1
Phase II Trial of Temozolomide and Pegylated Liposomal
Doxorubicin in the Treatment of Patients with Glioblastoma
Multiforme following concurrent radiotherapy and
chemotherapy
1
Sumitra Ananda, 2,6Anna Nowak, 3Lawrence Cher, 4Anthony Dowling,
5
Chris Brown, 5John Simes, 1,5Mark A Rosenthal for the Cooperative
Trials Group for Neuro-Oncology (COGNO).
Departments of Medical Oncology: 1Royal Melbourne Hospital, Victoria; 2Sir Charles
Gardiner Hospital, Western Australia; 3Austin Health, Victoria; 4St Vincent’s
Hospital, Victoria; 5NHMRC Clinical Trials Centre, University of Sydney,
6
School
of Medicine and Pharmacology, University of Western Australia.
Running Title:
Temozolomide and liposomal doxorubicin in GBM
Corresponding author:
Dr Sumitra Ananda
Department of Medical Oncology
Royal Melbourne Hospital
Grattan Street
Victoria
Australia 3050
Key words:
Telephone:
+61-3-93427695
Fax:
+61-3-93477508
E-mail:
sumitra.ananda@mh.org.au
Glioblastoma, Temozolomide, Pegylated liposomal doxorubicin
2
Funding- This investigator-initiated trial was supported by an unrestricted grant from
Schering-Plough and by Cancer Australia. The study was conducted and analysed
independently of S-P and CA
3
Abstract
Introduction: Concurrent and post-radiotherapy temozolomide (T) significantly improves survival in
patient (pts) with newly diagnosed Glioblastoma Multiforme (GBM). The combination of T and PLD
can be used safely at full doses and Phase 2 data supports efficacy of this combination in recurrent
GBM. We aimed to assess the activity of this combination as part of treatment for newly diagnosed
GBM. Methods: In this study, the combination of T (200mg/m2 orally, days 1-5) and PLD (40mg/m2 iv
day 1) was given every 4 weeks for a maximum of 6 cycles following combination chemo-radiotherapy
as post-operative treatment for GBM. The primary endpoint was 6 month progression free survival
(6PFS) measured from treatment commencement using a Simon two stage approach. Results: 40
patients were enrolled: median age was 53 years and 73% were males. 6PFS was 58% (95%CI 4172%). The median time to progression was 6.2 months (range 95%CI 5.6-8.0 months) and for overall
survival (OS) was 13.4 months (95%CI 12.7-15.8 months) respectively. Of 34 patients with measurable
disease, one had a complete response (3%), 28 had stable disease (70%), 5 (12%) progressive disease
and the rest were not evaluable. Treatment was well tolerated: hematological toxicity included grade 3
neutropenia in 3 patients (8%) but no Grade 3/4 thrombocytopenia was observed. Grade 3 nonhematologic toxicity included nausea and vomiting (8%) and palmar-plantar toxicity (5%).
Conclusions: Combination T and PLD is well tolerated but does not appear to add significant clinical
benefit regarding 6PFS and OS in the treatment of newly diagnosed GBM.
Word count: 249
4
Introduction
The annual incidence of malignant gliomas is approximately five cases per 100,000 people, with more
than 14,000 new cases diagnosed annually and 13,000 deaths in the United States.1,
2, 3
The current
standard of care for suitable patients with newly diagnosed Glioblastoma Multiforme (GBM) is
maximum surgical resection followed by concurrent temozolomide and irradiation followed by six
months of temozolomide. The two and five year survival rates from initial diagnosis with this regimen
are 26.5% and 9.8% respectively; more effective treatments are needed.4, 5
Pegylated liposomal doxorubicin (PLD) is a formulation of doxorubicin in which the drug is
encapsulated in liposomes (Stealth liposomes) that can avoid uptake by the reticuloendothelial
system.6 Liposomal encapsulation may ameliorate the toxicity of doxorubicin by reducing both the
non-specific drug delivery to normal tissues and the high peak plasma levels of free drug. Once
concentrated in tumours, the liposomes of PLD may deliver high levels of doxorubicin locally,
reducing toxicity without compromising efficacy, and improving the therapeutic index.7 Liposomal
doxorubicin has been tested in preclinical glioma models and appears to have significantly improved
penetration compared with doxorubicin itself.8-10 However, there is only limited data regarding its use
in the treatment of recurrent high grade glioma. One Phase I/II study demonstrated that it is well
tolerated and a number of patients achieved stabilisation of their disease. 9
The combination of PLD and temozolomide is appealing given the documented efficacy of
temozolomide coupled with the preclinical and clinical data supporting pegylated liposomal
doxorubicin in the treatment of GBM. A phase I study of PLD and temozolomide in patients with
advanced cancer demonstrated that the regimen was well tolerated and recommended a phase II dose
of PLD 40mg/m2 day one and temozolomide 200mg/m2 days 1-5 every four weeks.11
We have previously published a phase II pilot study of temozolomide and PLD in recurrent GBM. Our
data demonstrated good tolerability, modest myelosuppression, and an objective response rate of 19%
in 22 patients.12 More striking were the high disease stabilisation rate of 50% and six month
progression free interval in 32% of patients. In view of the apparent efficacy of the combination in the
5
recurrent setting, we chose to evaluate the combination of PLD and temozolomide in the adjuvant
setting.
6
Patients and Methods
Patient Eligibility
Eligible patients were >18 years old with histologically proven GBM. All patients had completed
concurrent irradiation and temozolomide chemotherapy, and were planning to continue with adjuvant
temozolomide treatment as per current approved indications. Patients were not required to have
residual disease on a post-radiation scan.
Eligibility criteria included: Eastern Cooperative Oncology Group Performance Status (ECOG PS) 02, serum creatinine  1.5 times the upper limit of normal, total granulocyte count > 1500/l; platelet
count > 100,000/l, AST  2.5 times the upper limit of normal and total bilirubin within normal limits.
Patients must have received 60Gy in 30 fractions of conformal radiotherapy, recovered from the
toxicity and completed radiotherapy at least 3 weeks before protocol entry. Corticosteroid doses
needed to be stable for one week prior to entry and effective contraceptive measures were practiced.
Patients were excluded if they received prior adjuvant chemotherapy other than temozolomide during
whole-brain irradiation. Exclusion criteria included prior hypofractionated radiotherapy, patients with
clinical evidence of cardiac failure, pregnant or breast feeding women, patients who had not recovered
from surgery, those with severe intercurrent illnesses, exposure to other investigational agents within
four weeks and during study. Prior use of biodegradeable carmustine wafers was not permitted.
Patients must have signed an institutionally approved Committee on Human Research consent form.
Study Design
This study was a multi-institutional, prospective, open label phase II study. Patients were treated with
intravenous PLD at a dose of 40mg/m2 on day one and oral temozolomide at an initial dose of
150mg/m2 increasing to 200mg/m2 on days 1 to 5 for cycle 2 if tolerated. Doses were based on actual
body weight but capped at a body surface area of 2.0m2. Treatment commenced between three and six
weeks after completion of combined chemoradiotherapy, with a recommended start date four weeks
after completion. The start of treatment could be delayed for a maximum of six weeks after combined
treatment until adequate hematological recovery.
7
PLD was diluted in 100 ml 5% dextrose with the initial infusion being administered more slowly
because of the prior reports of acute reactions to the first dose. Five percent of the total dose was given
over 15 minutes, and if this rate was tolerated, the infusion rate was doubled. The remaining infusion
was completed over 60 minutes for a total infusion time of 90 minutes. Further courses of PLD could
be infused over an hour if no reactions occurred during the first dose. If the patient experienced an
infusion reaction, the infusion was ceased, and appropriate premedications such as an antihistamine
and/or corticosteroids were given. The infusion was then recommenced at a lower rate. Temozolomide
was administered orally on wakening in a fasting state, with all doses being rounded up to the nearest
5mg to accommodate capsule strength. Treatment with PLD and temozolomide was administered
every 28 days up to a planned total of six cycles, or until disease progression or dose-limiting toxicity
occurred.
Toxicity and dose modifications were based on National Cancer Institute Common Toxicity Criteria
version 3.0. Criteria for retreatment were an absolute neutrophil count (ANC)>1500 cells/dl, platelet
>100,000/dl, hemoglobin >10 g/dl, liver function test values <2 times the upper limit of normal,
creatinine <1.5 times the upper limit of normal, total bilirubin within normal limits, and all other
toxicity resolved to baseline or Grade one except palmar-plantar erythrodysesthesia where specific
dose delays were included in the protocol. (
Dose Modifications
The nadir ANC or platelet count on Day one was used to determine the doses of temozolomide and
PLD administered for subsequent cycles. For patients with nadir ANC of 500 to 999 cells/dl and nadir
platelet count of 50 to 74,999 cells/dl or nadir platelet count of 25 to 49,999 cells/dl alone,
temozolomide and PLD were both reduced by 25%. Both drugs were reduced by 50% if the nadir ANC
was less than 500 cells/dl or nadir platelet count was less than 25,000 cells/dl. Treatment was delayed
by a week if patients experienced grade 2 palmar-plantar toxicity. PLD was reduced by 25% if grade
one toxicity persisted after a two week delay. If grade three or four toxicity persisted beyond two
weeks, patients discontinued PLD and continued temozolomide if clinically indicated.
8
Treatment was withheld for all grades three and four non hematological toxicity, until the toxicity
improved to grade one or less, and both PLD and temozolomide doses were reduced by 25%. Patients
who developed grade 4 toxicity were taken off study. Patients received a 5-hydroxytryptamine
serotonin antagonist at the same time as they took temozolomide and 8mg of intravenous
dexamethasone as an antiemetic prior to the administration of PLD.
Patient Evaluation
All patients who received at least one course of chemotherapy were eligible for response evaluation.
Patients who did not have residual disease post-irradiation were not included in the response efficacy
endpoint but were eligible for all other endpoint estimations: time to disease progression, overall
survival and toxicity. (including stable disease (SD) and progressive disease (PD)). Patients who did
have evaluable residual disease on a contrast-enhanced magnetic resonance imaging study (MRI) or
computed tomography (CT) scan (for patients with medical contraindication for MRI) were eligible
for all endpoint estimations including response rate (CR and PR).
Clinical examination, performance status evaluation, neurological examination and hematological and
clinical chemistry tests were performed monthly. Tumour status was determined with an MRI
performed every three months and evaluated by an independent radiologist using the MacDonald
criteria.13 CR was defined as the disappearance of all enhancing tumor on MRI at least one month
apart, discontinuation of steroids, and neurologically stable. PR was at least 50% reduction in the size
of enhancing tumor according to the MacDonald criteria maintained for at least one month, steroids
stable or reduced and neurologically stable or improved. PD was at least 25% increase in the size of
enhancing tumor according to MacDonald criteria or any new tumor on MRI or a neurological
assessment of “definitely worse”, and steroids stable or increased. All other assessments were
considered SD.
Statistical Methods
This study was designed to evaluate the safety and efficacy of PLD used in combination with
temozolomide in the treatment of GBM following concurrent radiotherapy and chemotherapy. The
primary endpoint was six-month progression free survival from the time of first cycle of temozolomide
9
and PLD. Sample size was based on the Optimal design proposed by Simon for a two-stage Phase II
trial.14
Assuming a 6-month PFS of 40% for adjuvant temozolomide alone and a PFS6 of less than 50% for
the combination was considered of no interest, then a total of 40 patients would allow exclusion of a
50% 6-month PFS rate if fewer than 26 of the 40 patients remained progression-free at 6 months, with
α = 0.10 and β = 0.10. The planned interim analysis occurred after 21 patients had been enrolled and
followed for at least 6 months by which time all 40 patients had already been recruited. Nevertheless,
the criterion for trial continuation was met.
10
Results
Patient Characteristics
Forty patients were enrolled from four Australian sites between April 2007 and August 2008. Six
patients did not have residual disease on post radiation MRI and were therefore not included in the
response efficacy endpoint (Table 2) but were included in time to disease progression.
Patient characteristics are shown in Table 1. All patients had completed concurrent irradiation with 60
Gray in 30 fractions and temozolomide chemotherapy and planned to continue with adjuvant
temozolomide as part of the study. The median age was 53 years (range 24-76 years). There were 29
males (73%) and 11 females (27%). Most patients had an Eastern Cooperative Oncology Group
(ECOG) performance status (PS) of 0 (53%) or one (40%). The tumours were mainly in the temporal
lobe (38%) and frontal lobe (35%). The median duration of radiotherapy was six weeks and the
median number of weeks from completion of radiation to commencement on study was four weeks
(range one-eight weeks). The median number of cycles of treatment delivered was six cycles (range
one-six).
Response Rates, Disease Progression and Overall Survival
Table 2 summarizes the response to therapy among the 34 evaluable patients. One patient achieved a
CR (3%) and none had a PR. The median duration of response was 11.7 months. Of the remaining
patients 28 (82%) had SD and five patients (15%) had disease progression.
Among all 40 patients, the median follow-up time was 14.8 months (range 1.2- 20.8 months). At the
time of analysis, 35 patients had progressed (88%). Two patients withdrew from the study prior to
completing the six months of follow-up and three patients remain progression free. The median time to
progression (TTP) was 6.2 months (95%CI 5.6-8.0 months). The six month PFS was 58% (95%CI 4172%). At last analysis, 32 patients were alive and eight (20%) were dead. The median overall survival
was 13.4 months (range 1.2 - 20.9 months). Figures 1 and 2 show Kaplan-Meier curves for PFS and
OS respectively.
11
Toxicity
Treatment related adverse events are listed in Table 3. Overall the combination was well tolerated, and
there were no treatment related deaths. Haematological toxicity included grade 3 neutropenia in three
patients (9%), and there was one documented episode of febrile neutropenia. Two patients developed
pneumocyctis carinii pneumonia in association with lymphopenia but without neutropenia. There was
no grade 3 thrombocytopenia.
Treatment related grade 3 non-haematologic toxicity included: palmar-plantar syndrome in two patients
(6%), mucositis in one patient (3%) and a hypersensitivity reaction to PLD in one patient (3%). The
most common grade 1 or 2 treatment related non-haematologic toxicities observed were rash, lethargy,
nausea, vomiting and mucositis.
Two patients received only one cycle of therapy. For the remaining patients, 11 (29%) required dose
reductions of PLD and ten (26%) required dose reductions of temozolomide. Dose delays were
necessary in 16 patients (40%) and 15 patients (38%) due to PLD and temozolomide related toxicity
respectively.
12
Discussion
The value of conventional chemotherapy for malignant gliomas has been modest and GBM has been
considered refractory to most cytotoxic agents. 15, 16 Occasional responses have been documented but
these have generally been short-lived with the rapid emergence of resistance. The blood-brain barrier
(BBB) has been a major obstacle to the effective delivery of chemotherapy, especially to the infiltrating
component of the tumour that is intercalated with normal brain parenchyma. 17,
18
Usually only
lipophilic molecules such as the nitrosureas can cross the BBB.
The use of PLD has been of interest for several reasons. First, its ability to cross the blood brain barrier
more effectively than conventional chemotherapy, given its lipophilic nature, makes it appealing in this
tumor. A Phase II evaluation of a novel morphalino-anthracycline, MX-2 has been previously reported
that demonstrated preclinical evidence of improved blood brain barrier penetration and proved to be
active and well tolerated in patients with high grade gliomas.19 Doxorubicin has been noted to be
effective in glioma cell lines and tumour models but its activity is curbed by low lipid solubility and
inability to cross the BBB. Secondly, the toxicity of profile of PLD is more favourable than
doxorubicin, in particular with regards to hand-foot syndrome and stomatitis. Third, Fabel et al
reported significant and prolonged disease stabilisation with PLD in malignant glioma.20
The combination of temozolomide and PLD was chosen given the established role of temozolomide in
the treatment of GBM. Temozolomide has demonstrated survival benefit and modest toxicity. In a
phase 1 study, Volm et al demonstrated that the combination was safe and could be given at full dose.
In a Phase II study conducted by our group, we concluded that the combination of temozolomide and
PLD was well tolerated, resulted in a modest objective response rate, but had encouraging disease
stabilization in the treatment of recurrent GBM. Of interest, the six month PFS was 32% that compared
favourably with data from studies of single agent temozolomide in recurrent GBM in which the six
month PFS was 20%.21-24
13
This current study demonstrates that the combination of PLD and temozolomide is well tolerated but
does not appear to add significant clinical benefit in the treatment of newly diagnosed GBM. We
reported a 6PFS of 57.9% and a median OS of 13.4 months. The objective radiological response rate to
treatment was 3% which was inferior to that achieved in our study in recurrent disease, where a
response rate of 19% was noted.25
The European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer
Institute of Canada Clinical Trials Group (NCIC) 26981 trial reported an improved median survival
(14.6 months) and 2-year survival of 26.5% with adjuvant radiotherapy and temozolomide as compared
with radiotherapy alone.4 This has recently been updated with 5 year overall survival of 9.8 months.5
Although the survival may appear to be similar to our data, clearly added to this is a significant bias in
outcome in our cohort as these patients were those who had successfully completed concurrent therapy
and were well enough to be considered for the 6 months of temozolomide.
In the EORTC 26981 database, patients who completed the concurrent radiotherapy and temozolomide
component of their treatment and were about to embark on the six months of temozolomide therapy
had a 6PFS of 50% and a median OS of 14.1 months (Roger Stupp, personal communication). In the
Radiation Therapy Oncology Group (RTOG)/EORTC study 26052 intensified temozolomide trial,
where patients are also randomised before starting their six months of post-irradiation temozolomide, a
median survival of 14 months was taken as null hypothesis and 17.5 months as alternative hypothesis.
There are other limitations to our study. First, like many studies in high grade glioma, we chose six
month PFS as the primary end point of our study. There is increasing evidence that 6PFS is a strong
predictor of survival, and 6PFS is a valid end point for trials of therapy for recurrent malignant
glioma.26 However, there continues to be difficulty in defining radiological response especially post
radiotherapy.27 In addition, we cannot discount the possibility that patients assessed as progressing may
have experienced radiological pseudo-progression. Second, we added PLD only to the post-irradiation
component of the EORTC protocol. Most current studies add the novel agent to the concurrent
irradiation/chemotherapy component of the standard EORTC protocol. However, we were concerned
about additional toxicity associated with the potential interaction between PLD and radiotherapy.
14
Third, MGMT methylation status was not evaluated and this may impact on the interpretation of the
results. Finally, the numbers in our study were relatively small and would be insufficient to exclude a
modest incremental beneficial effect of the combination.
In conclusion, our findings suggest that the combination of temozolomide and PLD in the adjuvant
treatment of GBM post radiotherapy is well tolerated but does not provide significant additional benefit
when compared to the current standard of care. Although there has been marked improvement in the
survival of these patients with the addition of temozolomide to radiotherapy, the survival of these
patients remains poor. With the advent of new targeted therapies, further investigation of these new
agents in combination with the standard treatment should be explored to improve the outcomes of
patients with GBM given the lack of efficacy with conventional chemotherapy.
15
Acknowledgments
This investigator-initiated trial was supported by an unrestricted grant from Schering-Plough and by
Cancer Australia. The study was conducted and analysed independently of S-P and CA.
16
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Walker MD, Alexander E, Jr., Hunt WE, et al. Evaluation of BCNU and/or radiotherapy in the
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Randomized trial of procarbazine, lomustine, and vincristine in the adjuvant treatment of
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Clarke K, Basser RL, Underhill C, et a. KRN8602 (MX2-hydrochloride): an active new agent
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Fabel K, Dietrich J, Hau P, et al. Long-term stabilization in patients with malignant glioma
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Brada M, Hoang-Xuan K, Rampling R, et al. Multicenter phase II trial of temozolomide in
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19
Table 1: Patient Characteristics
Characteristics
Eligible patients
Sex
Male
Female
Median age (range)
ECOG performance status
0
1
2
40 patients
29 (73%)
11 (27%)
53 years (24-76 years)
21 (53%)
16 (40%)
3 (7%)
Median time from radiotherapy (range)
4 weeks (1-8 weeks)
Median cycles of chemotherapy (range)
6 (1-6)
Neurological deficit at registration
14 (35%)
Residual disease on MRI
34 (85%)
20
Table 2: Response rates in 34 patients with evaluable disease *
Response
Number of Patients (%)
Complete response
1 (3%)
Partial response
0 (0%)
Stable disease
28 (82%)
Progressive disease
5 (15%)
*Six (15%) of the 40 patients were not evaluable for response
21
Table 3. Treatment related Grade 3 toxicities (40 patients)
Grade 3 (%)
Thrombocytopenia
0 (0%)
Neutropenia
3 (9%)
Anaemia
0 (0%)
Hand-foot syndrome
2 (6%)
Nausea/Vomiting
0 (0%)
Mucositis
1 (3%)
Reaction to Caelyx
1 (3%)
22
Figure 1. Progression free survival at 6 months
23
Figure 2. Overall survival