding cold-induced pain in the extremities,
which can result from treatment with oxaliplatin.
The neurotoxicity assessment will be administered prior to receiving the first cycle of therapy,
just before starting the fourth cycle of chemotherapy, after the final cycle of chemotherapy, and
one year after completing the final cycle of chemotherapy regardless if the ovarian cancer has
remained in remission or has recurred.
Although we may know many of the toxicities associated with these chemotherapy regimens,
we do not know their effects on QOL. We hypothesize that although oxaliplatin and
capecitabine +/- bevacizumab will improve OS and PFS when compared to carboplatin and
paclitaxel +/- bevacizumab, the acute and chronic toxicities of the oxaliplatin/capecitabine
regimen may affect QOL more adversely than carboplatinum/paclitaxel regimen. These data
may prove invaluable both for patient education prior to initiating therapy as well as for helping
physicians and patients choose the best treatment regimen for them.
In addition to traditional chemotherapeutics, bevacizumab (Avastin), a monoclonal antibody to
vascular endothelial growth factor (VEGF), has improved outcomes in patients with colorectal
cancer. For untreated colorectal cancers, the combination of 5-FU with bevacizumab
significantly improved response rate, progression-free interval, and overall survival when
compared to 5-FU alone.29 Furthermore, in a randomized phase III trial in which patients were
randomized in a 2 x 2 factorial design to receive either XELOX or FOLFOX-4, and then to
bevacizumab or placebo, the addition of bevacizumab significantly improved PFS, but there
was no difference in OS.30 This agent should have potent activity in mucinous carcinomas of
the ovary, as studies have shown high levels of VEGF production by these tumors.31,32
Multiple phase II studies of bevacizumab in recurrent epithelial ovarian cancer have revealed
response rates in the range of 16% to 24%.33-35
Recent findings suggest that the VEGF receptors are present on the ovarian cancer cells as well
as being present on the tumor-associated endothelial cells.36 Specifically, VEGFR-2 was the
predominant receptor noted on ovarian cancer cells. Therefore, it is possible that VEGFtargeted therapy may affect both the tumor vasculature as well as the tumor cells. While
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GOG-0241
previous studies have attempted to relate the presence of ligand with response to therapy, data
regarding the presence of total and activated VEGF-receptors on the tumors cells are largely
lacking. Thus, the studies proposed here will provide new information regarding VEGF and
EGF receptors on mucinous ovarian cancers.
Other monoclonal antibodies such as cetuximab (Erbitux) target the epidermal growth factor
receptor (EGFR). Although there has been mixed reporting of EGF ligand and receptor
expression in epithelial ovarian cancers, there is support in the literature for the idea that
mucinous tumors express EGF and EGFR37,38 which could be potential targets for biologic
agents in the treatment of advanced-stage mucinous tumors. Also, activating mutations of the
KRAS oncogene, specifically affecting codon 12, are observed in approximately 50% of
invasive epithelial ovarian carcinomas of mucinous histology, but rarely in ovarian cancers of
other histologic subtypes.39 This is intriguing in light of the fact that KRAS mutation appears to
represent an early event in a similar fraction of colorectal carcinomas.40 Therefore, the
translational component of this study will quantify expression of VEGF ligand, receptor, and
activated receptor as well as EGF ligand, receptor, and activated receptor via
immunohistochemistry in mucinous adenocarcinoma of the ovary to determine the potential
utility of biologic agents directed at these proteins for inclusion in future studies of mucinous
carcinomas of the ovary. We will also assess the mutational status of the KRAS oncogene in
primary mucinous ovarian carcinomas obtained prior to treatment with oxaliplatin and
capecitabine and then determine whether evidence exists for a correlation between the presence
of KRAS mutation and response to therapy in this group of patients with ovarian cancer.
Pathology
Primary mucinous carcinomas of the ovary are uncommon, and historically it was reported that
their biologic behavior and survival rates were better than that of serous carcinoma.41-43 This
interpretation is complicated by several features not initially recognized, including the
following: 1) more than 60% to 80% of mucinous carcinomas of the ovary are of Stage I;43-47 2)
most mucinous carcinomas found in the ovary are metastatic rather than primary;42,47,48 3)
primary mucinous carcinomas represent only 3-12% of mucinous ovarian neoplasms; 4)
primary mucinous carcinomas represent fewer than 11% of ovarian carcinomas; and 5) the
survival of advanced stage primary ovarian mucinous carcinoma appears to be significantly
worse than that of serous carcinoma matched for stage.43-50 (M. Brady, personal
communication) It is unclear whether the poor prognosis relates to an intrinsic aggressiveness
of these tumors, a lack of sensitivity to chemotherapeutic agents effective in the therapy of
serous carcinoma, or a failure to recognize some of the mucinous carcinomas as metastatic
rather than primary to the ovary.
In several recent reviews of mucinous tumors of the ovary, the authors have found that they had
previously misdiagnosed a surprisingly large proportion of their cases as primary and later
identified an occult gastric, colonic, pancreatic or other site of origin.47,48,51,52 These studies led
to efforts to better delineate criteria which would distinguish primary from metastatic mucinous
carcinomas of the ovary. Immunohistochemical stains of potential diagnostic utility include
CK7, CK 20, CDX2, beta-catenin, P504S, MUC2 and MUC5AC.47,48,53,54 In addition, a variety
of gross morphologic and histologic criteria have also been proposed in the last 3 years that
appear to help in distinguishing primary from metastatic mucinous carcinomas of the ovary,
including the following: features favoring a metastatic mucinous tumor - bilaterality, size less
than 10cm, solid growth pattern, multinodularity, surface involvement by neoplastic cells,
infiltrative pattern of stromal invasion, signet ring cells, hilar involvement, single cell invasion;
features favoring a primary mucinous tumor - unilaterality, size greater than 10 cm, expansile
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GOG-0241
pattern of invasion; complex papillary growth pattern.48 An algorithm based on a few features
has been recently proposed that classified correctly 90% of ovarian mucinous carcinomas as
primary or metastatic, as follows: all bilateral tumors, and unilateral tumors less than 10cm in
diameter are metastatic, while those that are unilateral and greater than 10 cm are primary.52 In
contrast to past experience, the vast majority of metastatic mucinous carcinomas of the ovary
can now be reliably discriminated from those which arise in the ovary by routine histologic
assessment.48,55
Previous phase III trials, principally from the GOG, have shown that mucinous histology is a
poor prognostic factor. Taxane/platinum front-line chemotherapy appears to be relatively
ineffective based on response rates and overall survival data. Based on colorectal cancer trials
using regimens such as FOLFOX or XELOX, we hypothesize that the XELOX regimen will
offer a better response, longer progression-free survival, and longer overall survival than
current taxane/platinum strategies in patients with mucinous ovarian cancers. Almost
concomitantly, UK investigators have independently developed an identical therapeutic
strategy for this subset of epithelial ovarian cancer patients. An international collaboration as
proposed is ideal for exploring this approach. While improvement in overall survival is the
primary objective of this study, symptom assessment for neurotoxicity will be an important
component of this trial. If this trial is positive, it would most certainly change the standard
primary chemotherapy approach for women with mucinous cancers of the ovary. If negative,
then other novel regimens should be pursued.
2.1
Inclusion of Women and Minorities
The Gynecologic Oncology Group and GOG participating institutions will not exclude
potential subjects from participating in this or any study solely based on ethnic origin or
socioeconomic status. Every attempt will be made to enter all eligible patients into this
protocol and therefore address the study objectives in a patient population
representative of the entire ovarian carcinoma population treated by participating
institutions.
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3.0
GOG-0241
PATIENT ELIGIBILITY AND EXCLUSIONS
3.1
Eligible Patients
3.11
Patients with a histologic diagnosis of mucinous adenocarcinoma of the ovary
with either optimal (≤ 1 cm residual disease) or suboptimal residual disease
following initial surgery (See Section 7.2).
3.12
All patients must have had appropriate surgery including appendectomy for
ovarian or fallopian tube carcinoma with appropriate tissue available for
histologic evaluation to confirm diagnosis and stage.
3.13
Patients must have stage II-IV disease or recurrent Stage I disease (chemonaïve).
3.14
Patients must be entered within 8 weeks of primary debulking surgery for their
mucinous adenocarcinoma.
3.15
Patients with a negative colonoscopy within 1 year of enrolling in the study.
3.16
Patients must have adequate:
3.141 Bone marrow function: Absolute neutrophil count (ANC)
≥1,500/mcl, equivalent to Common Terminology Criteria for
Adverse Events version 3.0 (CTCAE v3.0) grade 1. Platelets
≥100,000/mcl. (CTCAE v3.0 grade 0-1).
Renal function: Creatinine less than or equal to 1.5 x institutional
upper limit normal (ULN), CTCAE v3.0 grade 1.
3.142 Hepatic function: Bilirubin ≤1.5 x ULN (CTCAE v3.0 grade 1).
SGOT and alkaline phosphatase ≤to 2.5 x ULN (CTCAE v3.0
grade 1).
3.143 Neurologic function: Neuropathy (sensory and motor) less than
or equal to CTCAE v3.0 grade 1.
3.17
Urine dipstick for proteinuria <2+. If urine dipstick is 2+, 24 hour urine must
demonstrate ≤ 1g protein in 24 hours.
3.18
Adequate coagulation parameters (within 14 days of randomization):
3.18.1 International Normalized Ratio (INR) ≤ 1.5xULN
3.18.2 Activated Pro Thrombin Time (APTT) ≤ 1.5xULN
3.19
Patients who have met the pre-entry requirements specified in Section 7.0.
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3.2
GOG-0241
3.20
Patients must have signed an approved informed consent and authorization
permitting release of personal health information.
3.21
Patients with GOG Performance Grade of 0, 1 or 2.
3.22
Patients must be greater than or equal to 18 years of age.
3.23
Patients with life expectancy >3 months
Ineligible Patients
3.21
Patients with known colon cancer or history of colon cancer.
3.22
Patients with primary peritoneal carcinoma.
3.23
Patients with a history of other invasive malignancies, with the exception of
non-melanoma skin cancer, are excluded if there is any evidence of other
malignancy being present within the last 5 years. Patients are also excluded if
their previous cancer treatment contraindicates this protocol therapy.
3.24
Patients who have received either chemotherapy or radiotherapy for ovarian
cancer prior to enrollment.
3.25
Patients with a major surgical procedure anticipated during the course of the
study.
3.26
Patients with minor surgical procedures anticipated during the course of study.
3.261 Minor surgical procedures (i.e., mediport insertion), fine needle
aspiration or core biopsies within 7 days prior to the first date of
bevacizumab therapy.
3.27
Patients with major surgery or significant traumatic injury within 28 days prior
to study entry.
3.28
Patients with a history of abdominal fistula or perforation within the past 12
months.
3.29
Patients with a current, serious, non-healing wound, ulcer, or bone fracture.
3.30
Patients who have had prior therapy with docetaxel or gemcitabine or
bevacizumab.
3.31
Patients with known know hypersensitivity to Chinese hamster cell products or
other recombinant human or humanized antibodies.
3.32
Patients with mixed epithelial ovarian cancer histology.
3.33
Patients with tumors of low malignant potential
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GOG-0241
3.34
Patients with a history or evidence of upon physical examination of CNS
disease, including history of primary brain tumor, or any history of brain
metastases, or seizures not controlled with standard medical therapy.
3.35
Clinically significant cardiac function. Specifically, patient may not have:
3.351
Uncontrolled hypertension, defined as systolic > 150mm Hg or
diastolic > 100mm Hg.Patients with a history of hypertension are
permitted, but patient must have BP less than or equal to 140/90 mm
Hg. Use of blood pressure medications to achieve and maintain
blood pressure control is permitted.
3.352
Myocardial infarction or unstable angina within 6 months of the first
date of bevacizumab therapy.
3.353
New York Heart Association (NYHA) Grade II or greater congestive
heart failure (See Appendix II) or serious cardiac arrhythmia
requiring medication. Women who have received prior treatment
with anthracycline (including doxorubicin and/or liposomal
doxorubicin) and have an ejection fraction < 50% will be excluded
from the study.
3.354
Grade 1, Category 2 or greater, peripheral vascular disease (Please
see Appendix III). Patient cannot have anything worse than mild,
symptomatic claudication with exercise.
3.355
History of cerebrovascular accident (CVA, stroke), transient
ischemic attack (TIA) or subarachnoid hemorrhage within six months
of the first date of bevacizumab therapy.
3.36
History of pulmonary embolism or deep vein thrombosis in the past 6 months.
3.37
Patients with any symptoms or history of peripheral neuropathy.
3.38
Previous history of malabsorption or other conditions preventing oral
treatment.
3.39
Patients who are pregnant or nursing.
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GOG-0241
STUDY MODALITIES
4.1
Oxaliplatin (Eloxatin) (NSC #266046)
4.11
Other Names: l-OHP, SR96669
4.12
Chemical Name: trans-l-diaminocyclohexane oxalatoplatinum, cis[oxalato(trans-l-1,2-diaminocyclohexane) platinum (II)]
4.13
Molecular Formula: C8H14N2O4Pt M.W: 397.33
4.14
Description: Oxaliplatin is an organoplatinum complex in which the platinum
atom is complexed with 1,2-diaminocyclohexane (DACH) with an oxalate
ligand as a leaving group. Platinum content is 48.1% to 50.1%. White crystalline
powder.
4.15
How Supplied: Freeze-dried powder for IV infusion in vials containing
50 mg and 100 mg of oxaliplatin. The excipient is lactose monohydrate,
450 mg and 900 mg respectively. The freeze-dried powder is stable for
three years at room temperature. The pH of an aqueous solution of 2
mg/mL is between 4.8 and 5.7.
4.16
Solution Preparation: The powder is reconstituted by adding 10 mL (for the 50
mg vials) or 20 mL (for the 100 mg vials) of Water for Injection or
Dextrose 5% in Water, which yields a 5 mg/mL solution. Do not administer
the reconstituted solution without further dilution. This solution is then
further diluted in an infusion solution of 250 mL to 500 mL Dextrose 5% in
Water. The reconstitution or final dilution must never be performed with a
sodium chloride solution.
4.17
Route of Administration: intravenous. (See Section 5.2)
4.171 Maximum body surface area used for dose calculations will be 2.0 m2 as
per GOG Chemotherapy Procedures Manual.
4.18
Storage: Store at room temperature, protect from light. Shelf life: 3 years under
these conditions.
4.19
Stability: Use product within 8 hours after withdrawing desired dose, as the
product contains no bacteriostatic agent. Reconstituted solution: in Sterile Water
for Injection or Dextrose 5% in Water in the original vial; the solution may be
stored for 24 to 48 hours at 2 to 8 C. Infusion solution: after dilution in
Dextrose 5% in Water, the shelf life is 24 hours at room temperature.
-8-
GOG-0241
4.110 Incompatibilities:
Do not mix or administer with saline or other chloride-containing
solution. Oxaliplatin is unstable in the presence of chloride.
Do not combine with alkaline solutions such as 5-fluorouracil (pH 9.2)
or other alkaline medications (pH >7) or media. Oxaliplatin is
unstable under alkaline conditions and will degrade.
Do not simultaneously administer other drugs by the same infusion
line.
All IV lines/catheters must be flushed with Dextrose 5% in Water,
both before and after oxaliplatin administration.
Do not use needles or intravenous infusion sets containing aluminum
components for preparation or administration due to the risk of
degradation of oxaliplatin upon contact with aluminum.
4.111 Supplier: Sanofi-synthelabo
4.112 Adverse Effects:
In company studies, the WHO grading scale was used for the toxicities
described below except for neurotoxicity. Sanofi developed a grading scale for
the sensory neuropathies to accommodate the unique neuropathies observed (see
below)
4.1121 Neurotoxicity: The most commonly observed oxaliplatin toxicity is acute
and cumulative neurotoxicity, observed in patients treated at doses above
100 mg/m2/cycle. This neurotoxicity has included paresthesias and
dysesthesias of the hands, feet, and perioral region as well as unusual
pharyngo-laryngodysesthesias characterized by a loss of sensation of
breathing without any objective evidence of respiratory distress
(hypoxia, laryngospasm, or bronchospasm). Oxaliplatin neurotoxicity
appears to be exacerbated by exposure to cold. Patients on this study will
be counseled to avoid cold drinks and exposure to cold water or air.
Should a patient develop pharyngo-laryngodysesthesia, their oxygen
saturation should be evaluated via a pulse oximeter; if normal, an
anxiolytic agent should be given and the patient observed in the clinic
until the episode has resolved. Because this syndrome may be associated
with the rapidity of oxaliplatin infusion, subsequent doses of oxaliplatin
should be administered as a 6-hour infusion (instead of the normal 2hour infusion).
Due to the unique and cumulative nature of the reversible neurotoxicity
reported for oxaliplatin, Sanofi developed a grading scale for the sensory
neuropathies, which has been used in all company-sponsored studies. A
fusion of the NCI Common Toxicity Criteria (CTC) version 2.0 sensory
neuropathy grading scale and the neurologic toxicity grading scale used
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in the company-sponsored studies is provided below (Table 4.1). This
grading scale will be used for the evaluation of oxaliplatin-associated
sensory neuropathies and for the determination of dose modifications.
(For more information on dose modifications due to toxicity, see Section
6.)
Table 4.1: Toxicity Scale for the Sensory Neuropathies Associated
with Oxaliplatin
Grade
Symptoms
Grade 0
None
Grade 1
Paresthesias/dysesthesias* of short duration that resolve and
do not interfere with function
Grade 2
Paresthesias/dysesthesias* interfering with function, but not
activities of daily living (ADL)
Grade 3
Paresthesias/dysesthesias* with pain or with functional
impairment that also interfere with ADL
Grade 4
Persistent paresthesias/dysesthesias* that are disabling or
life-threatening
*May be cold-induced.
Acute and cumulative neurotoxicities are dose limiting for oxaliplatin.
The acute neurotoxicity is characterized by paresthesias and dysesthesias
that may be triggered or exacerbated by exposure to cold. These
symptoms occur within hours of exposure and are usually reversible over
the following hours or days. Cumulative doses of oxaliplatin above 680
mg/m2 may produce functional impairment characterized by difficulty
performing activities requiring fine sensory-motor coordination;
impairment is caused by sensory rather than motor changes.
The likelihood of experiencing neurotoxicity is directly related to the
total cumulative dose of oxaliplatin administered. The relative risk of
developing neurotoxicity was 10%, 50%, and 75% in patients who
received total cumulative oxaliplatin doses of 780 mg/m2, 1,170 mg/m2,
and 1,560 mg/m2, respectively. Both acute and cumulative
neurotoxicities due to oxaliplatin have lessened in 82% of patients within
4 to 6 months, and have completely disappeared by 6 to 8 months in 41%
of patients. In addition, the likelihood that neurologic symptoms will
regress has been shown to correlate inversely with cumulative dose.
Consider using prophylactic calcium gluconate and magnesium sulfate
(administered in the same bag), 1 g each, delivered i.v. over 15 min just
before the oxaliplatin infusion and repeated at the same dose after the
completion of the oxaliplatin infusion. Ca gluconate and Mg sulfate were
-10-
GOG-0241
given. Ca/Mg infusions should not be administered to patients with
known hypercalcemia, or treated with thiazidie diuretics or digitalis.40
Clinical ototoxicity occurs in less than 1% of patients following
oxaliplatin administration, and severe ototoxicity has not been reported.
Rarely, mental status changes and confusion have been associated with
oxaliplatin in combination with 5-FU/LV. In one patient with a grade 5
infection and confusion after treatment with oxaliplatin and 5-FU/LV,
work-up revealed a cerebrovascular accident. A seizure has been
reported with the treatment of oxaliplatin.
4.1122 Hematologic: Single-agent oxaliplatin generally produces only mild
hematologic toxicity; no Grade 4 anemia has been reported, and less than
1% of patients have Grade 4 neutropenia or thrombocytopenia. When
oxaliplatin is combined with 5-FU/LV schedules for which
myelosuppression is dose-limiting, the resulting toxicity is greater than
that observed with the 5-FU/LV regimen alone.
4.1123 Gastrointestinal: Nausea and vomiting are common side effects of
oxaliplatin treatment and require premedication with antiemetic
medications (anti-5HT 3 medications are effective). Diarrhea is also
common, and occurs in 44% of patients treated with single-agent
oxaliplatin and 68% of those treated with oxaliplatin plus 5-FU/LV. The
addition of oxaliplatin to the regimen produces a significant increase in
both the frequency and severity of diarrhea and mucositis usually
expected in patients receiving 5-FU/LV on an infusion schedule. The
addition of oxaliplatin to 5-FU/LV has also been associated with ileus,
enterocolitis, and typhilitis. Rarely, this has been associated with
ischemic bowel requiring bowel resection. Grade 1-2 elevation of liver
enzymes is common during oxaliplatin therapy. Elevation of liver
enzymes is often associated with hepatic metastases.
4.1124 Cutaneous: Erythema or skin eruptions are uncommon with single agent
oxaliplatin, and the incidence of alopecia is < 2%. The incidence of
cutaneous toxicity is much higher in combination with 5-FU (overall 22%; Grade 3 & 4 - 2%). When oxaliplatin in combination with 5-FU is
administered by infusion, the incidence of alopecia is higher (6% overall;
Grade 3 & 4 - 2%).
4.1125 Allergic Reactions: Other platinum compounds are associated with
allergic reactions, but such reactions have been uncommon with
oxaliplatin and have varied from rashes to anaphylaxis. Severe allergic
reactions were reported in 0.5% of patients during clinical development.
One patient has died of an anaphylactic-like reaction. In all other known
cases, the reaction resolved with symptomatic treatment.
4.1126 Pulmonary: Pulmonary fibrosis and adult respiratory distress syndrome
(ARDS) are rarely associated with this agent. During the period from
1996 to April 2000, approximately 9,000 patients were treated in clinical
trials and 45,000 patients were treated with oxaliplatin in post-marketing
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GOG-0241
and compassionate use studies. During this period, pulmonary fibrosis
was suspected in eleven patients. On external review, a relationship with
oxaliplatin was thought to be possible in at least six of the eleven
patients. Among the eleven patients, four patients died, two of which
were due to pulmonary fibrosis. In addition, two cases of eosinophilic
pneumonia and one case of interstitial pneumonitis were reported for
which the causal relationship with oxaliplatin could not be excluded.
4.1127 Other: Other toxicities include fever (with or without infection) in 15%
of patients receiving monotherapy and 5% of those receiving oxaliplatin
in combination therapy. Transient decreased vision has been reported in
< 0.1% of patients. Rarely has significant cardiac toxicity with death
been observed in patients treated with oxaliplatin. Three patients
experienced reversible supraventricular arrhythmias during oxaliplatin
administration; one of these patients tolerated additional cycles of
oxaliplatin with a recurrence of the arrhythmia. (Hypotension and
syncope have been observed with oxaliplatin treatment). Few cases of
hemolytic-uremic syndrome and disseminated intravascular coagulation
(DIC), phlebitis, and extravasations have been observed.
Oxaliplatin monotherapy is associated with an extremely low incidence
of treatment-related deaths (1 of 244 patients; 0.4%). The single patient
who died of an acute anaphylactic reaction following oxaliplatin was
receiving ondansetron concurrently. One patient with pre-existing
pulmonary fibrosis had continued worsening of the condition,
subsequently developed sepsis, and died; the investigator thought the
relationship to oxaliplatin was unknown. The incidence of treatment
related deaths following combination 5-FU/oxaliplatin therapy was 1.1%
(13 of 1183 patients), similar to the incidence seen with 5-FU alone
(Sanofi Clinical Investigator's Brochure, May 1998).
4.2
Capecitabine (Xeloda) (NSC #712807)
4.21
Formulation: Capecitabine is supplied as biconvex, oblong, film-coated tablets.
150 mg tablets are light peach in color engraved with Xeloda on one side and
150 on the other and come packaged in bottles of 120. 500 mg tablets are peach
in color engraved with Xeloda on one side and 500 on the other and come
packaged in bottles of 240.
4.22
Storage: Store at room temperature 25C (77F), excursions permitted to 1530C (59-89F). Keep tightly closed.
4.23
Administration: The patient will take a daily dose of 2000 mg/m2 in two divided
doses for 14 consecutive days followed by seven-day rest period. The tablets are
to be swallowed with water and taken within 30 minutes after the end of a meal.
(See Sec. 5.22)
4.24
Adverse effects:
Hematologic: neutropenia, thrombocytopenia, anemia, lymphopenia
Gastrointestinal: diarrhea, nausea, vomiting, stomatitis, abdominal pain,
constipation, dyspepsia, hyperbilirubinemia, anorexia, dehydration
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Skin: hand and foot syndrome, dermatitis, edema
Neurological: paresthesias, headache, dizziness, insomnia
Constitutional: fatigue, fever, myalgias
Ophthalmic: eye irritation
Alteration of coagulation parameters in patients taking anticoagulants was also
seen.
4.25
4.3
Supplier: Commercially available. Roche laboratories
In the event that a patient cannot obtain study drug (indigent patient, no
insurance, refusal of third party payer), contact Roche Patient Assistance
Program: 1-800-443-6676, selection #2.
Carboplatin (Paraplatin, NSC #241240)
4.31
Formulation: Carboplatin is supplied as a sterile lyophilized powder available in
single-dose vial containing 50 mg, 150 mg and 450 mg of carboplatin for
administration by intravenous infusion. Each vial contains equal parts by weight
of carboplatin and mannitol.
4.32
Preparation: Immediately before use, the content of each vial must be
reconstituted with either sterile water for injection, USP, 5% dextrose in water,
or 0.9% sodium chloride injection, USP, according to the following schedule:
Vial strength Diluent volume
50 mg
150 mg
450 mg
5 ml
15 ml
45 ml
These dilutions all produce a carboplatin concentration of 10 mg/ml. When
prepared as directed, carboplatin solutions are stable for eight hours at room
temperature, since no antibacterial preservative is contained in the formulation it
is recommended that carboplatin solutions be discarded eight hours after
dilution.
NOTE: Aluminum reacts with carboplatin causing precipitate formation and
loss of potency, therefore, needles or intravenous sets containing aluminum parts
that may come in contact with the drug must not be used for the preparation or
administration of carboplatin.
4.33
Storage: Unopened vials of carboplatin are stable for the life indicated on the
package when stored at controlled room temperature and protected from light.
4.34
Adverse effects: Some of the adverse events expected with carboplatin treatment
are listed below.
 Hematologic: Myelosuppression is the major dose-limiting toxicity.
Thrombocytopenia, neutropenia, leukopenia, and anemia are common, but
typically resolve by Day 28 when carboplatin is given as a single agent.
-13-
GOG-0241

Allergic reactions: Hypersensitivity to carboplatin has been reported in 2%
of patients receiving the drug as first line therapy and in approximately 28%
of patients being retreated with Carboplatin after receiving platinum as first
line therapy. Symptoms include rash, urticaria, erythema, pruritus, and rarely
bronchospasm and hypotension. The reactions can be successfully managed
with standard epinephrine, corticosteroid, and antihistamine therapy.

Neurologic: Peripheral neuropathies have been observed in 4% of patients
receiving carboplatin with mild paresthesia being the most common.

Gastrointestinal: Nausea and vomiting are the most common GI events; both
usually resolve within 24 hours and respond to antiemetics. Other GI events
include diarrhea, weight loss, constipation, and gastrointestinal pain.

Hepatic toxicity: Elevated alkaline phosphatase, total bilirubin, and SGOT
have been observed.

Metabolic: Hypomagnesemia, hypokalemia, hypocalcemia.

Secondary malignancy: Potential risk of other malignancies when used in
multi-agent therapy.

Renal toxicity: Increased serum creatinine and blood urea nitrogen are
uncommon, mild, and usually reversible.

Other: Pain and asthenia are the most common miscellaneous adverse
events. Alopecia has been reported in 3% of the patients taking carboplatin.
4.35
Supplier: Commercially available. Bristol-Myers Squibb Co.*
4.36
Administration: Carboplatin dosed to an AUC 5 mg/ml/min will be given IV
every 3 weeks. Pretreatment with a 5-HT3 inhibitor and dexamethasone 20 mg
IV or PO 30 minutes prior to infusion is suggested. The carboplatin infusion
should begin after the Cetuximab infusion and may begin during the observation
period.
*Refer to package insert for additional information.
4.4
Paclitaxel (NSC #673089)
4.41
Formulation: Paclitaxel is supplied as a 6mg/mL non-aqueous solution in
multidose vials containing 30mg/5mL, 100mg/16.7mL, or 300mg/50mL of
paclitaxel. In addition to 6mg of paclitaxel, each mL of sterile non-pyrogenic
solution contains 527mg of purified Cremophor® EL (polyoxyethylated castor
oil) and 49.7% (v/v) dehydrated alcohol, USP.
4.42
Storage: Unopened vials of paclitaxel are stable to the date indicated on the
package when stored between 20 to 25°C (68 to 77°F). Protect from light.
4.43
Preparation: Paclitaxel must be diluted prior to infusion. Paclitaxel should be
diluted in 0.9% Sodium Chloride for Injection, USP; 5% Dextrose Injection,
USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose
in Ringer’s Injection to a final concentration of 0.3 to 1.2mg/mL. The solutions
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GOG-0241
are physically and chemically stable for up to 27 hours at ambient temperature
(approximately 25°C / 77°F) and room lighting conditions.
NOTE: In order to minimize patient exposure to the plasticizer DEHP, which
may be leached from PVC infusion bags or sets, diluted paclitaxel solutions
should be stored in bottles (glass, polypropylene) or plastic (polypropylene,
polyolefin) bags and administered through polyethylene-lined administration
sets.
Paclitaxel should be administered through an inline filter with a microporous
membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2®
or IVEX-HP®, which incorporate short inlet and outlet PVC-coated tubing, has
not resulted in significant leaching of DEHP.
All patients should be premedicated with corticosteroids, diphenhydramine, and
H2 antagonists prior to paclitaxel administration in order to prevent severe
hypersensitivity reactions. Patients who experience severe hypersensitivity
reactions to paclitaxel should not be rechallenged with the drug.
Adverse Effects: Consult the package insert for the most current and complete
information. Incidence rates of adverse events associated with paclitaxel are
provided in the product package insert. The following events are expected with
the administration of paclitaxel:
Hematologic: Myelosuppression is the major dose-limiting toxicity.
Neutropenia is both dose-and schedule-dependent and typically resolves rapidly.
Fever is common and infectious episodes are seen in about 1/3 of the patients
receiving paclitaxel. Thrombocytopenia is uncommon and the cases that occur
are usually mild to moderate. Bleeding episodes may occur. While anemia is
common, it is severe only in 16% of the cases.
Allergic reactions: Although patients are premedicated, hypersensitivity
reactions still occur in approximately 40% of patients receiving paclitaxel (20%
of cycles). Severe reactions are rare and generally occur within the first hour of
administration; no severe reactions have been reported after the third cycle. The
most common symptoms observed in severe reactions include dyspnea, flushing,
chest pain, and tachycardia. Minor hypersensitivity reactions include flushing,
rash, hypotension, dyspnea, tachycardia, and hypertension.
Cardiovascular: Cardiovascular events observed with paclitaxel therapy
include hypotension and bradycardia; typically, neither discontinuation of
paclitaxel nor specific therapy for the event is required. Cardiovascular events
that are possibly related to paclitaxel therapy occur in approximately 1% of
patients and include syncope, rhythm abnormalities (asymptomatic ventricular
tachycardia, bigeminy, and complete AV block requiring a pacemaker),
hypertension, and venous thrombosis.
Neurologic: The frequency and severity of neurologic events are dosedependent. Peripheral neuropathy is rarely severe and may be the cause of
paclitaxel discontinuation in 1% of patients. Sensory symptoms usually
improve or resolve within several months of paclitaxel discontinuation. Serious
neurologic events, such as grand mal seizures, syncope, ataxia, and
neuroencephalopathy, are rare.
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GOG-0241
Gastrointestinal: The most common GI toxicities, which include nausea,
vomiting, diarrhea, and mucositis, are typically mild or moderate and rarely
severity. Mucositis is schedule-dependent and occurs more frequently with a
24-hour infusion than a 3-hour infusion of paclitaxel.
Other: Although 60% of all patients experience arthralgia and myalgia, there is
no consistent relationship between the dose or schedule of paclitaxel and the
frequency of these events. The symptoms, which usually begin 2 or 3 days after
paclitaxel treatment, are generally transient. Injection site reactions are more
common with the 24-hour infusion of paclitaxel and are typically mild,
consisting of erythema, tenderness, skin discoloration, or swelling at the
injection site. Almost all of the patients receiving paclitaxel experience
alopecia, but nail changes are uncommon. Edema may occur, but it is rarely
severe enough to lead to discontinuation of treatment.
Paclitaxel Premedication
4.44 Patients should receive decadron 20 mg p.o. 14 and 7 hours prior to
paclitaxel administration. Intravenous premedication as listed, or institutional
guidelines may be followed.
4.44
4.5
Supplier: Commercially available from both Bristol-Myers Squibb Oncology as
well as generic manufacturers. Consult the American Hospital Formulary
Service Drug Information guide, Facts and Comparisons, or the package insert
for additional information.
Bevacizumab (NSC #704865, IND #7921)
4.51
Other Name: rhuMAb VEGF
4.52
Molecular Weight: Approximate molecular weight is 149,000 daltons
4.53
Description: Bevacizumab is a recombinant humanized anti-VEGF monoclonal
antibody, consisting of 93% human and 7% murine amino acid sequences. The
agent is composed of human IgG framework and murine antigen-binding
complementarity-determining regions. Bevacizumab blocks the binding of
vascular endothelial growth factor (VEGF) to its receptors resulting in inhibition
of angiogenesis.
4.54
How supplied: Bevacizumab is a clear to slightly opalescent, colorless to pale
brown, sterile liquid concentrate for solution for IV infusion. Bevacizumab will
be supplied in 5-mL (100 mg) or 20-mL (400 mg) glass vials containing 4-mL
or 16-mL of bevacizumab, respectively (25 mg/mL for either vial). Vials
contain bevacizumab with phosphate, trehalose, polysorbate 20, and Sterile
Water for Injection (SWFI), USP. Vials contain no preservative and are suitable
for single use only.
4.55
Storage and Stability: Upon receipt of bevacizumab, vials are to be refrigerated
at 2C-8C (36F-46F) and should remain refrigerated until just prior to use. DO
NOT FREEZE. DO NOT SHAKE. PROTECT FROM LIGHT. Open vials
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GOG-0241
must be used within 8 hours. VIALS ARE FOR SINGLE USE ONLY. Vials
used for one subject may not be used for any other subject.
4.56
Preparation: Vials contain no preservative and are intended for single use only.
Place the calculated dose in 100mL of 0.9% sodium chloride for injection. Once
diluted in 0.9% Sodium Chloride for Injection, the bevacizumab solution must
be administered within 8 hours.
4.57
Administration: Bevacizumab is administered intravenously as a continuous
infusion. The dose should be based on the patient’s actual body weight; the
dose will be recalculated if there is a weight change of > 10% from baseline.
The initial dose should be administered over a minimum of 90 minutes. If no
adverse reactions occur after the initial dose, the second dose should be
administered over a minimum of 60 minutes. If no adverse reactions occur after
the second dose, all subsequent doses should be administered over a minimum
of 30 minutes. If infusion-related adverse reactions occur at any time, patient
should be pre-medicated (see section 5.2) prior to next dose and infusion time
may not be reduced for the subsequent infusion.
To insure complete delivery of bevacizumab, the IV infusion line must be
flushed with 0.9% sodium chloride. The following are two recommended
methods for flushing the bevacizumab IV infusion line:
1.
2.
When the bevacizumab infusion is complete, add an additional 50mL of
0.9% sodium chloride for injection to the bevacizumab infusion bag.
Continue the infusion until a volume equal to that of the volume
contained in the tubing has been administered.
Replace the empty bevacizumab infusion bag with a 50mL bag of 0.9%
sodium chloride for injection and infuse a volume equal to the volume
contained in the tubing.
Please note: The flush is not included in the total recommended infusion times.
4.58
Clinical Supplies: Bevacizumab (NSC 704865) will be provided free of charge
by Genentech and distributed by the Pharmaceutical Management Branch
(PMB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer
Treatment and Diagnosis (DCTD), National Cancer Institute (NCI).
4.59
Drug Ordering and Accountability
NCI supplied agents may be requested by the Principal Investigator or their
authorized designee at each participating institution. Pharmaceutical
Management Branch (PMB) policy requires that drug be shipped directly to the
institution where the patient is being treated. PMB does not permit the transfer
of agents between institutions (unless prior approval from PMB is obtained).
The CTEP assigned protocol number must be used for ordering all CTEPsupplied investigational agents. The responsible investigator at each
participating institution must be registered with CTEP, DCTD, through an
annual submission of FDA Form 1572, Supplemental Investigator Data Form
(IDF), and Financial Disclosure Form. If there are several participating
investigators at one institution, CTEP supplied investigational agents for the
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GOG-0241
study should be ordered under the name of one lead investigator at that
institution.
Agent may be requested by completing a Clinical Drug Request (CDR [NIH986]) available on the CTEP web site at http://ctep.cancer.gov/requisition/ and
faxing it to the Pharmaceutical Management Branch, DCTD, NCI, EPN, Room
7149, Bethesda, MD 20892 or faxing it to (301) 480-4612. Beginning 11/10/03,
all CDR’s for PMB-distributed agents sent to the PMB must be signed by the
investigator in whose name the agent is ordered OR by the shipping designee
OR by an ordering designee whom the investigator has listed on their most
recent IDF on file with the PMB.
If the investigator has not designated the individual signing the CDR as a
shipping or ordering designee, or if the shipping or ordering designees at a
clinical site change, the first two pages of the IDF should be updated to reflect
the current designees, the IDF should be signed and dated by the investigator
and returned to the PMB by fax at (301) 402-4870. For questions (or the first
two pages of the investigator’s current IDF) call the PMB at (301) 496-5725
Monday through Friday from 8:30 am to 4:30 pm Eastern Time.
The Investigator, or a responsible party designated by the investigator, must
maintain a careful record of the inventory and disposition of all agents received
from the PMB using the NCI Drug Accountability Record Form (DARF). See
the CTEP web site for Policy and Guidelines for Accountability and Storage of
Investigational Drugs at http://ctep.cancer.gov/requisition/
Requests for Investigator’s Brochures (IB) should be e-mailed to
ibcoordinator@mail.nih.gov or you may call the IB coordinator at 301-4965725.
4.591 Drug Returns: Only unreconstituted drug supplies should be returned to
the PMB. When it is necessary to return study drug, investigators should return
the study drug to the PMB using the NCI Return Drug List available on the
CTEP home page (http://ctep.cancer.gov) or by calling the PMB at 301-4965725.
4.592 Comprehensive Adverse Events and Potential Risks List (CAEPR) for
Bevacizumab (NSC #704865)
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a
single, list of reported and/or potential adverse events (AE) associated with an
agent using a uniform presentation of events by body system. In addition to the
comprehensive list, a subset, the Agent Specific Adverse Event List (ASAEL),
appears in a separate column and is identified with bold and italicized text. This
subset of AEs (ASAEL) contains events that are considered 'expected' for
expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse
Event Reporting Requirements' http://ctep.cancer.gov/reporting/adeers.html for
further clarification. The CAEPR does not provide frequency data; refer to the
Investigator's Brochure for this information. Below is the CAEPR for
Bevacizumab.
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GOG-0241
Version 1.2, June 19, 20071
Category
Adverse Events with Possible
(Body
Relationship to Bevacizumab
System)
(CTCAE v3.0 Term)
ALLERGY/IMMUNOLOGY
Allergic reaction/hypersensitivity (including drug fever)
Allergic rhinitis (including sneezing, nasal stuffiness,
postnasal drip)
'Agent Specific Adverse Event List'
(ASAEL)
Allergic reaction/hypersensitivity (including drug fever)
Allergic rhinitis (including sneezing, nasal stuffiness,
postnasal drip)
BLOOD/BONE MARROW
Hemoglobin
Leukocytes (total WBC)
Neutrophils/granulocytes (ANC/AGC)
Hemoglobin
Leukocytes (total WBC)
Neutrophils/granulocytes (ANC/AGC)
CARDIAC ARRHYTHMIA
Supraventricular arrhythmia NOS
Ventricular fibrillation
Supraventricular arrhythmia NOS
CARDIAC GENERAL
Cardiac ischemia/infarction
Cardiac troponin I (cTnI)
Hypertension
Hypotension
Left ventricular diastolic dysfunction
Left ventricular systolic dysfunction
Cardiac ischemia/infarction
Hypertension
CONSTITUTIONAL SYMPTOMS
Fatigue (asthenia, lethargy, malaise)
Fever (in the absence of neutropenia, where neutropenia is
defined as ANC <1.0 x 109/L)
Rigors/chills
Weight loss
Fatigue (asthenia, lethargy, malaise)
Fever (in the absence of neutropenia, where neutropenia is
defined as ANC <1.0 x 109/L)
Rigors/chills
DERMATOLOGY/SKIN
Pruritus/itching
Rash/desquamation
Ulceration
Urticaria (hives, welts, wheals)
Wound complication, non-infectious
Pruritus/itching
Rash/desquamation
Urticaria (hives, welts, wheals)
GASTROINTESTINAL
Anorexia
Colitis
Constipation
Diarrhea
Fistula, GI - Select
Heartburn/dyspepsia
Ileus (functional obstruction of bowel, i.e.,
neuroconstipation)
Leak (including anastomotic), GI: large bowel
Mucositis/stomatitis (functional/symptomatic) - Select
Nausea
Perforation, GI - Select
Ulcer, GI - Select
Vomiting
Anorexia
Constipation
Diarrhea
Heartburn/dyspepsia
Mucositis/stomatitis (functional/symptomatic) - Select
Nausea
Vomiting
HEMORRHAGE/BLEEDING
Hemorrhage, GI - Select
Hemorrhage, CNS
Hemorrhage, GU: vagina
Hemorrhage, pulmonary/upper respiratory: lung
Hemorrhage, pulmonary/upper respiratory: nose
Hemorrhage GI - Select
Hemorrhage, CNS
Hemorrhage, GU: vagina
Hemorrhage, pulmonary/upper respiratory: lung
Hemorrhage, pulmonary/upper respiratory: nose
-19-
Category
(Body
System)
INFECTION
Adverse Events with Possible
Relationship to Bevacizumab
(CTCAE v3.0 Term)
GOG-0241
'Agent Specific Adverse Event List'
(ASAEL)
Infection with normal ANC or Grade 1 or 2 neutrophils Select
Infection with normal ANC or Grade 1 or 2 neutrophils Select (pelvis, peritoneal cavity, rectum, scrotum, skin,
wound)
METABOLIC/LABORATORY
Alkaline phosphatase
ALT, SGPT (serum glutamic pyruvic transaminase)
AST, SGOT (serum glutamic oxaloacetic transaminase)
Bilirubin (hyperbilirubinemia)
Creatinine
Proteinuria
Alkaline phosphatase
ALT, SGPT (serum glutamic pyruvic transaminase)
AST, SGOT (serum glutamic oxaloacetic transaminase)
Bilirubin (hyperbilirubinemia)
Proteinuria
NEUROLOGY
CNS cerebrovascular ischemia
Dizziness
Neurology - Other: (Leukoencephalopathy syndrome
including reversible posterior leukoencephalopathy
syndrome [RPLS])
CNS cerebrovascular ischemia
Dizziness
Pain - abdomen NOS
Pain - chest/thorax NOS
Pain - head/headache
Pain - joint
Pain - muscle
Pain - NOS
Pain - abdomen NOS
Pain - chest/thorax NOS
Pain - head/headache
Pain - joint
PAIN
PULMONARY/UPPER RESPIRATORY
Bronchospasm, wheezing
Cough
Dyspnea (shortness of breath)
Fistula, pulmonary/upper respiratory - Select
Nasal cavity/paranasal sinus reactions
Voice changes/dysarthria (e.g., hoarseness, loss or
alteration in voice, laryngitis)
Pulmonary/Upper Respiratory - Other (nasal-septal
perforation)
Cough
Dyspnea (shortness of breath)
Nasal cavity/paranasal sinus reactions
Voice changes/dysarthria (e.g., hoarseness, loss or
alteration in voice, laryngitis)
RENAL/GENITOURINARY
Fistula, GU - Select
Renal failure
SYNDROMES
Cytokine release syndrome/acute infusion reaction
Cytokine release syndrome/acute infusion reaction
VASCULAR
Thrombosis/thrombus/embolism
Visceral arterial ischemia (non-myocardial)
1This
Thrombosis/thrombus/embolism
table will be updated as the toxicity profile of the agent is revised. Updates will be distributed to
all Principal Investigators at the time of revision. The current version can be obtained by contacting
ADEERSMD@tech-res.com. Your name, the name of the investigator, the protocol and the agent
should be included in the e-mail.
-20-
GOG-0241
Also reported on bevacizumab trials but with the relationship to bevacizumab still
undetermined:
BLOOD/BONE MARROW - Idiopathic thrombocytopenia purpura; platelets
CARDIAC GENERAL - Cardiac arrest; pericardial effusion; pulmonary hypertension
COAGULATION - DIC
DEATH - Sudden death (cause unknown)
DERMATOLOGY/SKIN - Hypopigmentation
GASTROINTESTINAL - Rectal abscess/necrosis; small bowel obstruction; taste alteration
METABOLIC/LABORATORY - Hyperglycemia; hypoglycemia; hypomagnesemia; hyponatremia
MUSCULOSKELETAL/SOFT TISSUE - Aseptic necrotic bone; gait/walking; myasthenia gravis
NEUROLOGY - Aseptic meningitis; confusion; peripheral neuropathy; seizure; syncope
OCULAR/VISUAL - Cataract; watery eye
PULMONARY/UPPER RESPIRATORY - ARDS; pneumonitis/pulmonary infiltrates;
pneumothorax
RENAL/GENITOURINARY - Urinary frequency
Note: Bevacizumab in combination with other agents could cause an exacerbation of any adverse event
currently known to be caused by the other agent, or the combination may result in events never
previously associated with either agent.
-21-
5.0
GOG-0241
TREATMENT PLAN AND ENTRY/RANDOMIZATION PROCEDURE
All initial and continuing reviews must be submitted to the CTSU Regulatory Office. A CTSU
IRB/Regulatory Approval Transmittal Sheet should be submitted along with the CTSU IRB
Certification Form or its equivalent. (CTSU forms can be downloaded at
https://www.ctsu.org/rss2_page.asp). IRB submissions can be faxed or mailed to:
CTSU Regulatory Office
Coalition of National Cancer Cooperative Groups
1818 Market Street, Suite 1100
Philadelphia, PA 19103
1-888-823-5923
FAX 215-569-0206
5.1
Patient Entry and Registration
When a suitable candidate has been obtained for protocol entry, the following steps
should be taken:
5.11
An approved informed consent form and authorization permitting release of
personal health information must be signed by the patient or guardian. Current
FDA, NCI, and institutional regulations concerning informed consent will be
followed.
5.12
All eligibility requirements indicated in section 3.0 have been satisfied.
5.13
Fast Fact Sheet data should be gathered.
5.14
The institution must register the patient using the web-based registration
application or by phone if necessary (800-523-2917). Instructions for web-based
registration and randomization can be found by going to the GOG Web Menu
page, selecting “Start/finish a patient registration,” and then selecting
“Directions” found on the left side of the page.
5.15
Entry/Randomization will take place on the telephone after consideration of Fast
Fact Sheet data.
5.16
The institution will enter the patient’s name, GOG number, and assigned
regimen in the appropriate place in their Log Book to verify the patient’s entry.
5.17
Treatment should start within 14 days of randomization and no later than 6
weeks after surgery (if applicable). For patients randomized to receive
bevacizumab, treatment with bevacizumab should not start until at least 28 days
after surgery due to concerns about its impact on wound healing. It is recognized
that there may be clinical reasons to start chemotherapy within 28 days of
surgery; therefore, for patients randomized to receive bevacizumab, there is the
option to give the first cycle of chemotherapy without bevacizumab. In this
situation, the missed dose of bevacizumab will not be replaced and patients will
receive 5 doses of bevacizumab with chemotherapy and 12 cycles as
-22-
GOG-0241
maintenance. Investigators will be asked to state at randomization whether or
not they intend to start chemotherapy before 4 weeks have elapsed after surgery.
5.2
Treatment Plan
5.21
Arm I – 6 cycles of:
Paclitaxel
Carboplatin
175 mg/m2 IV over 3 h on day 1, q 21 days, followed by
AUC = 6 on day 1, q 21 days
5.211 Paclitaxel will be administered as a 3-hour infusion on this study. For all
courses in which paclitaxel is to be administered, it is recommended that
a preparative regimen be employed to reduce the risk associated with
hypersensitivity reactions. This regimen should include dexamethasone
(either IV or PO), anti-histamine H1 (such as diphenhydramine) and
anti-histamine H2 (such as cimetidine, ranitidine, or famotidine).
5.212 The dose of carboplatin will be calculated to reach a target area under the
curve (AUC) of concentration x time according to the Calvert formula
using an estimated glomerular filtration rate (GFR) from the Jelliffe
formula. The initial dose of carboplatin must be calculated using GFR. In
the absence of new renal obstruction or other renal toxicity greater than
or equal to CTC grade 2 (serum creatinine >1.5 x ULN), the dose of
carboplatin will not be recalculated for subsequent cycles, but will be
subject to dose modification as noted. In patients with abnormally low
serum creatinine (less than or equal to 0.6 mg/dl), due to reduced protein
intake and/or low muscle mass, the creatinine clearance should be
estimated using a minimum value of 0.6 mg/dl. If a more appropriate
baseline creatinine value is available within 4 weeks of treatment that
may also be used for the initial estimation of GFR.
Calvert Formula: Carboplatin dose (mg) = target AUC x (GFR + 25)
For the purpose of this protocol, the GFR is considered to be equivalent
to the creatinine clearance. The creatinine clearance (Ccr) is estimated by
the method of Jelliffe using the following formula for females:
GFR = 0.9 x (98 - 0.8 (age* - 20))
Cr (mg/dl)
*Age rounded to the nearest decade
Where
Ccr
Age
Scr
=
=
=
estimated creatinine clearance in ml/min
patient’s age in years (from 20-80)
serum creatinine in mg/dl
In the absence of new renal obstruction or elevation of serum creatinine
above 1.5 x ULN (CTC grade 2), the dose of carboplatin will not be
recalculated for subsequent cycles, but will be subject to dose
modification for hematologic criteria and other events as noted.
-23-
GOG-0241
The conversion equation below should be used for converting the IDMS
serum creatinine (SrCr) value to the non-IDMS serum creatinine (SrCr)
value prior to using the Calvert Formula to calculate the carboplatin
dose.
Non-IDMS SrCr (mg/dL) = IDMS SrCr (mg/dL) x 1.065 +0.067
Conversion of Common SrCr Values:
5.22
Clinic Station
Reported IDMS
SrCr Value
(mg/dL)
Needs to be converted
to Non-IDMS SrCr to
use for Carboplatin
dosing (mg/dL)
Less than 0.6
0.7
0.8
0.9
1
1.1
1.2
1.3
1.5
Use assigned 0.8
0.8
0.9
1.0
1.1
1.2
1.3
1.5
1.7
Arm II– 6 cycles of:
Oxaliplatin 130 mg/m2 IV infusion over 2 h, Day 1, q 21 days
Capecitabine 850 mg/m2 orally twice daily, Days 1-14, followed by 7-day rest
period
5.221 This is an outpatient regimen. All patients should be given antiemetics
(e.g. ondansetron or granisetron and dexamethasone) prior to and after
the oxaliplatin infusion. On day 1 of each 21-day treatment cycle,
patients receive 130 mg/m² oxaliplatin diluted in 250 to 500 mL
Dextrose 5% in Water infused intravenously over 2 hours through a
peripheral or central vein. Following the infusion of oxaliplatin, the
infusion line should be flushed immediately with Dextrose 5% in Water.
Cycles will be repeated every 21 days.
Precautions and Warnings Regarding Oxaliplatin Administration:
-24-
GOG-0241
Oxaliplatin is unstable in the presence of chloride or alkaline
solutions. Do NOT mix or administer oxaliplatin with saline or other
chloride-containing solutions. Do NOT administer other drugs or
solutions in the same infusion line. Flush IV lines/catheters with
Dextrose 5% in Water both before and after oxaliplatin
administration.
All patients must be premedicated for nausea and vomiting using the
standard antiemetic regimen for platinum-based therapies at the
institution. [Anti-5HT 3 medications are effective].
Patients on this study should be counseled to avoid cold drinks and
exposure to cold water or air because the neurotoxicity often seen
with oxaliplatin appears to be exacerbated by exposure to cold. The
period of time during which the patient is at risk for these coldinduced sensory neuropathies is not well documented. Patients
should exercise caution regarding cold exposure during the
treatment period. Peripheral sensory neuropathies can occur at any
time after receiving oxaliplatin therapy.
5.222 The patient will also take a daily dose of capecitabine 1700 mg/m2 (the
total daily dose will be divided in two doses given approximately every
12 hours) starting on day 1 of each 21 day cycle for 14 consecutive days
followed by 7-day rest period. The tablets are to be swallowed with
water and taken within 30 minutes after the end of a meal. If a patient
vomits or misses a dose, they must not take the missed dose at all and
must not double the next dose. Instead, patients should continue with the
dosing as scheduled.
-25-
GOG-0241
5.223 Antiemetic Regimens
It is anticipated that nausea and vomiting may be a significant side effect
of each regimen. The following representative antiemetic regimens are
suggested:


Ondansetron 8-32 mg IV 30 minutes prior to administration of
chemotherapy and dexamethasone 10-20 mg IV 30 minutes prior to drug
administration, or,
Granisetron 10 mcg/kg IV (or 2 mg PO) 30 minutes prior to
chemotherapy, with or without lorazepam 0.5-2.0 mg IV 30 minutes
prior to chemotherapy.
5.224 The minimum treatment period will be one course.
5.225 If side effects are not severe, a patient may remain on the study agents
until 6 cycles are completed or documented disease progression.
5.226 Maximum body surface area used for dose calculations will be 2.0 m2 as
per GOG Chemotherapy Procedures Manual. (See Table 5.1 for
calculation of capecitabine dose)
Table 5.1: Calculation of Dose and Dose Administration for Capecitabine
Number of tablets to be taken in the
100% Dose Level
Morning
= twice daily 850 mg/m2
Evening
Surface Area (m2)
Total Daily Dose (mg)*
150 mg
500 mg
150 mg
500 mg
< 1.6
2300
1
2
1
2
< 1.6-1.8
3000
0
3
0
3
> 1.8
3300
1
3
1
3
Number of tablets to be taken in the
75% Dose Level
Morning
= twice daily 637.5 mg/m2
Evening
Surface Area (m2)
Total Daily Dose (mg)*
150 mg
500 mg
150 mg
500 mg
< 1.6
1750
2
1
3
1
< 1.6-1.8
2300
1
2
1
2
> 1.8
2600
2
2
2
2
-26-
GOG-0241
Number of tablets to be taken in the
50% Dose Level
Morning
= twice daily 425 mg/m2
Evening
Surface Area (m2)
Total Daily Dose (mg)*
150 mg
500 mg
150 mg
500 mg
< 1.6
1150
0
1
1
1
< 1.6-1.8
1500
0
1
0
2
> 1.8
1600
2
1
2
1
5.23
Arm III--Bevacizumab When Given With Carboplatin + Paclitaxel
Six cycles of chemotherapy (See Section 5.21) plus bevacizumab (15 mg/kg)
given on day 1 every 3 weeks. The total dose of bevacizumab should only be
readjusted according to the current body weight if the body weight changes by
more than 10%, as compared to baseline (excluding changes due to development
or drainage of ascites, pleural effusions, or fluid retention). Bevacizumab may
be omitted from cycle one as specified in Section 5.17.
Drugs must be administered in the following order:

Bevacizumab 15 mg/kg IV
o First cycle infused over 90 minutes
o If no problems, then second cycle infused over 60 minutes
o If no problems, then third and subsequent cycles infused over 30
minutes
 Hypersensitivity prophylaxis
 Antiemetics
 Paclitaxel infusion 175 mg/m2 over 3 hours (maximum BSA 2.0m2)
 Carboplatin AUC 6 over 30-60 minutes
 Post-chemotherapy antiemetics
Then: 12 cycles of bevacizumab 15 mg/kg IV over 30 minutes (or fastest rate
given previously) given on day 1 every 3 weeks
5.24
Arm IV--Bevacizumab When Given With Oxaliplatin + Capecitabine:
Six cycles of chemotherapy (See Section 5.22) plus bevacizumab (15 mg/kg)
given on day 1 every three weeks. The total given dose of bevacizumab should
only be readjusted according to the current body weight if the body weight
changes by more than 10%, as compared to baseline (excluding changes due to
development or drainage of ascites, pleural effusions, or fluid retention).
Bevacizumab may be omitted from cycle one as specified in Section 5.17.
Drugs should be administered in the following order:

Bevacizumab 15 mg/kg IV
o First cycle infused over 90 minutes
-27-
GOG-0241
o If no problems, then second cycle infused over 60 minutes
o If no problems, then third and subsequent cycles infused over 30
minutes
 Anitemetics
 Oxaliplatin 130 mg/m2 over 2-6 hours (maximum BSA = 2.0m2)
 Capecitabine 850 mg/m2 orally twice daily
 Post-chemotherapy antiemetics
Then: 12 cycles of bevacizumab 15 mg/kg IV over 30 minutes (or fastest rate
given previously) given on day 1 every 3 weeks
5.3
Supportive Care Guidelines for Bevacizumab:
Prior to each treatment, the patient should be carefully assessed with special
attention to blood pressure, proteinuria, bleeding and cardiovascular events.
Decisions for retreatment/interruption should follow the dose modification
guidelines in Section 6.0.
The initial dose will be delivered over a minimum of 90 minutes. If the first
infusion is tolerated without infusion-associated adverse events, the second
infusion may be delivered over a minimum of 60 minutes. If the 60-minute
infusion is well tolerated, all subsequent infusions may be delivered over a
minimum of 30 minutes. If an infusion reaction occurs, subsequent doses of
bevacizumab should be administered over the shortest period that was well
tolerated.
5.331 If a subject experiences a bevacizumab infusion-associated adverse
event, such as Grade 1 anaphylactoid reaction, she may be premedicated
for the next bevacizumab infusion (see details below in bullet points).
Patients who experience a Grade 2 or greater bevacizumab infusionassociated adverse event will not receive any additional bevacizumab.
Anaphylaxis precautions should be observed during bevacizumab
administration (See Appendix IV).
In the event of a prior bevacizumab hypersensitivity reaction, the
following prophylactic regimen is recommended upon re-exposure to
bevacizumab:

H1 blocker (diphenhydramine 25-50 mg IV or orally one hour
prior to infusion; or an equivalent dose of an alternate H1
blocker)

H2 blocker (ranitidine 50 mg IV or 150 mg orally one hour prior
to infusion; or an equivalent dose of an alternate H2 blocker)

Dexamethasone (Suggested dosing for dexamethasone, if needed
prior to bevacizumab administration, is 10 mg administered
orally or 20 mg IV prior to bevacizumab infusion)

Acetaminophen for symptom control or premedication as needed.
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GOG-0241
5.332 Hypertension: Hypertension is a known and potentially serious adverse
event associated with bevacizumab treatment. Patients receiving
bevacizumab should have their blood pressure monitored
weekly during the first cycle of therapy, and subsequently, prior to each
infusion of bevacizumab. Home monitoring is permitted. Patients who
elect to monitor blood pressure at home will be provided with a Blood
Pressure Check Calendar (Appendix V). Patients who monitor their
blood pressure at home should be instructed to call their doctor if the
systolic blood pressure is >140 mmHg or the diastolic blood pressure is
> 90 mmHg. Hypertensive medication should be initiated or increased
per routine practice. Bevacizumab treatment modifications due to
hypertension should follow the instructions in section 6.0.
5.333 Therapeutic anticoagulation: Patients on therapeutic anticoagulation
should have PT/INR or PTT (whichever is appropriate) monitored
closely during bevacizumab therapy. Bevacizumab should be held if the
coagulation parameters are higher than the intended therapeutic range.
5.334 Wound complications and surgery: The appropriate interval from
discontinuation of bevacizumab to subsequent elective surgery required
to reduce the risk of impaired wound healing has not been determined.
Decision on such an interval should take into consideration the half-life
of bevacizumab. It is generally recommended that bevacizumab should
be discontinued at least 4 weeks prior to major elective surgery. In
addition, bevacizumab should not be restarted until at least 4 weeks after
major surgery provided that the wound has adequately healed.
5.335 Re-imaging of measurable disease sites by CT scan of the
chest/abdomen/pelvis will be performed prior to every other cycle.
Patients who have complete response (CR), partial response (PR), or
stable disease will continue for additional cycles. Patients who have
progression of disease will be removed from study treatment. If the
patient’s response is CR, PR, or stable disease, and if side effects are not
severe, a patient may remain on a study agent indefinitely at the
investigator's discretion.
5.336 Chemotherapy Guidelines
If a patient receiving chemotherapy (with or without bevacizumab)
experiences a > 10% weight change, the chemotherapy dose to be
administered with a subsequent cycle must be recalculated.
For 21 day cycles, a patient will be permitted to have a new cycle of
chemotherapy delayed up to 7 days (without this being considered to be
a protocol violation) for major life events (e.g., serious illness in a family
member, vacation which is unable to be re-scheduled). Documentation
to justify this decision should be provided in the physician’s clinic note.
It will be acceptable for individual chemotherapy doses to be delivered
within a “24-hour window before and after the protocol-defined date” for
-29-
GOG-0241
21 day cycles. If the treatment due date is a Friday, and the patient
cannot be treated on that Friday, then the window for treatment would
include the Thursday (1 day earlier than due) through the Monday (day 3
past due).
Chemotherapy doses can be “rounded” to +/- 5% of the calculated dose
without being considered a protocol violation.
Please note: If bevacizumab is interrupted for ANY reason for > 8
weeks, the patient should discontinue bevacizumab therapy on protocol.
Patients will continue to receive carboplatin/paclitaxel and
oxaliplatin/capecitabine on study.
5.337 Patients who have an ongoing study agent-related serious adverse event
upon study completion or at discontinuation from the study treatment
will be contacted by the investigator or his/her designee periodically
until the event is resolved or determined to be irreversible.
5.4
Dexamethasone and G-CSF (Neupogen) Compliance
The use of a Patient Pill Calendar (see Appendix V) during study therapy will be
utilized by the patient and the treating clinic to help promote and monitor compliance
with dexamethasone. Patients who are treated with G-CSF (Neupogen) or Neulasta at
home will also record G-CSF use on this calendar.
5.5
Blood Pressure Check Compliance
The use of a Blood Pressure Check Calendar (see Appendix VI) during study therapy
will be utilized by the patient whenever blood pressure is taken at home to help promote
and monitor compliance with this study parameter. Patients may elect to check their
blood pressure at home if they have access to a blood pressure monitor (home blood
pressure monitors will not be provided by the study). Alternatively, blood pressure
checks may be done in other outside settings, such as a pharmacy or outside physician’s
office, with results recorded on the Blood Pressure Check Calendar.
5.6
Criteria for removal from treatment
5.61
Inability to tolerate the lowest doses because of toxicity.
5.62
The patient may withdraw from the study at any time for any reason.
5.63
Patients with evidence of progressive disease or other patients with significant
side effects or deterioration of performance status may be removed from study at
the investigator's discretion.
-306.0
GOG-0241
TREATMENT MODIFICATIONS
In order to maintain dose-intensity and cumulative dose-delivery on this study,
reasonable efforts will be made to minimize dose reduction and treatment delays as
specified. Any patient whose treatment is delayed must be evaluated on a weekly basis
until adequate hematologic and non-hematologic parameters have been met. No dose
escalation is planned for this study.
6.1
Arm I: Paclitaxel + Carboplatin:
6.11
General Guidelines for Hematologic Toxicity
6.111 Initial treatment modifications will consist of cycle delay and/or dose
reduction as directed.
6.112 Treatment decisions will be based on the absolute neutrophil count
(ANC) rather than the total white cell count (WBC).
6.113 Subsequent cycles of therapy will not begin until the ANC > 1500
cells/mm3 (CTC Grade 1) and the platelet count is > 75,000/mm3 (CTC
Grade 1).
 Therapy will be delayed for a maximum of three weeks until these values
are achieved. Patients who fail to recover adequate counts within a threeweek delay will no longer receive protocol-directed chemotherapy.
 Patients who received G-CSF prior to the current cycle may begin with
ANC > 1000 cells/mm3, if clinically appropriate, to allow for transient
reductions in ANC after discontinuation of G-CSF.
 Patients who are delayed more than 7 days may begin with ANC > 1000
cells/mm3, if clinically appropriate, as they will receive G-CSF with
subsequent therapy.
6.114 The use of hematopoietic cytokines and protective reagents are restricted
as noted:
6.1141 In general, patients will NOT receive prophylactic filgrastim (GCSF), PEG-filgrastim (Neulasta), or sargramostim (GM-CSF)
unless they experience treatment delays or recurrent neutropenic
complications after treatment modifications as specified. In
particular, hematopoietic growth factors should NOT be used to
avoid initial chemotherapy dose modifications as stipulated in the
protocol. However, patients may receive growth factors for
management of neutropenic complications in accordance with
clinical treatment guidelines. If required, it is recommended that
growth factors be initiated the day after the last dose of
chemotherapy. NeupogenTM should continue for a minimum of
10 days or until the ANC is sustained above > 1000/mm3. Growth
factors should be discontinued if the ANC exceeds 10,000/mm3
and should not be used within 72 hours of a subsequent dose of
chemotherapy.
-31-
GOG-0241
6.1142 Patients should NOT receive prophylactic thrombopoietic agents
unless they experience recurrent grade 4 thrombocytopenia after
treatment modifications as specified below.
6.1143 Patients may receive erythropoietin (EPO), iron supplements,
and/or transfusions as clinically indicated for management of
anemia, but should NOT receive EPO when the Hb is > 10.0 g/dl.
6.1144Patients may NOT receive amifostine or other protective
reagents unless indicated in the study design.
6.12
Modifications for Hematologic Toxicity (Nadirs)
6.121 Initial occurrences of dose-limiting neutropenia (defined in 6.122) and
dose-limiting thrombocytopenia (defined in 6.223) will be performed
according to Table A, using the regimen modifications in Table B.
6.122 Dose-limiting neutropenia (DLT-ANC) is defined by the occurrence of
febrile neutropenia or grade 4 neutropenia. Febrile neutropenia is
defined within the CTC as fever of unknown origin without clinically or
microbiologically documented infection with ANC less than 1,000
cells/mm3 and fever greater than or equal to 38.5C. This is to be
distinguished from catheter-related infections and other documented
infections that occur within the setting of grade 3-4 neutropenia.
6.123 Dose-limiting thrombocytopenia (DLT-PLT) is defined by any
occurrence of grade 4 thrombocytopenia (< 10,000/mm3) or bleeding
associated with grade 3 thrombocytopenia (10,000 to < 50,000/mm3).
There will no modifications for uncomplicated grade 3
thrombocytopenia.
Table A:
DLT DLT
ANC PLT
Yes
No
Yes
Yes
No
Yes
Table B:
Modification Instructions for Dose-Limiting Hematoloigic Toxicity (In
conjunction with Table B)
First Occurrence
Second Occurrence
Third Occurrence
Reduce the regimen drug doses
by one level using Table B.
Reduce the regimen drug doses
by one level using Table B.
For carboplatin AUC 6,
decrease one AUC unit and
maintain other drug doses.
Add G-CSF and maintain
all drug doses.
Add G-CSF and decrease
carboplatin one AUC unit.
For carboplatin AUC 5,
decrease one AUC unit
and maintain other drug
doses.
Off Study
Treatment
Off Study
Treatment
Off Study
Treatment
Regimen Modifications for Hematologic Toxicity (In conjunction with
Table A
-32Drug
Carboplatin
Paclitaxel
Regimen -2 Level
AUC 4
175 mg/m2
6.13
Regimen -1 Level
AUC 5
175 mg/m2
GOG-0241
Regimen Starting Dose Level
AUC 6
175 mg/m2
Modifications for delayed hematologic recovery
6.131 Delay on the basis of neutropenia (Delay-ANC) is defined if the ANC is
less than 1500 cells/mm3 (CTC grade 2 or worse) within 24 hours prior
to scheduled therapy, or less than 1000 cells/mm3, if the patient received
G-CSF during the previous cycle.
6.132 Delay on the basis of thrombocytopenia (Delay-PLT) is defined if the
platelet count is less than 75,000/mm3 (CTC grade 2 or worse) within 24
hours prior to scheduled therapy.
6.133 Modifications noted below are only required for management of delays
in the absence of dose reductions stipulated by nadir DLT-ANC and/or
DLT-PLT (as noted above). In other words, if the patient experiences
DLT-ANC and Delay-PLT, make the modifications as indicated for the
nadir counts without additional modifications based on delayed recovery.
Table C:
Category
Delay-ANC
Delay-PLT
Modifications for Delayed Hematologic Recovery
Delay (days)
1-7
8-21
>21
1-7
8-21
>21
6.14
Modification
No change
Add G-CSF with next cycle
Off study treatment
No change
Decrease carboplatin one AUC unit, but not lower than AUC 4
Off study treatment
Modifications for Non-Hematologic Toxicity
Table D:
Drug
Carboplatin
Paclitaxel
-2 Level
AUC 5
110 mg/m2
Allowable Dose Levels for Individual Drugs
-1 Level
AUC 6
135 mg/m2
0 Level
AUC 6
175 mg/m2
6.141 Grade 2 peripheral neuropathy requires reduction of one dose level in
paclitaxel and delay in subsequent therapy for a maximum of 3 weeks
until recovered to grade 1. For grade > 3 neurotoxicity, paclitaxel should
be permanently discontinued and subjects treated with single-agent
carboplatin with no dose reduction.
-33-
GOG-0241
6.142 Renal toxicity associated with reduction in GFR is not expected as a
direct complication of chemotherapy in this untreated patient population
using the prescribed dose and schedule of this regimen. As such, there
are no specific dose modifications for renal toxicity. However, the target
AUC dose of carboplatin must be recalculated each cycle in any patient
who develops renal toxicity, defined by serum creatinine greater than 1.5
x institutional upper limit normal (ULN), CTCAE Grade > 2.
6.143 Hepatic toxicity is not expected as a direct complication of this regimen
in this untreated patient population using the prescribed dose and
schedule. However, the development of Grade 3 (or greater) elevations
in SGOT (AST), SGPT, (ALT), alkaline phosphatase or bilirubin
requires reduction of one dose level in paclitaxel and delay in subsequent
therapy for a maximum of three weeks until recovered to Grade 1.
6.144 There will be no dose modifications for alopecia, constipation, or nausea.
It is recommended that routine medical measures be employed to
manage nausea, and constipation.
Note: Once the dose has been reduced, it should not be increased at a later time.
6.2
Arm II: Oxaliplatin + Capecitabine
Toxicity
Myelosuppression
Grade 0 or 1
Grade 2
Grade 3
Capecitabine
Oxaliplatin
Maintain dose
Decrease 1 D.L
Delay dose, then
decrease 1 D.L. when
resolved to < gr 1
Maintain dose
Maintain dose
Maintain dose for neutropenia;
for thrombocytopenia delay dose
then decrease 1 D.L.
Grade 4
Delay dose, then
decrease 1 D.L. when
resolved to < gr 1
Delay dose then decrease 1 D.L.
when resolved to ANC>1500
Febrile Neutropenia
Delay dose, then
decrease 1 D.L. when
resolved
Delay dose, then decrease 1 D.L.
when resolved
Diarrhea
Grade 0
Grade 1
Grade 2 or 3
Maintain dose
Maintain dose
Delay dose then resume Delay then maintain dose
at same dose when
resolved
Delay dose, then
decrease 1 D.L. when
resolved
Delay then maintain dose
-34Grade 4
Mucositis
Grade 0 or 1
Grade 2
Grade 3
Grade 4
GOG-0241
Delay dose, then
Delay then maintain dose
decrease 2 D.L. when
resolved or discontinue
at investigator discretion
Maintain dose
Decrease 1 D.L
Delay dose, then
decrease 1 D.L. when
resolved
Maintain dose
Maintain dose
Delay then maintain dose
Delay dose, then
Delay then maintain dose
decrease 2 D.L. when
resolved or discontinue
at investigator discretion
1 Dose level (D.L.) = 75% of initial dose; 2 Dose levels (D.L.) = 50% of initial dose
Toxicity
Vomiting
Grade 0 or 1
Grade 2
Capecitabine
Oxaliplatin
Maintain dose
Delay dose, then
decrease 1 D.L. when
resolved
Maintain dose
Delay then Maintain dose
Grade 3
Delay dose, then
decrease 1 D.L. when
resolved
Delay dose, then Maintain dose;
consider modification of
antiemetic schedule
Grade 4
Delay dose, then
Delay dose, then decrease 1 D.L.
decrease 2 D.L. when when resolved to < gr 1
resolved or discontinue
at investigator discretion
Neuropathy/Parasthesia
Dysethesias with cold
Parasthesias
Parasthesias with pain < 7
days
Maintain dose
Maintain dose
Maintain dose
Maintain dose
Maintain dose
Maintain dose
Parasthesias with pain > 7
days (normal exam)
Maintain dose
Reduce 1 D.L.
Parasthesias with pain > 7
days (abnormal exam)
Maintain dose
Omit oxaliplatin one cycle then
restart with a reduction of 1 D.L.
-35Parasthesias with pain:
Persistent
Maintain dose
GOG-0241
Stop until improvement. If
improvement, restart with a
reduction of 1 D.L.
Parasthesias with functional Maintain dose
impairment <7 days
Maintain dose
Parasthesias with functional Maintain dose
impairment >7 days
(normal exam)
Normal exam and not interfering
with ADL's: Reduce 1 D.L.
Parasthesias with functional Maintain dose
impairment >7 days
(abnormal exam)
Omit oxaliplatin one cycle then
restart with a reduction of 1 D.L.
Parasthesias with functional Discontinue protocol
impairment - Persistent
Discontinue protocol
1 Dose level (D.L.) = 75% of initial dose; 2 Dose levels (D.L.) = 50% of initial dose
Toxicity
Hand-Foot Syndrome
Grade 0 or 1
Grade 2 (1st appearance)
Grade 2 (2nd appearance)
Grade 3 (1st appearance)
Grade 3 (2nd appearance)
Grade 4
Capecitabine
Maintain Dose
Maintain Dose
Decrease 1 D.L.
Decrease 1 D.L.
Decrease 2 D.L.
Discontinue protocol
Thromboembolic Events
Grade 0,1, or 2
Maintain dose
Grade 3 or 4
Delay chemotherapy,
start anticoagulation,
resume at investigator
discretion
Oxaliplatin
Maintain Dose
Maintain Dose
Maintain Dose
Maintain Dose
Maintain Dose
Discontinue protocol
Maintain dose
Delay chemotherapy, start
anticoagulation, resume at
investigator discretion
All other nonhematological toxicities,
except alopecia
Grade 0 or 1
Grade 2
Maintain dose
Delay dose, then
decrease 1 D.L. when
resolved
Maintain dose
Maintain dose
-36-
GOG-0241
Grade 3
Delay dose, then
decrease 1 D.L. when
resolved
Delay dose, then decrease 1 D.L.
when resolved
Grade 4
Delay dose, then
Delay dose, then decrease 1 D.L.
decrease 2 D.L. when when resolved
resolved or discontinue
at investigator discretion
1 Dose level (D.L.) = 75% of initial dose; 2 Dose levels (D.L.) = 50% of initial dose
Note: Dose delays can be for up to a maximum of three weeks.
Laryngopharyngeal dysesthesia
If laryngopharyngeal dysesthesia occurs, the next dose of oxaliplatin should be
administered as a six-hour infusion. Cold exposure should be strictly avoided.
6.3
Bevacizumab Treatment Modification Criteria and Guidelines for Management
Event
Allergic reactions
or
Acute infusional
reactions/cytokine
release syndrome
CTCAE.v3.0
Action to be Taken
Grade
Grade 1-3
If infusion-related or allergic reactions occur
with bevacizumab, premeds should be given
with the next dose, and infusion time may not
be reduced for the subsequent infusion. Follow
the guidelines in Section 5.2 for bevacizumab
administration.
For patients with Grade 3 reactions,
bevacizumab infusion should be stopped and
not restarted on the same day. At the
physicians’ discretion, bevacizumab may be
permanently discontinued or re-instituted with
premeds and at a rate of 90+15 min. If
bevacizumab is re-instituted, the patient
should be closely monitored for a duration
comparable to or longer than the duration
of the previous reactions.
Discontinue bevacizumab
Discontinue bevacizumab.
Grade 4
Arterial Thrombosis Grade 2 ( if
- Cardiac ischemia/
new or
infarction
worsened since
- CNS ischemia
bevacizumab
(TIA, CVA)
therapy)
- any peripheral or
Grade 3-4
Discontinue bevacizumab
visceral arterial
ischemia/throm-
-37-
GOG-0241
bosis
Venous Thrombosis
Grade 3
OR
asymptomatic
Grade 4
Venous Thrombosis
(continued)

Hold bevacizumab treatment. If the
planned duration of full-dose
anticoagulation is <2weeks, bevacizumab
should be held until the full-dose
anticoagulation period is over.

If the planned duration of full-dose
anticoagulation is >2 weeks,
bevacizumab may be resumed during the
period of full-dose anticoagulation IF all
of the criteria below are met:
- The subject must have an in-range INR
(usually 2-3) on a stable dose of
warfarin or on a stable dose of heparin
prior to restarting bevacizumab.
- The subject must not have pathological
conditions that carry high risk of
bleeding (e.g. tumor involving major
vessels or other conditions).
- The subject must not have had
significant hemorrhagic events while on
study.
 If thromboemboli worsen/recur upon
resumption of study therapy, discontinue
bevacizumab
Discontinue bevacizumab
Hypertension
Proteinuria
Grade 4
(symptomatic)
[Treat with anti-hypertensive medication as needed. The goal
of BP control should be consistent with general medical
practice]
Controlled BP at Continue bevacizumab
the discretion of
the treating
physician
Persistent or
Hold bevacizumab. If treatment is delayed
symptomatic
for > 8 weeks due to uncontrolled
HTN
hypertension, discontinue bevacizumab.
Grade 4
Discontinue bevacizumab.
[Proteinuria should be monitored by urine analysis for urine
protein creatinine (UPC) ratio prior to every other dose of
bevacizumab]
UPC ratio
Continue bevacizumab.
< 3.5
-38UPC ratio
> 3.5
Grade 4 or
nephrotic
syndrome
Wound dehiscence requiring medical
or surgical intervention
GI perforation, GI leak or fistula
Other clinically
significant AEs
attributable to
bevacizumab (except
controlled
nausea/vomiting).
Grade 3
Hold bevacizumab until UPC recovers to
< 3.5. If therapy is held for > 2 months (8
weeks) due to proteinuria, discontinue
bevacizumab.
Discontinue bevacizumab.
Discontinue bevacizumab
Discontinue bevacizumab


Grade 4
GOG-0241


Hold bevacizumab until symptoms
resolve to < grade 1
If treatment delay is >3-4 weeks due to
toxicity, discontinue bevacizumab.
Discontinue bevacizumab
Upon consultation with the study
chair, resumption of bevacizumab may
be considered if a patient is benefiting
from therapy, and the G4 toxicity is
transient, has recovered to < grade 1 and
unlikely to recur with retreatment.
*Current CTCAE definitions used by CTEP:
 Grade 1: asymptomatic, transient (< 24 hours) increase by > 20 mmHg (diastolic) or to >150/100 if
previously WNL; intervention not indicated
 Grade 2: recurrent or persistent (> 24 hours) or symptomatic increase by > 20 mmHg (diastolic) or to
> 150/100 if previously WNL; monotherapy may be indicated
 Grade 3: requiring more than one drug or more intensive therapy than previously
 Grade 4: life threatening (e.g. hypertensive crisis)
Patients who interrupt or discontinue bevacizumab for bevacizumab-related toxicity
should continue on-time treatment with gemcitabine and docetaxel. Imaging (CT scans)
should continue to be performed on time in order to determine if there is evidence of
progression of disease.
6.4
Dose escalations
There will be no dose escalations or re-escalations on this study.
-397.0
GOG-0241
STUDY PARAMETERS
7.1
Observations and Tests
The following observations and tests are to be performed and recorded on the
appropriate form(s)
-40-
Prior to
Study
Therapy
Prior to each
cycle for
cycles 1-6
History & Physical
1
Blood pressure
1
Coagulation
parameters (INR,
APTTN)
2
Toxicity Assessment
2
Serum pregnancy test
3
CBC with Diff,
Platelets
Between
cycles 3 and 4,
and 1 month
post cycle 6
GOG-0241
Post Cycle 6 (weeks 18-54).
Post Treatment
No Bevacizumab†
12 cycles of
Bevacizumab
(Cycles 7-18)
‡
q 3 months in Year 2
then q 6 months in
Years 3-5, then
annually
X
X
X
X
X
X
X
X
X
X11
X
X
2
X*
X
X
5
Lytes, BUN, Creat, Ca,
Mg, PO4, Bili, SGOT,
Alk Phos, Total
protein, albumin
2
X
X
X
5
EKG
1
CT Scan of chest
X1
X
Radiographic Tumor
Measurement (MRI or
CT abdomen/pelvis)
X1
X
6, 8
6, 8
7, 8
CA-125, Carcinoembryonic Antigen
(CEA), CA19-9
X2
X
X
X
X
Colonoscopic colon
cancer screening
4
Urinalysis
2
X
X
X
FACT-TOI/Ntx-4 and
EQ-5D™
X
9
9
PARAMETER
X
10
Telephone Call
11

If grade 4 neutropenia is documented (ANC<500/mm3), obtain weekly until resolved to grade 3.

Only if the initial CT scan of the chest is abnormal
† Assessments via clinical visits every 3 months and telephone calls every 3 weeks between clinic visits.
‡ Assessments every 3 weeks unless otherwise specified.
1. Must be obtained within 28 days prior to initiating protocol therapy. Patients undergoing surgery need a scan
of the abdomen/pelvis pre- and post-surgery. The same scanning technique must be used throughout the
whole trial.
2. Must be obtained within 14 days prior to initiating protocol therapy. Urine dipstick for proteinuria <2+. If
urine dipstick is >2+ on two occasions more than one week apart, then a 24-hour urine must demonstrate <1g
of protein in 24 hours. For patients on full anticoagulation, refer to Section 6.3 for appropriate management.
3. Must be obtained within 72 hours prior to initiating protocol therapy.
4. Must have within 1 year of enrolling on protocol. Patients with bowel resection at time of debulking and
without prior colonoscopy may have colonoscopy 4 weeks after surgery and prior to enrolling on protocol.
5. As clinically indicated.
6. CT or MRI scan of abdomen and pelvis (MRI pelvis optional) every 3 months. Imaging can be obtained with
asymptomatic CA125 rise in accordance to local practice.
-41-
GOG-0241
7. CT or MRI scan of abdomen and pelvis (MRI pelvis optional) every 6 months during year 2 and every 12
months during years 3-5. Imaging can be obtained with asymptomatic CA125 rise in accordance to local
practice.
8. Patients with measurable disease and a newly documented response (CR or PR) at the conclusion of therapy
should undergo repeat imaging in at least 4 weeks (but within 3 months) to confirm the persistence of
response in accordance with RECIST version 1.1.
9. QOL questionnaires to be completed:
 6 months after end of chemotherapy
 after completion of maintenance bevacizumab therapy (or 36 weeks after completion of chemotherapy
in the non-bevacizumab arms).
10. QOL questionnaires to be completed:
 6 months after completion of bevacizumab (or 14 months after completion of chemotherapy)
 every 12 months in years 2-5.
11. Telephone Assessments:
This applies to patients who are not receiving bevacizumab
During weeks 18-54, patients who are not receiving bevacizumab will be seen every 3 months.
Every 3 weeks, between each 3-month visit, the research nurse must make a telephone call to the patient
(Please note: this duty must be signed off on the delegation of responsibilities)
The following questions must be asked:
 How have you been feeling in general?
 Have you noticed any new symptoms, discomfort or pain?
 Has there been any change to your existing symptoms?
 Have there been any changes to your medication?
Answers must be acted on accordingly, as they would be if the patient were in clinic.
Blank CRFs will be provided for completion, to record the content of the telephone call. These must be
completed by the research nurse, and a copy returned to the GOG Statistical Center.
7.2
Pathology Requirements
The histopathologic diagnosis of primary advanced stage mucinous adenocarcinoma is
made based on pathology review at each institutional site. To verify that patients on
this protocol actually have a primary mucinous ovarian carcinoma, one block should be
taken for every centimeter diameter of the tumor, taking the maximum dimension as the
diameter. Sampling should concentrate particularly on solid areas and potential areas of
capsular involvement by tumor. Where the ovarian hilum can still be identified, it
should be sampled in particular for the detection of vessel invasion.
As an entry requirement, immunohistochemistry must be performed upon a section of
the primary tumor with antibodies directed against CK7, CK20, and CDX2. (Whenever
possible, immunostaining with monoclonal CEA, CA 19-9, CA 125, estrogen receptor
(ER), and progesterone receptor (PR), is recommended, but it is not required for patient
entry). In addition to the surgical pathology report, all H&E stained slides of the
ovarian tumor,all immunostained slides and one slide to show the most advanced stage
of disease must be submitted for central review by the two study pathologists. Slides
from recurrence and/or persistent disease are required only for Stage I tumors, when
recurrence/persistent disease is the basis for eligibility.
In addition to the immunohistochemical results, it is recommended that the institutional
pathologists consider the WHO and other publications that have identified criteria that
help to distinguish primary mucinous carcinomas of the ovary from those that are
-42-
GOG-0241
metastatic to the ovary from other sites. Features suggestive of metastasis follow, and
the datasheet with this information must be completed and sent by the institutional
pathologist:
1) bilaterality
2) a nodular pattern of ovarian involvement
3) an infiltrative pattern of stromal invasion
4) microscopic surface deposits of tumour
5) modest sized ovarian tumours
6) extensive lymphovascular invasion, especially in the hilum and perihilar tissues
7) single cell infiltration
8) signet ring differentiation
9) mucin pooling with individual cells floating in the mucinous material
10) marked pattern variation in tumour from one nodule to another
11) immunohistochemical phenotype showing stronger cytokeratin 20 than 7 positivity
12) particularly for metastatic bowel tumour, the presence of dirty necrosis, segmental
necrosis and surviving ribbons of glandular cells in a garland-like pattern.
13) a florid stromal luteinised cellular response
Any of these features may also be seen in primary ovarian mucinous carcinomas.
However, the chance of a tumor being a metastasis is increased when these features are
present in combination.
When submitting pathology material to the GOG SDC, individual slides must be
labeled with GOG Patient ID, patient initials and the surgical / pathology accession
number (e.g., S08-2355) and block identifier (e.g., A6). Don’t not label with disease
site or collection date. Pack the labeled slides into plastic slide cassette(s). Tape plastic
slide cassettes shut and wrap in bubble wrap or another type of padded material prior to
shipping. Please include the GOG Patient ID, patient initials, and protocol number on
all pages of the pathology report and black out the patient’s name. Ship pathology
slides, three copies of both the Pathology Form F and the official pathology report
directly to the Pathology Materials Coordinator at the GOG Statistical and Data Center,
Roswell Park Cancer Institute, Research Studies Center, Carlton and Elm Streets,
Buffalo, New York, 14263; phone (716) 845-5702. The GOG Upload Application is an
alternative method for submitting stained slides, pathology reports and Form F.
Central pathology review by two GOG pathologists will be required but not prior to
enrollment on this protocol, and is not the basis for determination of eligibility for entry
on this protocol. This review will include study of H & E sections and immunostaining,
with careful adherence to the distinction between primary versus metastatic ovarian
involvement based on WHO criteria.
7.3
Specimen Requirements and Laboratory Testing
Specimen (Specimen
Code)
Collection Time Point
Shipping
-43Formalin-fixed,
paraffin-embedded
primary tumor tissue (a
block or 15 charged
slides) (FP01)
Formalin-fixed,
paraffin-embedded
primary tumor tissue (a
50-micron curl) (FP02)
7.31
Archival
GOG-0241
Ship at room temperature to
the GOG Tissue Bank using
your own container
Archival
VEGF/EGF Ligand, Receptor, and Activated Receptor Immunohistochemistry
7.311 A block or fifteen serial sections from archived formalin-fixed, paraffinembedded primary tumor tissue should be obtained from your pathology
department. Serial sections will be placed on charged slides suitable for
immunohistochemistry (IHC). Slides will be used in IHC assays to
determine protein levels of VEGF, EGF, VEGF receptor, EGF receptor,
and phosphorylated EGF-R and VEGF-R.
7.32
KRAS DNA Analysis
7.321 A 50 micron curl from fixed and embedded primary tumor will also be
required. Isolation of DNA and direct sequence analysis of KRAS will
be performed as previously described in detail.31
7.4
Quality of Life Assessments
Quality of life (QOL) assessments will include the FACT-TOI (26 questions),
FACT-GOG/NTX-4 (4 questions), and EQ-5D™ (6 questions)
The time to complete these surveys should be 5 minutes or less based on prior
quality of life studies. They will be administered to the patient as a self-report
assessment. Patients will be instructed to read the brief instructions at the top of
the form, and after the patients’ understanding of the instructions has been
confirmed, the patient should be instructed to complete every item in order,
without skipping any items. If a patients’ family member remains with the patient
while she is completing the surveys, the data managers should encourage patients
to answer the questions on their own.
If patients are unable to come to the clinic, the questionnaire may be mailed to
them with a request to complete it at home and to return it via mail to the
appropriate individual using a self-addressed stamped envelope provided by the
study team. This request should be followed by a telephone call by the data
manager to make sure the patient has received the materials and to ensure
completion of the material.
-448.0
GOG-0241
EVALUATION CRITERIA
8.1
Parameters of Response – RECIST (version 1.1) Criteria56
8.11
Measurable disease (“Target”) is defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be
recorded). Each lesion must be  10 mm when measured by CT (CT scan
slice thickness no greater than 5 mm*); > 10 mm caliper measurement by
clinical exam (lesions which cannot be accurately measured with calipers
should be recorded as non-measurable); and > 20 mm by chest x-ray.
*If CT scan with slice thickness > 5 mm is used, the minimum lesion size
must have a longest dimension twice the actual slice thickness.
Malignant lymph nodes: To be considered pathologically enlarged and
measurable, a lymph node must be > 15 mm in short axis when assessed
by CT scan (CT scan slice thickness recommended to be no greater than 5
mm). At baseline and in follow-up, only the short axis will be
measured and followed.
Clinical lesions will only be considered measureable when they are
superficial and > 10 mm diameter as assessed using calipers (e.g. skin
nodules). When lesions can be evaluated by both clinical exam and
imaging, imaging evaluation should be undertaken since it is more
objective and my also be reviewed at the end of the study.
CT is the best currently available and reproducible method to measure
lesions selected for response assessment. MRI may be substituted for
contrast enhanced CT for some sites (e.g. for abdomen and/or pelvis), but
NOT lung. The minimum size for measurability is the same as for CT (10
mm) as long as the scans are performed with slice thickness of 5 mm and
no gap. In the event the MRI is performed with thicker slices, the size of a
measurable lesion at baseline should be two times the slice thickness.
Tumors within a previously irradiated field will be designated as “nontarget” lesions unless progression is documented or a biopsy is obtained to
confirm persistence at least 90 days following completion of radiation
therapy.
Bone lesions:
 Bone scan, PET scan or plain films are NOT considered adequate
imaging techniques to measure bone lesions.
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft
tissue components, that can be evaluated by cross sectional imaging
techniques such as CT or MRI can be considered as measurable if the
-45-

GOG-0241
soft tissue component meets the definition of measurability described
above.
Blastic bone lesions are non-measurable.
Cystic lesions:
 Lesions that meet the criteria for radiographically defined simple cysts
should not be considered as malignant lesions (neither measurable nor
non-measurable).
 Cystic lesions thought to represent cystic metastases can be considered
measurable lesions, if they meet the definition of measurability
described above. However, if non-cystic lesions are present in the
same patient, these are preferred for selection as target lesions.
8.12
Non-measurable disease (“Non-Target”) is defined as all other lesions,
including small lesions (<10 mm or pathological lymph nodes with > 10 to
< 15 mm short axis) as well as truly non-measurable lesions.
Lesions considered truly non-measurable include:
 Leptomeningeal disease
 Ascites
 Pleural or pericardial effusion
 Inflammatory breast disease
 Lymphangitic involvement of skin or lung
 Abdominal masses/abdominal organomegaly indentified by
physical exam that is not measureable by reproducible imaging
techniques
8.13
Baseline documentation of “Target” and “Non-Target” lesions
All measurable lesions up to a maximum of 5 lesions total (and a
maximum of two lesions per organ) representative of all involved organs
should be identified as target lesions and recorded and measured at
baseline. Target lesions should be selected on the basis of their size
(lesions with the longest diameter), be representative of all involved
organs, but in addition should be those that lend themselves to
reproducible repeated measurements. A sum of the diameters (longest for
non-nodal lesions, short axis for nodal lesions) for all target lesions will
be calculated and reported as the baseline sum diameters. The baseline
sum diameters will be used as reference to further characterize the
objective tumor response of the measurable dimension of the disease.
All other lesions (or sites of disease) should be identified as non-target
lesions and should also be recorded at baseline. Measurements are not
required and these lesions should be followed as “present” or “absent”. It
is possible to record multiple non-target lesions involving the same organ
-46-
GOG-0241
as a single item on the D2M form (e.g. ‘multiple enlarged pelvic lymph
nodes’ or ‘multiple liver metastates”).
All baseline evaluations of disease status should be performed as close as
possible to the start of treatment and never more than 4 weeks before the
beginning of the treatment.
The same method of assessment and the same technique should be used to
characterize each identified and reported lesion at baseline and during
follow-up. Imaging based evaluation should ALWAYS be done rather
than clinical examination unless the lesion(s) being followed cannot be
imaged but are assessable by clinical exam.
8.14
Response Criteria
8.141 Complete Response (CR): Disappearance of all target and nontarget lesions. Any pathological lymph nodes (whether target or
non-target) must have reduction in short axis to <10 mm.
Normalization of CA125, if elevated at baseline, is required for
ovarian/primary peritoneal/fallopian tube cancer studies.
8.142 Partial Response (PR): At least a 30% decrease in the sum of
diameters of target lesions, taking into reference the baseline sum
diameters.
8.143 Progressive Disease (PD): At least a 20% increase in the sum of
diameters of target lesions, taking as reference the smallest sum on
study (this includes the baseline sum if that is the smallest on
study). In addition to the relative increase of 20%, the sum
must also demonstrate an absolute increase of at least 5 mm.
(Note: the appearance of one or more NEW lesions is also
considered progression. Guidance on when a lesion is to be
considered new is provided in the above cited reference).
Unequivocal progression of existing non-target lesions is also
considered progression (a detailed description and examples of
unequivocal progression of existing non-target lesions is provided
in the above cited reference).
For equivocal findings of progression (e.g. very small and
uncertain new lesions; cystic changes or necrosis in existing
lesions), treatment may continue until the next scheduled
assessment. If at the next scheduled assessment, progression is
confirmed, the date of progression should be the earlier date
when progression was suspected.
-47-
GOG-0241
8.144 Stable Disease (SD): Neither sufficient shrinkage to qualify for PR
nor sufficient increase to qualify for PD, taking as reference the
smallest sum diameters while on study.
8.145 Not evaluable (NE) is when no imaging/measurement is done at all
at a particular time point. The patient is not evaluable (NE) at that
time point.
8.146 Early death is defined as having NO repeat tumor assessments
following initiation of study therapy resulting from the death of the
patient due to disease or treatment.
Patients with global deterioration of health status requiring
discontinuation of treatment without objective evidence of disease
progression at that time will be recorded as ‘symptomatic
deterioration’. Every effort should be made to document
objective progression even after discontinuation of treatment.
Confirmation of response (for both CR and PR): Complete or
partial response may only be claimed if the criteria for each are
met at a subsequent time point (> 4 weeks later) in studies with a
primary endpoint that includes response rate. When response rate
is a secondary endpoint (e.g. randomized phase II or III studies
with progression-free survival or overall survival as primary
endpoint) confirmation is NOT required.
Special note on lymph nodes: Lymph nodes identified as target
lesions should always have the actual short axis measurement
recorded (measured in the same anatomical plane as the baseline
examination), even if the nodes regress to below 10 mm on study.
This means that when lymph nodes are included as target lesions,
the ‘sum’ of lesions may not be zero even if complete response
criteria are met, since a normal lymph node is defined as having a
short axis of < 10 mm. For PR, SD and PD, the actual short axis
measurement of the nodes is to be included in the sum of target
lesions.
Special note on target lesions that become ‘too small to
measure’: While on study, all lesions (nodal and non-nodal)
recorded at baseline should have their actual measurements
recorded at each subsequent evaluation, even when very small (e.g.
2 mm). However, sometimes lesions or lymph nodes which are
recorded as target lesions at baseline become so faint on CT scan
that the radiologist may not feel comfortable assigning an exact
measure and may report them as being ‘too small to measure’.
When this occurs it is important that a value be recorded on the
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GOG-0241
D2M form. If it is the opinion of the radiologist that the lesion has
likely disappeared, the measurement should be recorded as 0 mm.
If the lesion is believed to be present and is faintly seen but too
small to measure, a default value of 5 mm should be assigned
(Note: It is less likely that this rule will be used for lymph nodes
since they usually have a definable size when normal and are
frequently surrounded by fat such as in the retroperitoneum;
however, if a lymph node is believed to be present and is faintly
seen but too small to measure, a default value of 5 mm should be
assigned in this circumstance as well).
8.15
Evaluation of best overall response is according to Tables 1-3:
Table 1 is used for patients with measurable disease at baseline.
Table 1: Time point response: patients with target (+/– non-target) disease
Target lesions
Non-target lesions
New lesions Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
No
NE
Not all evaluated Non-PD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Table 2 is used for patients with non-measurable disease.
Table 2: Time point response: patients with non-target disease only
Non-target lesions New lesions Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
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GOG-0241
Non-target lesions New lesions Overall response
Any
Yes
PD
Table 3 is used for phase II trials studies with a primary endpoint that includes
response rate.
Table 3: Best overall response when confirmation of CR and PR required
Overall response
Overall response
First time point
Subsequent time point
BEST overall response
CR
CR
CR
CR
PR
SD, PD or PR*
CR
SD
SD
CR
PD
SD
CR
NE
SD
PR
CR
PR
PR
PR
PR
PR
SD
SD
PR
PD
SD
PR
NE
SD
NE
NE
NE
*If a CR is truly met at first time point, then any disease seen at a subsequent time
point, even disease meeting PR criteria relative to baseline, makes the disease PD at
that point (since disease must have reappeared after CR). However, sometimes ‘CR’
may be claimed when subsequent scans suggest small lesions were likely still present
and in fact the patient had PR or SD, not CR at the first time point. Under these
circumstances, the original CR should be changed to PR or SD and the best response
is PR or SD.
8.16
Duration of response is defined as the time measurement criteria are first met
for CR/PR until the first date that recurrent or progressive disease is objectively
documented (taking as reference for progressive disease the smallest
measurement recorded on study).
8.17
Duration of stable disease is measured from the start of the treatment (in
randomized trials, from the date of randomization) until the criteria for
progression are met, taking as reference the smallest sum on study (if the
baseline sum is the smallest, this is the reference for calculation of PD).
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8.18
Progression-Free Survival is the period from study entry until recurrent or
progressive disease is objectively documented (taking as reference for
progressive disease the smallest measurement recorded on study), death or
date of last contact.
8.19
Survival is the observed length of life from entry into the study to death or the
date of last contact.
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-529.0
GOG-0241
DURATION OF STUDY
9.1
Patients will continue on study treatment until they complete 6 cycles of chemotherapy
or disease progression or adverse effects prohibit further treatment. The patient can
refuse the study treatment at any time.
9.2
All patients will be followed (with completion of all required case report forms) until
disease progression or study withdrawal. In addition, following disease progression,
patients will be monitored for delayed toxicity and survival for a period of 5 years with
Q forms submitted to the GOG Statistical and Data Center, unless consent is withdrawn.
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10.0
GOG-0241
STUDY MONITORING AND REPORTING PROCEDURES
10.1
ADVERSE EVENT REPORTING FOR A COMMERCIAL AGENT
10.11 Definition of Adverse Events (AE)
An adverse event (AE) is any unfavorable and unintended sign (including an
abnormal laboratory finding), symptom, or disease that occurs in a patient
administered a medical treatment, whether the event is considered related or
unrelated to the medical treatment.
This study will utilize the Common Terminology Criteria for Adverse Events
version 3.0 (CTCAE v3.0) for defining and grading specific adverse events. A
copy of the CTCAE v3.0 can be downloaded from the CTEP home page at
http://ctep.cancer.gov/reporting/ctc.html. A GOG CTCAE v3.0 Manual is also
available on the GOG member web site (http://www.gog.org under MANUALS)
and can be mailed to the institution registering a patient to this study if
requested.
10.12 Reporting Expedited Adverse Events
Depending on the phase of the study, use of investigational or commercial
agents, and role of the pharmaceutical sponsor, an AE report may need to reach
multiple destinations. For patients participating on a GOG trial, all expedited AE
reports should be submitted by using the CTEP automated system for expedited
reporting (AdEERS). All AdEERS submissions are reviewed by GOG before
final submission to CTEP. Submitting a report through AdEERS serves as
notification to GOG, and satisfies the GOG requirements for expedited AE
reporting. All adverse reactions will be immediately directed to the Study Chair
for further action.
The requirement for timely reporting of AEs to the study sponsor is specified in
the Statement of Investigator, Form FDA-1572. In signing the FDA-1572, the
investigator assumes the responsibility for reporting AEs to the NCI. In
compliance with FDA regulations, as contained in 21 CFR 312.64, AEs should
be reported by the investigator.
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10.13 Phase 2 and 3 Trials Utilizing a Commercial Agent: AdEERS Expedited
Reporting Requirements for Adverse Events That Occur Within 30 Days of the
Last Dose of Any Commercial Study Agent
Reporting Requirements for Adverse Events that occur within 30 Days¹ of the
Last Dose of the Commercial Agent on Phase 2 and 3 Trials
Grade 1
Grade 2
Grade 2
Grade 3
Unexpected
Unexpected
With
Without
and Expected Unexpected Expected Hospitali- Hospitalization
zation
Unrelated
Unlikely
Not
Required
Possible
Probable
Definite
Not
Required
Not
Required
Not
7 Calendar
Required
Days
7 Calendar
Not
7 Calendar
Days
Required
Days
Grade 3
Grades
4 & 52
Grades
4 & 52
Expected
With
Hospitalization
Without Unexpected Expected
Hospitalization
Not
Required
7 Calendar
Days
Not
Required
7
7 Calendar
Calendar
Days
Days
7 Calendar
Days
7 Calendar
Days
Not
Required
24-Hrs;
7
3 Calendar Calendar
Days
Days
1
Adverse events with attribution of possible, probable, or definite that occur greater than 30 days after the last dose of
treatment with a commercial agent require reporting as follows:
AdEERS 24-hour notification followed by complete report within 3 calendar days for:
 Grade 4 and Grade 5 unexpected events
AdEERS 7 calendar day report:
 Grade 3 unexpected events with hospitalization or prolongation of hospitalization
 Grade 5 expected events
2
Although an AdEERS 24-hour notification is not required for death clearly related to progressive disease, a full report
is required as outlined in the table.
Please see exceptions below under the section entitled, “Additional Instructions or Exceptions to AdEERS
Expedited Reporting Requirements for Phase 2 and 3 Trials Utilizing a Commercial Agent.” March 2005
Note: All deaths on study require both routine and expedited reporting regardless of causality.
Attribution to treatment or other cause must be provided.

Expedited AE reporting timelines defined:
 “24 hours; 3 calendar days” – The investigator must initially report the AE via AdEERS
within 24 hours of learning of the event followed by a complete AdEERS report within 3
calendar days of the initial 24-hour report.
“7 calendar days” – A complete AdEERS report on the AE must be submitted within 7 calendar
days of the investigator learning of the event.

Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization (or
prolongation of existing hospitalization) must be reported regardless of attribution and
designation as expected or unexpected with the exception of any events identified as protocolspecific expedited adverse event reporting exclusions.

Any event that results in persistent or significant disabilities/incapacities, congenital anomalies,
or birth defects must be reported to GOG via AdEERS if the event occurs following treatment
with a commercial agent.
-55
GOG-0241
Use the NCI protocol number and the protocol-specific patient ID provided during trial
registration on all reports.
Additional Instructions or Exceptions to AdEERS Expedited Reporting Requirements for Phase 2
and 3 Trials Utilizing a Commercial Agent:

There are no additional instructions or exceptions to AdEERS expedited reporting requirements
for this protocol.
10.14 Procedures for Expedited Adverse Event Reporting:
10.141 AdEERS Expedited Reports: Expedited reports are to be submitted using
AdEERS available at http://ctep.cancer.gov. The NCI guidelines for
expedited adverse event reporting requirements are also available at this
site. Please consult these guidelines for secondary malignancy (including
AML, MDS) reporting requirements.
10.15 Automated CDUS reporting
For studies using commercial agents, the GOG Statistical and Data Center
(SDC) routinely reports adverse events electronically to the CTEP Clinical Data
Update System (CDUS Version 3.0). The SDC submits this data quarterly. The
AEs reported through AdEERS will also be included with the quarterly CDUS
data submissions.
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GOG-0241
GOG DATA MANAGEMENT FORMS
The following forms must be completed and submitted to the GOG Statistical and Data
Center (SDC) in accordance with the schedule below. All forms except the BDR Form
and Pathology report must be submitted via the SDC Electronic Data Entry System
(SEDES) which is available through the GOG website (www.gogstats.org). The BDR
Form should be submitted via mail. The GOG Uploader Application in SEDES is an
alternate method for submitting pathology reports and BDR to the GOG SDC.
Form
Due within
Copies*
Comments
Weeks
2
Event
Registration
2
Form OSO
2
Registration
2
Form MEDH
2
Registration
2
Form DR
4
Registration
2
Form BDR****
4
Registration
2
Form D2M***
4
Registration
2
Primary disease:
Form F
Pathology Report
Slides
6
6
6
Registration
Registration
Registration
2
3
**
Submit to SDC via postal
mail or via report uploader
Submit to SDC via postal
mail or via report uploader
Form R
Recurrent or Persistent Disease:
Form F
Pathology Report
Slides
Immunohistochemistry on
section of primary tumor *****
Form D2R
6
6
6
Registration
Registration
Registration
2**
3**
**
12
2
N/A
2
Form D2M***
2
Form T
2
Form Q0
2
Form Q
2
Form SP-0241-FP01
Form SP-0241-FP02
8
8
Registration
Completion of each
cycle of therapy
Clinical response
assessment
Beginning of each
subsequent cycle
Completion of study Rx
and change in Rx
Disease progression;
death; normal follow-up
Registration
Registration
*
**
Submit to SDC via postal
mail or via report uploader
2
2
2
2
N/A
N/A
quarterly for 2 years, semiannually for 3 more years
Online (SEDES)
Online (SEDES)
The number of required copies including the original form which must be sent to the Statistical and Data Center.
At least one representative H&E stained slide(s) documenting the primary site, cell type and Stage of disease. For
recurrent or persistent disease submit Form F, Pathology Report, and slides only if histologically documented.
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GOG-0241
***
The original form is retained in the clinic and data is appended to this form each time the disease is reassessed. Three
copies of the form are submitted to the Statistical and Data Center at baseline and each time clinical response is
evaluated.
**** This form is only used in studies with measurable disease along with DR form or in studies where the C form is
being used.
***** In addition to the surgical pathology report and representative H&E stained slides, immunohistochemistry must be
performed upon a section of the primary tumor with antibodies directed against CK7, CK 20, and CDX2, and the
slides provided for review. (See Section 7.2)
This study will be monitored by the Abbreviated/Complete Clinical Data System (CDUS) Version
3.0. CDUS data will be submitted quarterly to CTEP by electronic means.
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GOG-0241
STATISTICAL CONSIDERATIONS
11.1
Design Summary
This is a randomized, 2x2 factorial (four-arm) Phase III clinical trial in patients with a
histologic diagnosis of mucinous adenocarcinoma of the ovary or the fallopian tube
with either optimal (≤ 1 cm residual disease) or suboptimal residual disease following
initial surgery.
The data from this trial will be combined with, and analyzed with, data from the
mEOC-1 trial being run by Cancer Research UK: “A multicentre randomized trial
comparing oxaliplatin + capecitabine versus carboplatin + paclitaxel in patients with
previously untreated mucinous ovarian (mEOC) cancer.” All analyses will be based on
the data from the combined GOG and GCIG trials.
All patients (including both U.S. and non-U.S. patients) will be registered centrally at
the GOG Statistical and Data Center. Prior to registration, eligibility will be reviewed
via Fast Fact Sheet verification. All reports will include a complete accounting of all
patients registered to this protocol.
Patients will be randomized in a 1:1:1:1 ratio to receive one of the following treatment
arms:
 Carboplatin + Paclitaxel
 Oxaliplatin + Capecitabine
 Carboplatin + Paclitaxel with Bevacizumab
 Oxaliplatin + Capecitabine with Bevacizumab
The randomization will be stratified using using minimization, using the folllowing
stratification factors:
1. Disease status:
(i) No gross residual disease (i.e. residual disease = 0)
(ii) Residual disease = >0
2. Stage:
(i) Recurrent stage I disease (chemonaϊve)
(ii) Not recurrent - stages II – IV
3. Country
The assigned study regimen will not be revealed until after the patient has been
successfully registered onto the study. All reports will include an accounting of all
patients registered onto the study, regardless of their eligibility status or compliance to
the assigned treatment.
11.2
Principal Parameters
The principle parameters employed to evaluate the primary, secondary, and translational
research objectives are:
11.21 Primary efficacy endpoint: overall survival
11.22 Secondary endpoints:
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11.221
Efficacy: progression-free survival and response rate
11.222
Safety: frequency and severity of adverse effects as assessed with CTC
AE version 3.0
11.223
Quality of life: FACT-O TOI and FACT-GOG/NTX4
11.23 Translational Research Endpoints: IgM and IgG antibody titers by ELISA to
antigens Tn-MUC1-32mer, GM2, Globo-H, TF, sTN, and Tn
11.3
Accrual Goal, Accrual Rate, and Study Duration
The primary endpoint of trial is overall survival. The expected median survival in this
patient population given carboplatin plus paclitaxel is about 12 months. The GCIG trial
aims to detect increases in median survival of at least 5 months, from 12 to 17 months
(or a hazard ratio of 0.71) for both capecitabine plus oxaliplatin versus carboplatin plus
paclitaxel and for bevacizumab versus no bevacizumab. This treatment effect would be
considered clinically worthwhile. We assume constant hazard ratios for each treatment
effect, which would mean multiplicative effects and thus no interaction on the hazard
ratio scale. Based on a recruitment period of 5 years and a follow-up period of 18
months after the end of recruitment, the GCIG trial requires 300 patients in the study in
order to give the study 80% power for each main comparison. Allowing for a 10% dropout rate, the trial aims to recruit 332 in total. Two-sided tests with α=0.05 will be used.
Table 11.1 shows the expected median survival in each treatment arm assuming a
hazard ratio for 0.71 for each treatment main effect and assuming no interaction.
Table 11.1: Expected Median Survival Time (months) by Treatment Group
Carboplatin
plus paclitaxel
Capecitabine
plus
oxaliplatin
No bevacizumab
12
17
Bevacizumab
17
24
Note: assuming a hazard ratio for 0.71 for each treatment
main effect and no interaction.
The GCIG protocol is projected to enroll the 332 patients in 5 years. In the GOG
portion of the study, the projected accrual is 12 patients per year or a total of 60 patients
across five years of accrual. This is based on the following: GOG-0182 accrued 59
patients who were classified as having mucinous cell type over a period of 43 months.
Of these, 17 were excluded for the following reasons: second primary (5), wrong cell
type (3), wrong primary (7), and inadequate pathology (2). Some of the excluded
patients in GOG-0182 could have been eligible for this study, boosting the expected
accrual rate. However, the rate of accrual to GOG-0182 was very high, so a comparable
accrual rate for this study may be considered optimistic. Therefore, the projected
accrual rate for this study is 12 patients per year.
-6011.4
GOG-0241
Design and Analyses for the Primary Objective
The primary outcome of overall survival will be examined using Kaplan-Meier curves,
and comparisons between each set of two arms (‘oxaliplatin + capecitabine’ vs.
‘carboplatin + paclitaxel,’ and ‘bevacizumab’ vs. ‘no bevacizumab’) will be based on
the logrank test and the hazard ratio (with 95% CI). The median survival time (with
95% CI) will also be calculated for each group. A stratified log rank test could be
performed, based on the randomization strata and the other treatment randomization.
For example, bevacizumab analysis will be stratified by residual disease, recurrent vs.
non-recurrent and chemotherapy regimen. Cox regression will be used to assess the
effects of the randomization strata (disease status and stage) and other prospectively
defined risk factors on these two outcomes (such as age), and any interactions with the
treatment group. The main effect size will be quantified by the hazard ratio and 95% CI.
Multivariate regression will also be used to examine whether there is an interaction
between oxaliplatin + capecitabine and bevacizumab.
The power to evaluate interactions in the study is limited. Assuming the overall main
effect hazard ratio of 0.71 is maintained with the underlying median survival times of
12 and 17 months in the treatment arms of interest (e.g., capecitabine plus oxaliplatin
and carboplatin plus paclitaxel), Table 11.2 shows the resulting power for a variety of
interactions.
Table 11.2: Power to Detect Specified Interactions
Factor Level†
Power to Detect
Specified
Interaction
–
+
Ratio of
Hazard Ratios
0.91
0.49
2.02
80%
0.89
0.51
1.75
73%
0.83
0.55
1.50
49%
† Factor levels could be, e.g., bevacizumab vs. no
bevacizumab, or KRAS mutation (yes or no).
Note: based on two-tailed test of interaction with α=0.10.
To further help judge which treatment is best, methods for survival endpoints in
factorial trials could be used, e.g., see Green S.(2006).56
All analyses will be performed on an intention-to-treat basis.
11.5
Interim Analysis
A futility analysis will be performed after a third of the patients have been entered
(n=110) and followed up for six months. Recruitment to the trial will continue during
the 6-month follow-up. This will determine whether either of the experimental arms are
unlikely to be associated with an improvement in survival. Formal futility rules will be
developed in partnership with the Independent Data Monitoring Committee (IDMC)
prior to reviewing the data. Methods like those described by Whitehead et al57 and
statistical software such as PEST 4 (Reading University) can be used to estimate the
probability of observing a hazard ratio of 0.71 or lower, if the trial continued to the end
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GOG-0241
but given the data up to that point in time. A low probability of less than 10% could be
used in support of stopping early.
Because futility analyses are based on several assumptions and are, in effect, a forecast
of data in the future, the futility analysis of overall survival alone will not be used to
determine whether the trial stops early. We will also examine other outcome measures
such as response rates and time to progression. This information, together with data on
toxicity, will be used by the IDMC to decide whether oxaliplatin and capecitabine, or
bevacizumab, is so ineffective that the trial or part of the trial (i.e. one of the
randomizations) should discontinue.
The interim analyses will also be used to examine whether there is likely to be an
interaction between bevacizumab and chemotherapy regimen (carboplatin + paclitaxel
vs. oxaliplatin + capecitabine), e.g. the survival using both regimens is greater than that
expected by adding the survival when each regimen is used on its own. If there is
evidence of an interaction (to be examined by the IDMC), the target sample size could
be increased to increase the statistical power to examine it. In the absence of any current
evidence on this, it is not possible to estimate how many more patients would be
recruited, it may, for example, be 50-75 more in the bevacizumab arm.
As part of ongoing quality assurance, investigators will assess what proportion of
patients enrolled actually have mucinous ovarian cancer. At an interim analysis this data
will be used to determine whether the sample size is appropriate and the study remains
feasible.
After the interim analysis has been conducted, if either comparison (ie bevacizumab vs.
no bevacizumab, or carboplatin + paclitaxel vs oxaliplatin + capecitabine) is judged to
be futile, that particular randomization will cease, and the trial would continue for the
other randomization, i.e. as a two-arm study.
11.6
Trial Monitoring
The data will be reviewed (approximately annually) by an Independent Data Monitoring
Committee (IDMC), consisting of at least two clinicians not entering patients into the
trial and an independent statistician. The IDMC will be asked to recommend whether
the accumulated data from the trial, together with results from other relevant trials,
justifies continuing recruitment of further patients. A decision to discontinue
recruitment, in all patients or in selected subgroups will be made only if the result is
likely to convince a broad range of clinicians including participants in the trial and the
general clinical community. If a decision is made to continue, the IDMC will advise on
the frequency of future reviews of the data on the basis of accrual and event rates. The
IDMC will make confidential recommendations to the trial steering committee (TSC).
The role of the TSC is to act on behalf of the funder, to provide overall supervision for
the trial, to ensure that it is conducted in accordance with ICH GCP, and to provide
advice through its independent Chairman. This independent committee will review the
recommendations from the IDMC and will decide on continuing or stopping the trial, or
modifying the protocol.
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GOG-0241
The GOG Data Safety and Monitoring Board (GOG-DSMB) reviews accumulating
summaries of toxicities and all serious adverse event (SAE) reports on an ongoing basis
(not efficacy results). This committee also reviews those deaths in which study
treatment may have been a contributing cause. The GOG-DSMB reports to the GOG
Data Monitoring Committee (GOG-DMC) and it may recommend study amendments
pertaining to patient safety. Data sheets from patients on this protocol will be reviewed
before each semi-annual meeting and will also be reviewed by the Study Chairperson in
conjunction with the Statistical and Data Center. In some instances, because of
unexpectedly severe toxicity, the Statistical and Data Center may elect, after
consultation with the Study Chairperson and the Medical Oncology Committee, to
recommend early suspension of a study.
The frequency and severity of all toxicities are tabulated from submitted case report
forms and summarized for review by the study chairperson, Ovarian Committee, and
GOG-DSMB in conjunction with each semi-annual GOG meeting. For studies
sponsored by the Cancer Therapy Evaluation Program (CTEP) of the National Cancer
Institute (NCI), standardized toxicity reports are also submitted to the drug and disease
monitors at the Investigational Drug Branch (IDB) and Clinical Investigation Branch
(CIB).
11.7
Analyses for Secondary Objectives
PFS will analyzed using the same methods described above the analysis of overall
survival.
The comparison of response rates (proportion of patients with complete and partial
response, stable and progressive disease) between treatment groups, will use a chisquare test. The difference in response rates between the groups and the odds ratio
(with corresponding 95% C.I.s) will also be calculated.
Toxicity grades will be tabulated showing the maximum toxicity grade experienced by
each patient. The proportions of patients experiencing a maximum grade of 3 or above
will be compared between the treatment groups.
Analysis of the QOL data will use the observed scores at each time point, where
available. For simplicity, we will examine the change from baseline to each of time
points specified in section 6.2 and 6.3. However, the main analysis will be a repeated
measures analysis (for example, based on a mixed model, Proc Mixed in SAS) used to
simultaneously compare all QOL scores between the two treatment groups. This method
allows for (i) that each patient provides several QOL scores, (ii) that scores withinpatients are likely to be correlated, and (iii) that QOL scores between proximate visits
are likely to be more correlated than separated visits.
All tests for exploratory and translational research objectives will be done using onesided tests with α=0.05. All analyses will be performed on an intention-to-treat basis.
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GOG-0241
Analyses for Exploratory and Translational Research Objectives
The numbers and percentages of patients with expression of VEGF and EGF ligand,
receptor, and activated receptor will be tabulated, as will the number and percentage of
patients with mutations in the KRAS oncogene. Interactions between the mutational
status of the KRAS oncogene and treatment will be examined. The power to test these
interactions are addressed above in section 11.4.
11.9
Anticipated Gender and Minority Inclusion
This study restricts entry to women by nature of the site of the disease. The table below
lists the projected percentages in the GOG portion of the study of patients by race
(based on GOG protocol 0182). There are no data that support differences in the
intervention effects between racial/ethnic subgroups; therefore, the study design does
not involve race. However, subsets defined by white and non-white will be analyzed in
this study to investigate this important question with the current therapies. The trial is
registered at clinicaltrials.gov, and all patients who meet eligibility criteria are invited to
participate.
2% Asian
7% Black
2% Other (e.g., American Indian/Alaskan Native)
89% White
100% Total
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12.0
BIBLIOGRAPHY
1.
McGuire V, Jesser CA, Whittemore AS. Survival among U.S. women with invasive epithelial
ovarian cancer. Gynecol Oncol 2002;84:399-403.
2.
Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2006. CA Cancer J Clin 2006 MarApr;56:106-130.
3.
Sherman ME, Mink PJ, Curtis R, et al. Survival among women with borderline ovarian tumors
and ovarian carcinoma: a population-based analysis. Cancer 2004;100:1045-1052.
4.
Hess V, A'Hern R, Nasiri N, et al. Mucinous epithelial ovarian cancer: a separate entity
requiring specific treatment. J Clin Oncol 2004;22:1040-1044.
5.
Marquez RT, Baggerly KA, Patterson AP, et al. Patterns of Gene expression in different
histotypes of epithelial ovarian cancer correlate with those in normal fallopian tube,
endometrium, and colon. Clin Cancer Res 2005; 11 (17): 6116-6216.
6.
Gemignani ML, Schlaerth AC, Bogomolniy F, et al. Role of KRAS and BRAF gene mutations
in mucinous ovarian carcinoma. Gynecol Oncol 2003;90:378-381.
7.
Boguski, M. S., and McCormick, F. (1993) Science 366, 643-654
8.
Williams AC, Browne SJ, Yeudal WA, et al. Molecular events including p53 and k-ras
alterations in the in vitro progression of a human colorectal adenoma cell line to an
adenocarcinoma. Oncogene 1993;8:3063-3072.
9.
Muggia FM, Braly PS, Brady MF, et al. Phase III randomized study of cisplatin versus
paclitaxel versus cisplatin and paclitaxel in patients with suboptimal stage III or IV ovarian
cancer: a Gynecologic Oncology Group study. J Clin Oncol 2000;18:106-115.
10.
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