PHASE I, II, or I/II
LETTER OF INTENT
Submission Form v2.0
National Cancer Institute
Division of Cancer Treatment and Diagnosis
Cancer Therapy Evaluation Program
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Lead
Group/Institution:
Southeast East Phase 2 Consortium
Emory University, Winship Cancer Institute
Lead
Institution/Group
CTEP ID:1
Other
Institutions/Groups on
study:
H Lee Moffitt Cancer Center /FL065
Emory University Winship Cancer Institute
Vanderbilt-Ingram University
University of North Carolina
Virginia Commonwealth University
Title of LOI:
Agent(s) supplied by
NCI:1
Commercial Agents
in Study:
A Phase I Study of ABT-263 in Combination with Topotecan
ABT-263
Topotecan
Tumor Type: [X] Solid Tumor
(Click within the [[ ]] [[ ]] Hematologic Malignancy (NOS)
and type ‘x’ to
indicate the tumor [[ ]] Disease-Specific
type)
Disease-Specific:1 1. Small Cell Lung Cancer 10041071
(Specify the Name 2. Ovarian Cancer, NOS 10033272
and Code of the
Study Disease)
Performance Status:
Abnormal Organ
Function Permitted?
Prior Therapy:
Phase of Study:
Treatment Plan:
1
ECOG 0-2
No
Prior Therapy Allowed
I
Primary Objectives:
1. To determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT),
and recommended phase II doses (RP2D) of ABT-263 and topotecan in patients with
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
Page 1 of 13
advanced solid organ malignancies.
2. To establish preliminary evidence of improved efficacy in an expanded cohort of
patients with ovarian cancer treated at the P2RD
Secondary Objectives:
1. To evaluate pharmacokinetics (PK) of ABT-263 and topotecan in order to identify
potential drug-drug interactions and correlate PK parameters with toxicity profile and
response.
2. Perform correlative analysis of the relationship between the expression of prosurvival (Bcl-2, Bcl-XL, Mcl-1 and Bcl-w), and proapoptotic (Noxa, Puma, Bim and
Bad) Bcl-2 proteins and tumor response using archival diagnostic tissue.
Design: Patients with advanced malignancies for which topotecan treatment is
appropriate will be enrolled and treated in cohorts of three patients per dose level.
Escalation of ABT-263 and topotecan will proceed in a modified Fibonacci 3+3
fashion with the requirement that dose escalation to the next level can only proceed if
0 of 3 or 1 of 6 patients experience a dose limiting toxicity (DLT). ABT-263 will be
administered orally starting at 150mg daily days 1-5 as recommended in combination
with cytotoxic agents. Topotecan will be administered concurrently on days 1-5 at a
starting dose of 1 mg/m2/day for 5 days. We plan to evaluate six dose cohorts starting
at dose level 1 with the provision to de-escalate 1 level should DLT be encountered
at the starting dose level as detailed in the table below. The RP2D will be defined as
the highest dose level at which < 33% of the dose cohort (0 of 3 or 1 of 6)
experiences DLT after 1 cycle.
Table 1
Dose Level
-1
Starting
Level 1
2
3
4
5
6
ABT-263 po daily,
Days 1-5
150 mg
150 mg
Topotecan iv daily
Days 1- 5
0.75 mg/m2
1 mg/m2
150 mg
150 mg
200 mg
250 mg
300 mg
1.25 mg/m2
1.5 mg/m2
1.5 mg/m2
1.5 mg/m2
1.5 mg/m2
Patients: Based on the dose escalation scheme outlined, a maximum of 36 patients
will be enrolled for the dose escalation if the MTD is the maximum planned dose and
if each cohort required six patients to be treated. An expansion cohort of 15 patients
will be treated at the RP2D to obtain additional safety information. In order to
establish preliminary evidence of improved efficacy, this cohort will be restricted to
ovarian cancer patients who are platinum refractory or who have relapsed following
frontline platinum therapy.
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
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Key inclusion criteria:
1. Histological/cytological confirmation of malignancy appropriate for treatment
with a topotecan-containing regimen
2. Progression following prior standard therapy
3. ECOG PS 0, 1 or 2
4. Adequate renal, hepatic and bone marrow function (Hemoglobin > 10; WBC >
4000/mm3 or ANC > 1500/mm3; notably platelets > 150,000/mm3), renal (CrCl
> 60 mL/min) and hepatic function < 1.5 x ULN
5. Archival tumor biopsy specimen (mandatory for the expansion cohort)
Key exclusion criteria:
1. Prior topotecan or ABT-263 treatment
2. Untreated or symptomatic brain metastasis
3. Inability to take oral medications on a regular basis
4. Severe intercurrent illness
Duration of Intervention and Evaluation:
Subjects will be treated until disease progression, withdrawal of consent or intolerable
adverse events.
Subjects will be evaluated for disease status at screening and after every 2 cycles, or
as clinically indicated.
Patients suffering a DLT will be treated off-study according to standard of care for
their stage of disease.
Assessment and Definition of DLT: Toxicity will be assessed by NCI Common
Terminology Criteria for Adverse Events (CTCAE) version 4.0. DLT will be assessed
during cycle 1 of therapy only. Response will be assessed by imaging studies after
every 2 completed cycles of therapy.
Rationale/Hypothesis:
1
The following will constitute DLT: Grade 4 neutropenia lasting more than 7
days; Grade 3/4 neutropenia of any duration with fever; Grade ≥3 nausea and or
vomiting in spite of standard supportive therapy; Grade ≥3 non-hematologic toxicity;
Inability to re-treat patient within 2 weeks of scheduled treatment due to a treatmentrelated event. Changes in laboratory parameters will be considered DLT only if
deemed to be related to therapy.
Topotecan is a camptothecin derivative that potently inhibits the topoisomerase I
enzyme. By stabilizing the covalent enzyme-DNA intermediate, topotecan promotes
persistent DNA torsional stress, resulting in DNA damage and cell death. Preclinical
work showed that cell death induced by topotecan is closely related to changes in a
proapoptotic Bcl-2 protein family member, Bcl2L12.1 Irinotecan, another
topoisomerase inhibitor, showed synergistic interaction with ABT-737, a Bcl-2
targeted compound (figure 1 below).2 This synergy correlates with the dissociation of
proapoptotic BH3 molecules and induction of Noxa, a potent negative regulator of
Mcl-1.
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
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Figure 1: ABT-737 and the topoisomerase I inhibitor irinotecan showed enhanced cytotoxicity in
human colorectal cancer cell lines. Isobologram showing CI < 1 indicates synergy.2
Figure 2: ABT-737 treatment unsequestered Bim from its complex with Bcl-xL or Bcl-2 in HCT116
cells compared with control-treated
cells (A). Bim displaced from its
complex with Bcl-xL in HT-29 cells
that lack endogenous Bcl-2 (B) while
ABT-737 induce Mcl-1 expression
and Bim/Mcl-1 complexes in both cell
lines (A and B) and displaced Bim
and Bak from their complex with Mcl1, Bcl-xL/Bcl-2 or Bcl-xL.2
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
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Figure 3: ABT-737 plus CPT-11 induced apoptosis to a greater extent than did either drug alone in
two colorectal cell lines (Fig. A-C ). Greater apoptosis induced in HCT116 versus HT-29 cells, in part
because of the lower levels of endogenous Mcl-1 and higher levels of Bcl-2 in HCT116 cells (Fig. D).2
Topotecan has clinical activity and is approved for the treatment of relapsed small cell
lung cancer based on comparable activity but better toxicity profile over multi-agent
chemotherapy.3 It also has demonstrable efficacy and is an approved agent as
salvage therapy for ovarian cancer after initial platinum therapy.4,5
Abnormalities in the Bcl-2 family of proteins have been described in SCLC and may
play a key role in the refractoriness of this disease to conventional therapy.6-8
Similarly, immunohistochemical studies showed very high level of expression of Bcl-2
in high grade epithelial ovarian cancer relative to low grade lesions.9 Further, Bax and
Bcl-2 expression correlate with disease free survival and chemosensitivity in ovarian
cancer patients treated with frontline platinum containing regimen. It is reasonable to
expect that recalibrating the balance between the pro-apoptotic and anti-apoptotic
members of the Bcl-2 family (Figure 4) using agents that selectively target the
antiapoptotic components will result in improved chemosensitivity and efficacy. 10-13
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
Page 5 of 13
Figure 4: Bcl-2 protein family and regulation of cancer cell survival
A previous attempt to target the Bcl-2 protein using antisense oligonucleotide
technology was not effective probably due to incomplete abrogation of Bcl-2 mRNA
translation as measured in peripheral mononuclear cells.14 Equally important for
cytotoxicity induced by BH3-mimetic inhibitors is the need to abrogate the prosurvival
action of Mcl-1, a Bcl-2 family member that is under stronger regulatory control of
Noxa than of any other BH3-molecules. The ability of a topoisomerase I inhibitor,
irinotecan, to induce the expression of Noxa provides a strong rationale to combine
topoisomerase I inhibitors with agents targeting the Bcl-2 protein family.
ABT-737 and ABT-263 represent 1st and 2nd generation compounds, respectively,
that target the BH-3 pocket of the Bcl-2 family protein members. Both have single
agent activity in solid tumors such as SCLC.15,16 ABT-263 has improved
pharmacological properties over ABT-737 making it better suited for clinical
development. It is an orally available agent with high nanomolar affinity for the BH-3
region of the pro-survival Bcl-2 family members including Bcl-XL, Bcl-w and Bcl-2. In
in vivo experiments, ABT-263 completely suppressed Bcl-2 expression in xenograft
tumor tissue at 100mg/kg dose with associated tumor regression including complete
regression. This dose was 3-fold less than the tolerable dose tested in mice.16
Preclinical work showed considerable synergy when ABT-737 was combined with
topoisomerase inhibitors such as etoposide and irinotecan leading to increased
apoptosis2,15 and greater tumor volume reduction in vivo.15 In addition, ABT-737 and
ABT-263 both displayed potent in vivo activity against xenograft derived from
paclitaxel-resistant breast cancer and SCLC cell lines irrespective of the level of
expression of pgp-1 efflux pump expression.16,17
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
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Figure 5: Irinotecan markedly induced Noxa expression in HCT116 (wild-type p53) but not HT-29
(mutated p53) cells with associated up-regulation of Bax compared with vehicle-only treated cells (A).
Irinotecan treatment enhance the interaction between Mcl-1 and Noxa (B) leading the release of Bak
from its interaction with Mcl-1 (B).
Based on the foregoing preclinical and clinical data, we propose to conduct a phase I
evaluation of the combination of ABT-263 and topotecan in patients with advanced
solid malignancies. We hypothesize that this combination will be well tolerated
without any exacerbation of the well-characterized and manageable toxicities
associated with topotecan. This combination will result in improved therapeutic
efficacy in appropriately selected patient populations such as those with relapsed
ovarian cancer and SCLC.
We hypothesize that:
I. The addition of ABT-263 will enhance the anti-cancer effects of topotecan in
patients with solid malignancies.
II. Pretreatment tumor expression of proapoptotic and antiapoptotic members of
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
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the Bcl-2 family of proteins (Bcl-2, Bcl-XL, Bim and Bcl-w) in archival
diagnostic biopsy specimens will correlate with response rate.
Laboratory
Correlates:
PK Analysis:
Blood will be drawn at the following time points for PK analysis of ABT-263 and
topotecan:
Cycle 1, day 1: 30 min before ABT-263 ingestion, and prior to topotecan infusion;
then at 15 minutes, 45 minutes, 2, 3, 4, 6, 8, and 24 h post drug administration. We
anticipate that ABT-263 PK analysis will be performed through a CTEP-designated
central laboratory. We plan to have all PK samples analyzed at such facility using a
validated standard operating procedure for PK sample collection, handling, storage
and shipping as currently obtained with other multicenter trials at our center (please
see appendix A). In the event that no lab is designated by CTEP for ABT-263, we
plan to work with the sponsor to develop the appropriate analytical method for the PK
samples. The analytical method for topotecan PK has been published previously and
will be performed at Emory.18
Pharmacodynamic Correlates:
1. BCL-2 pathway proteins expression by immunohistochemistry (IHC):
We plan to use the available expertise within the Winship Cancer Institute Pathology
Core facility to produce the IHC stained slides. Evaluation of the slides and scoring
for level of expression of the proteins of interest will be performed with our
collaborator in the department of pathology, Dr. Anthony Gal.
Funding for the proposed correlative studies will come from an unrestricted research
grant to the PI (Taofeek Owonikoko, MD, PhD) through the Georgia Cancer Coalition
Distinguished Clinician Scientist Award program. This award is worth $ 50,000 per
year over 5 years. Funding for pharmacokinetic evaluations up to $50,000.00 will be
made available from the research budget of the Emory Winship phase I clinical trial
program (R. Donald Harvey, PharmD).
Endpoints/Statistical
Considerations:
The frequency of all toxicities will be tabulated by grade for each dose cohort.
Descriptive statistics and graphic displays will be presented to characterize each
dose cohort in terms of disease features and for the PK and PD correlative endpoints.
Mean expression level of Bcl-2 pathway proteins will be assessed by semiquantitative
immunoscore in archival tissue. Correlation between immunoscore the administered
dose of ABT-263 and tumor response will be evaluated using Spearman correlation
coefficients and exact Chi-square tests. Due to the limited sample size and the phase
I clinical trial design, the results of these analysis will be deemed exploratory at this
time.
The expansion cohort:
Based on contemporary phase III evaluation of topotecan in ovarian cancer patients
previously treated with a platinum agent or a taxane, topotecan achieved a 27%
objective response rate.19 Assuming a doubling of the response rate to 54% when
topotecan is combined with ABT-263, 15 patients treated at the RP2D will have 70%
power to detect a 100% improvement in response rate at a one-sided alpha error rate
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
Page 8 of 13
of 0.05. Such a sample size will have 85% of truly calling an effective regimen and a
5% chance of accepting an ineffective regimen.
Estimated Monthly
Accrual:
2-3 per month
Proposed Sample
Size:
Minimum: 18 Maximum: 45
In the year ending December 31st 2008, a total of 159 patients were enrolled on
phase I clinical trials at the Winship Cancer Institute. This represents a 53% increase
in our enrolment over 2007. Of these patients, 45 were enrolled in broad, nondisease specific phase I clinical trials. We currently have 4 open phase I studies at
Emory University for patients with solid organ malignancies, of which 2 would be
completed by the time this study is ready for activation. The abundance of patients
referred to our phase I program and the long waiting list of patients available for phase
I studies will allow for timely and rapid accrual to multiple studies at any given time.
The Winship Cancer Institute has an active gynecology oncology clinic, staffed by three
full time medical oncologists with a large patient referral base. There is currently no
active clinical trials for patient with platinum refractory ovarian cancer at our center.
One of the physicians from the gynecology oncology team, Dr. Joan Cain is a coinvestigator on this application. We therefore anticipate that accrual to the expansion
phase of the study will proceed quickly.
Earliest date the
study can begin:
Projected Accrual
Dates:
(Month/Year format)
12/01/2009
Start:
01/ 01/ 2010
End:
12/31/2012
To document accrual
rate, list trials with
patients who had
similar Tumor
Type/Phase of
Study/Prior Therapy:
If more than one trial is similar, copy and paste the row below to the end of the form,
then add the additional study information.
Protocol Number / Title
/ Sponsor :
X05226 / Phase IB Dose Escalation Study of Bortezomib (VELCADE) Administered
Weekly for 4 Weeks and Sunitinib (SU-011248) Administered Daily for 4 Weeks
Followed by a 14 Day Rest in Patients with Refractory Solid Tumors / Institutional-IIT
/ March 2008 - September 2009/ 33 patients; trial based on adaptive design and we
are currently testing the last dose cohort
Trial Activation / Trial
Completion Dates:
No. of Patients
Enrolled:*
NCI 8063/ A Phase 1 and Pharmacokinetic Single Agent Study of Pazopanib in
Patients with Advanced Malignancies and Varying Degrees of Liver Dysfunction/
October 2008 – September 2009/ 2
NCI7967/ A Phase I Study of ABT-888 in Combination with Carboplatin and
Paclitaxel in Advanced Solid Malignancies/ March 2008 – September 2009/ 9
NCI8057 / Phase I and Pharmacokinetic Study of Vorinostat for Solid Tumors and
Lymphomas in Patients with Varying Degrees of Hepatic Dysfunction / 5
List all Active, If more than one trial is similar, copy and paste the row below to the end of the form, then add the additional study
Approved, or In Review information.
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
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31-LOI Submission Form
Revised 12/01/2008
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studies at your
institution for which this
patient population will
be eligible:
Protocol Number / [Click and enter Number] / [Click and enter Title] / [Click and enter Sponsor]
Title / Sponsor: (Include NCI Number if NCI-sponsored)
[Click and enter Activation Date] / [Click and enter Anticipated Completion Date]
Trial Activation Date /
Anticipated Completion
[Click and enter Patients Enrolled] /
Date:
[Click and enter enrollment start date] to [Click and enter enrollment end date] /
No. of Patients [Click and enter the number of months of enrollment] / [Click and enter Planned Enrollment]
Enrolled to Date / (*Only include patients enrolled at site(s) relevant to LOI proposal)
Patient Enrollment
Period /
Duration of Patient
Enrollment /
Total planned Patient
Enrollment:*
Is this LOI part of an
NIH Grant, Cooperative
Agreement or
Contract?
Y
If yes, provide the [Click and enter Award Number]
Award Number:
Will this study receive
support from non-NCI
sources (i.e., industry,
ACS)?
If the proposed trial
includes correlative
studies, CTEP
assumes funding is
available to support
them.
If yes, is it Grant
funding?
If yes, provide the
Grant Number:
Is this a Career
Development LOI?
If yes, please attach
and check off the
following:
N
YES
Y
Account 6-39419, GCC Distinguished Cancer Clinician
Y
Further information and instructions regarding the submission of a Career Development LOI may be found at
http://ctep.cancer.gov/protocolDevelopment/letter_of_intent.htm#instructions
PI curriculum vitae [X]
Institutional letter of commitment [X]
Mentor letter of commitment [X]
The Investigational Drug Steering Committee (IDSC) is designed to provide NCI with broad external scientific and clinical input for the
design and prioritization of phase I and phase II trials with agents for which CTEP holds an IND.
Membership of the IDSC includes the Principal Investigators of phase I U01 grants and phase II N01 contracts, representatives from the
NCI Cooperative Groups, NCI staff members, and additional representatives with expertise in biostatistics, correlative science
technologies, radiation oncology, etc., as well as patient advocates and community oncologists, as needed. Experts with specific expertise
will be included as ad hoc members for consideration of specific agents. The current membership list may be found at
http://ccct.nci.nih.gov/steering-committees/idsc
Periodically the IDSC will assess LOIs from a strategic perspective to determine whether the Clinical Development Plan for an agent
should be modified. When requested by CTEP, the IDSC will provide input on LOIs to assist in CTEP decision-making. Information in an
LOI assessed by IDSC is kept confidential and members with potential conflict of interest are recused from participating in the LOI
assessment. The IDSC strategic assessment is not part of the CTEP LOI review process and will not affect LOI review timelines.
For unsolicited LOIs only: Please check one of the following options (Note: While selecting an option is required, neither choice will affect
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
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31-LOI Submission Form
Revised 12/01/2008
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the outcome of the CTEP review of this LOI):
This LOI may
/may not
Principal Investigator
(PI) Name:
be looked at by the IDSC.
Taofeek K. Owonikoko, MD, PhD
PI Signature:
PI Street Address:
Date:
1/13/09
Room C4094
1365C Clifton Road, NE
Atlanta, GA 30322
PI Phone:
404-778-5575
PI Fax:
404-778-5230
PI E-mail:
Group
Chair/Cooperative
Agreement-PI
(GCCA-PI) Name:
towonik@emory.edu
Dan Sullivan, MD
GCCA-PI Signature:
GCCA-PI Address:
Date:
[Click and enter Room/Suite/Dept.]
[Click and enter Street Adress]
[Click and enter City, State, Postal Code]
GCCA-PI Phone: [Click and enter Phone No.]
GCCA-PI Fax: [Click and enter Fax No.]
GCCA-PI E-mail: Dan.Sullivan@moffitt.org
Non Group Grant-PI [Click and enter Name]
Name:
Non Group Grant-PI
Signature:
Date:
Non Group Grant-PI [Click and enter Room/Suite/Dept.]
Address:
[Click and enter Street Adress]
[Click and enter City, State, Postal Code]
Non Group Grant-PI [Click and enter Phone No.]
Phone:
Non Group Grant-PI [Click and enter Fax No.]
Fax:
Non Group Grant-PI [Click and enter E-mail Address]
E-mail:
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
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31-LOI Submission Form
Revised 12/01/2008
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Please submit Letter of Intent forms (LOIs) to the Protocol and Information Office (PIO) via e-mail at:
pio@ctep.nci.nih.gov, Attention: LOI Coordinator
Notes:
LOIs from Cooperative Group must be submitted through the Group Operations.
Proposals for trials to be conducted under a Cooperative Agreement must include complete contact information for the
Principal Investigator and Protocol Chair.
Questions? Please call LOI Coordinator at (301) 496-1367.
1
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31-LOI Submission Form
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Reference:
1.
Floros KV, Talieri M, Scorilas A: Topotecan and methotrexate alter expression of the
apoptosis-related genes BCL2, FAS and BCL2L12 in leukemic HL-60 cells. Biological Chemistry
387:1629-1633, 2006
2.
Okumura K, Huang S, Sinicrope FA: Induction of Noxa sensitizes human colorectal
cancer cells expressing Mcl-1 to the small-molecule Bcl-2/Bcl-xL inhibitor, ABT-737. Clin Cancer
Res 14:8132-42, 2008
3.
von Pawel J, Schiller JH, Shepherd FA, et al: Topotecan versus cyclophosphamide,
doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol 17:65867, 1999
4.
Eckardt JR: Emerging role of weekly topotecan in recurrent small cell lung cancer.
Oncologist 9 Suppl 6:25-32, 2004
5.
Vandenput I, Amant F, Neven P, et al: Effectiveness of weekly topotecan in patients
with recurrent epithelial ovarian cancer. Int J Gynecol Cancer 17:83-7, 2007
6.
Ben-Ezra JM, Kornstein MJ, Grimes MM, et al: Small cell carcinomas of the lung
express the Bcl-2 protein. Am J Pathol 145:1036-40, 1994
7.
Kim YH, Girard L, Giacomini CP, et al: Combined microarray analysis of small cell
lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene
amplification. Oncogene 25:130-8, 2006
8.
Olejniczak ET, Van Sant C, Anderson MG, et al: Integrative genomic analysis of smallcell lung carcinoma reveals correlates of sensitivity to bcl-2 antagonists and uncovers novel
chromosomal gains. Mol Cancer Res 5:331-9, 2007
9.
O'Neill CJ, Deavers MT, Malpica A, et al: An immunohistochemical comparison
between low-grade and high-grade ovarian serous carcinomas: significantly higher expression of p53,
MIB1, BCL2, HER-2/neu, and C-KIT in high-grade neoplasms. Am J Surg Pathol 29:1034-41, 2005
10.
Certo M, Del Gaizo Moore V, Nishino M, et al: Mitochondria primed by death signals
determine cellular addiction to antiapoptotic BCL-2 family members. Cancer Cell 9:351-65, 2006
11.
Kim H, Rafiuddin-Shah M, Tu HC, et al: Hierarchical regulation of mitochondriondependent apoptosis by BCL-2 subfamilies. Nat Cell Biol 8:1348-58, 2006
12.
Chen L, Willis SN, Wei A, et al: Differential targeting of prosurvival Bcl-2 proteins by
their BH3-only ligands allows complementary apoptotic function. Mol Cell 17:393-403, 2005
13.
Willis SN, Fletcher JI, Kaufmann T, et al: Apoptosis initiated when BH3 ligands engage
multiple Bcl-2 homologs, not Bax or Bak. Science 315:856-9, 2007
14.
Rudin CM, Kozloff M, Hoffman PC, et al: Phase I study of G3139, a bcl-2 antisense
oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J
Clin Oncol 22:1110-7, 2004
15.
Hann CL, Daniel VC, Sugar EA, et al: Therapeutic efficacy of ABT-737, a selective
inhibitor of BCL-2, in small cell lung cancer. Cancer Res 68:2321-8, 2008
16.
Shoemaker AR, Mitten MJ, Adickes J, et al: Activity of the Bcl-2 family inhibitor
ABT-263 in a panel of small cell lung cancer xenograft models. Clin Cancer Res 14:3268-77, 2008
17.
Kutuk O, Letai A: Regulation of Bcl-2 family proteins by posttranslational
modifications. Curr Mol Med 8:102-18, 2008
18.
Bai F, Kirstein MN, Hanna SK, et al: Determination of plasma topotecan and its
metabolite N-desmethyl topotecan as both lactone and total form by reversed-phase liquid
chromatography with fluorescence detection. J Chromatogr B Analyt Technol Biomed Life Sci
784:225-32, 2003
19.
Meier W, du Bois A, Reuss A, et al: Topotecan versus treosulfan, an alkylating agent, in
patients with epithelial ovarian cancer and relapse within 12 months following 1st-line
platinum/paclitaxel chemotherapy. A prospectively randomized phase III trial by the
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
31-LOI Submission Form
Revised 12/01/2008
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Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group (AGO-OVAR).
Gynecol Oncol 114:199-205, 2009
1
Detailed Institution, Group, Agent NSC, and Disease codes are available on the CTEP Home Page at
http://ctep.cancer.gov/protocolDevelopment/codes_values.htm
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