Temozolomide Alone or in Combination With Thalidomide and/or Isotretinoin and/or Celecoxib in Treating Patients Who Have Undergone Radiation Therapy for Glioblastoma Multiforme

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Thalidomide may stop the growth of glioblastoma multiforme by blocking blood flow to the tumor. Isotretinoin may help cells that are involved in the body's immune response to work better. Celecoxib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known which temozolomide-containing regimen is more effective in treating glioblastoma multiforme. PURPOSE: This randomized phase II trial is studying eight different temozolomide-containing regimens to compare how well they work in treating patients who have undergone radiation therapy for glioblastoma multiforme.

Detailed Description
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OBJECTIVES: Compare the efficacy of adjuvant temozolomide (TMZ) alone or in combination with thalidomide and/or isotretinoin and/or celecoxib, in terms of 6-month progression-free survival, in patients who have undergone radiotherapy for supratentorial glioblastoma multiforme. Compare the toxicity of these regimens in these patients. OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 8 treatment arms. Arm I: Patients receive oral temozolomide once daily on days 1-7 and 15-21. Arm II: Patients receive temozolomide as in arm I and oral thalidomide once daily on days 1-28. Arm III: Patients receive temozolomide as in arm I and oral isotretinoin twice daily on days 1-21. Arm IV: Patients receive temozolomide as in arm I and oral celecoxib twice daily on days 1-28. Arm V: Patients receive temozolomide as in arm I, thalidomide as in arm II, and isotretinoin as in arm III. Arm VI: Patients receive temozolomide as in arm I, thalidomide as in arm II, and celecoxib as in arm IV. Arm VII: Patients receive temozolomide as in arm I, isotretinoin as in arm III, and celecoxib as in arm IV. Arm VIII: Patients receive temozolomide as in arm I, thalidomide as in arm II, isotretinoin as in arm III, and celecoxib as in arm IV. In all arms, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity. Patient may receive additional courses of therapy at the discretion of the treating physician. After completion of study treatment, patients are followed for at least 30 days and then every 3 months thereafter. PROJECTED ACCRUAL: A total of 180 patients will be accrued for this study.

Official Title
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A Randomized, Factorial-Design, Phase II Trial of Temozolomide Alone and in Combination With Possible Permutations of Thalidomide, Isotretinoin and/or Celecoxib as Post-Radiation Adjuvant Therapy of Glioblastoma Multiforme

Conditions
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Brain and Central Nervous System Tumors, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Celecoxib
* Drug: Isotretinoin
* Drug: Temozolomide
* Drug: Thalidomide


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed supratentorial glioblastoma multiforme Must have undergone a biopsy OR subtotal or gross total resection of the tumor Must have completed post-operative (or post-biopsy) radiotherapy within the past 5 weeks No progressive disease after radiotherapy PATIENT CHARACTERISTICS: Age 18 and over Performance status Karnofsky 60-100% Life expectancy Not specified Hematopoietic Absolute neutrophil count ≥ 1,500/mm^3 Platelet count ≥ 100,000/mm^3 Hepatic Serum glutamate pyruvate transaminase (SGPT) < 2 times upper limit of normal (ULN) Alkaline phosphatase < 2 times ULN Bilirubin ≤ 1.5 mg/dL Renal blood urea nitrogen (BUN) ≤ 1.5 times ULN Creatinine ≤ 1.5 times ULN Immunologic No history of allergic reactions attributed to compounds of similar chemical or biological composition to celecoxib or to sulfonamides No asthma, urticaria, or allergic reactions to aspirin or other NSAIDs No active infection Gastrointestinal No inflammatory bowel disease No history of peptic ulcer disease No gastrointestinal bleeding within past 3 months Other Not pregnant or nursing Negative pregnancy test Fertile patients must use effective double-method contraception during and for 2 months after study participation Fertile female patients randomized to receive thalidomide must use effective double-method contraception for ≥ 4 weeks before, during, and ≥ 4 weeks after completion of study therapy Fertile male patients randomized to receive thalidomide must use effective contraception during and for ≥ 4 weeks after completion of study therapy No blood donation (for patients randomized to receive thalidomide) No history of any other cancer except nonmelanoma skin cancer or carcinoma in situ of the cervix or cancer that is in complete remission and patient completed all therapy for that disease ≥ 3 years ago No other disease that would obscure toxicity or dangerously alter drug metabolism (e.g., severe connective tissue disease) No other serious medical illness PRIOR CONCURRENT THERAPY: Biologic therapy Not specified Chemotherapy Prior temozolomide in combination with radiotherapy allowed No other prior or concurrent chemotherapy Endocrine therapy Not specified Radiotherapy See Disease Characteristics See Chemotherapy Surgery See Disease Characteristics No concurrent surgery Other No other concurrent non-steroidal anti-inflammatory drugs (NSAIDs) (for patients randomized to receive celecoxib) No other concurrent investigational drugs No other concurrent anticancer therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I: TMZ<br>Oral Temozolomide (TMZ) 150 mg/m^2 once daily on days 1-7 and 15-21. | Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;|
| Experimental: Arm II: TMZ + Thalidomide<br>Temozolomide as in arm I and oral Thalidomide (Thal) once daily on days 1-28 (starting dose 200 mg). | Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;Drug: Thalidomide<br>* 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved)<br>* Other names: Thalomid;|
| Experimental: Arm III: TMZ + Isotretinoin<br>Temozolomide as in Arm I and oral Isotretinoin 40 mg/m^2 twice daily on days 1-21. | Drug: Isotretinoin<br>* 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.<br>* Other names: 13-Cis-Retinoic Acid;Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;|
| Experimental: Arm IV: TMZ + Celecoxib<br>Temozolomide as in arm I and oral Celecoxib 400 mg twice daily on days 1-28. | Drug: Celecoxib<br>* 400 mg orally twice a day continuous dosing<br>* Other names: Celebrex;Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;|
| Experimental: Arm V: TMZ + Thalidomide + Isotretinoin<br>Temozolomide as in arm I, Thalidomide as in arm II, and Isotretinoin as in arm III. | Drug: Isotretinoin<br>* 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.<br>* Other names: 13-Cis-Retinoic Acid;Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;Drug: Thalidomide<br>* 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved)<br>* Other names: Thalomid;|
| Experimental: Arm VI: TMZ + Thalidomide + Celecoxib<br>Temozolomide as in Arm I, Thalidomide as in Arm II, and Celecoxib as in Arm IV. | Drug: Celecoxib<br>* 400 mg orally twice a day continuous dosing<br>* Other names: Celebrex;Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;Drug: Thalidomide<br>* 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved)<br>* Other names: Thalomid;|
| Experimental: Arm VII: TMZ + Isotretinoin + Celecoxib<br>Temozolomide as in Arm I, Isotretinoin as in Arm III, and Celecoxib as in Arm IV. | Drug: Celecoxib<br>* 400 mg orally twice a day continuous dosing<br>* Other names: Celebrex;Drug: Isotretinoin<br>* 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.<br>* Other names: 13-Cis-Retinoic Acid;Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;|
| Experimental: Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib<br>Temozolomide as in Arm I, Thalidomide as in Arm II, Isotretinoin as in Arm III, and Celecoxib as in Arm IV. | Drug: Celecoxib<br>* 400 mg orally twice a day continuous dosing<br>* Other names: Celebrex;Drug: Isotretinoin<br>* 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.<br>* Other names: 13-Cis-Retinoic Acid;Drug: Temozolomide<br>* 150 mg/m2 orally daily, 7 days on treatment, 7 days off.<br>* Other names: Temodar;Drug: Thalidomide<br>* 400 mg orally every day continuous dosing (starting at 200 mg each day and escalating weekly by 100 mg until the maximum dose of 400 mg/day is achieved)<br>* Other names: Thalomid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-Free Survival (PFS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | Thalidomide versus not Thalidomide analysis: Comparison of median PFS outcome of participants in arms II, VI, VII and VIII, versus participants in arms I, III, IV and V. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up, up to one year (12 study cycles). | 
| Median Progression-Free Survival (PFS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | Celecoxib versus not Celecoxib analysis: We compared the median PFS outcome of participants in arms III, V, VI and VIII, versus participants in arms I, II, IV and VII. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 
| Median Progression-Free Survival (PFS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | Isotretinoin versus not Isotretinoin analysis: We compared the median PFS outcome of participants in arms IV, V, VII and VIII, versus participants in arms I, II, III and VI. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-Free Survival (PFS) Comparison of Doublet Versus Triplet Therapy | Doublet (2 agents) versus Triplet (3 agents) therapy analysis: We compared the median PFS outcome of participants in arms II, III, IV, versus participants in arms V, VI and VII. Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 
| Median Progression-Free Survival (PFS) of Individual Arms | Median PFS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 
| Median Overall Survival (OS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | Thalidomide versus not Thalidomide analysis: We compared the median OS outcome of participants in arms II, VI, VII and VIII, versus participants in arms I, III, IV and V. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 3 months from randomization until progression of disease, death or last follow-up. | 
| Median Overall Survival (OS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | Celecoxib versus not Celecoxib analysis: We compared the median OS outcome of participants in arms III, V, VI and VIII, versus participants in arms I, II, IV and VII. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 3 months from randomization until progression of disease, death or last follow-up. | 
| Median Overall Survival (OS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | Isotretinoin versus not Isotretinoin analysis: We compared the median OS outcome of participants in arms IV, V, VII and VIII, versus participants in arms I, II, III and VI. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 3 months from randomization until progression of disease, death or last follow-up. | 
| Median Overall Survival (OS) Comparison of Doublet Versus Triplet Therapy | Doublet (2 agents) versus Triplet (3 agents) therapy analysis: We compared the median OS outcome of participants in arms II, III, IV, versus participants in arms V, VI and VII. Median OS was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 3 months from randomization until progression of disease, death or last follow-up. | 
| Overall Survival of Individual Arms | Overall Survival (OS) was estimated using the Kaplan-Meier method from time of randomization to time of progression, death, or last follow-up. Progression defined as 25% increase in the sum of products of all measurable lesions over smallest sum observed (over baseline if no decrease) using the same techniques as baseline, OR clear worsening of any evaluable disease, OR appearance of any new lesion/site, OR failure to return for evaluation due to death or deteriorating condition (unless clearly unrelated to this cancer). | Every 3 months from randomization until progression of disease, death or last follow-up. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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adult giant cell glioblastoma, adult gliosarcoma, adult glioblastoma