Brain and Central Nervous System Tumors, Glioblastoma Multiforme
Conditions
Keywords
adult giant cell glioblastoma, adult gliosarcoma, adult glioblastoma
Brief summary
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
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.
Interventions
DRUGCelecoxib
400 mg orally twice a day continuous dosing
DRUGIsotretinoin
40 mg/m\^2 orally twice a day (total daily dose = 80 mg/m\^2) days 1-21 of a 28 day cycle.
DRUGTemozolomide
150 mg/m2 orally daily, 7 days on treatment, 7 days off.
DRUGThalidomide
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)
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-Free Survival (PFS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | 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). | 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). |
| Median Progression-Free Survival (PFS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 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). |
| Median Progression-Free Survival (PFS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Overall Survival (OS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | Every 3 months from randomization until progression of disease, death or last follow-up. | 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). |
| Median Overall Survival (OS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | Every 3 months from randomization until progression of disease, death or last follow-up. | 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). |
| Median Progression-Free Survival (PFS) Comparison of Doublet Versus Triplet Therapy | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 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). |
| Overall Survival of Individual Arms | Every 3 months from randomization until progression of disease, death or last follow-up. | 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). |
| Median Overall Survival (OS) Comparison of Doublet Versus Triplet Therapy | Every 3 months from randomization until progression of disease, death or last follow-up. | 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). |
| Median Progression-Free Survival (PFS) of Individual Arms | Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up. | 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). |
| Median Overall Survival (OS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | Every 3 months from randomization until progression of disease, death or last follow-up. | 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). |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: September 2005 to February 2011 from various hospitals and institutions representing the Community Clinical Oncology Program (CCOP). A total of 146 participants were accrued at MD Anderson Cancer Center and 32 at the remaining participating sites.
Participants by arm
| Arm | Count |
|---|---|
| Arm I: TMZ Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21. | 22 |
| Arm II: TMZ + Thalidomide Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Thalidomide: 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). | 22 |
| Arm III: TMZ + Celecoxib Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Celecoxib: 400 mg orally twice a day continuous dosing. | 22 |
| Arm IV: TMZ + Isotretinoin Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Isotretinoin: 40 mg/m\^2 orally twice a day (total daily dose = 80 mg/m\^2) days 1-21 of a 28 day cycle. | 22 |
| Arm V: TMZ + Isotretinoin + Celecoxib Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Celecoxib: 400 mg orally twice a day continuous dosing.
Isotretinoin: 40 mg/m\^2 orally twice a day (total daily dose = 80 mg/m\^2) days 1-21 of a 28 day cycle. | 23 |
| Arm VI: TMZ + Thalidomide + Celecoxib Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Celecoxib: 400 mg orally twice a day continuous dosing.
Thalidomide: 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). | 22 |
| Arm VII: TMZ + Thalidomide + Isotretinoin Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Isotretinoin: 40 mg/m\^2 orally twice a day (total daily dose = 80 mg/m\^2) days 1-21 of a 28 day cycle.
Thalidomide: 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). | 23 |
| Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib Oral Temozolomide (TMZ): 150 mg/m\^2 once daily on days 1-7 and 15-21.
Celecoxib: 400 mg orally twice a day continuous dosing.
Isotretinoin: 40 mg/m\^2 orally twice a day (total daily dose = 80 mg/m\^2) days 1-21 of a 28 day cycle.
Thalidomide: 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). | 22 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 |
|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 | 4 | 2 | 5 | 3 | 7 |
Baseline characteristics
| Characteristic | Arm IV: TMZ + Isotretinoin | Arm V: TMZ + Isotretinoin + Celecoxib | Arm VI: TMZ + Thalidomide + Celecoxib | Arm VII: TMZ + Thalidomide + Isotretinoin | Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib | Total | Arm I: TMZ | Arm II: TMZ + Thalidomide | Arm III: TMZ + Celecoxib |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized <=19 years: | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants |
| Age, Customized >=60 years: | 7 participants | 3 participants | 4 participants | 8 participants | 5 participants | 47 participants | 5 participants | 10 participants | 5 participants |
| Age, Customized Between 20 and 59 years: | 14 participants | 20 participants | 18 participants | 15 participants | 17 participants | 130 participants | 17 participants | 12 participants | 17 participants |
| Region of Enrollment United States | 22 participants | 23 participants | 22 participants | 23 participants | 22 participants | 178 participants | 22 participants | 22 participants | 22 participants |
| Sex: Female, Male Female | 8 Participants | 4 Participants | 6 Participants | 6 Participants | 9 Participants | 55 Participants | 7 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 14 Participants | 19 Participants | 16 Participants | 17 Participants | 13 Participants | 123 Participants | 15 Participants | 12 Participants | 17 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 22 | 21 / 21 | 21 / 21 | 18 / 18 | 21 / 21 | 17 / 17 | 20 / 20 | 15 / 15 |
| serious Total, serious adverse events | 11 / 22 | 9 / 21 | 7 / 21 | 8 / 18 | 12 / 21 | 15 / 17 | 8 / 20 | 7 / 15 |
Outcome results
Primary
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).
Time frame: Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Progression-Free Survival (PFS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | 8.3 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Progression-Free Survival (PFS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | 7.4 months |
95% CI: [0.6, 1.2]
Primary
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).
Time frame: Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Progression-Free Survival (PFS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | 6.6 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Progression-Free Survival (PFS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | 9.1 months |
95% CI: [0.9, 1.8]
Primary
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).
Time frame: 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).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Progression-Free Survival (PFS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | 7.6 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Progression-Free Survival (PFS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | 8.7 months |
95% CI: [0.8, 1.7]
Secondary
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).
Time frame: Every 3 months from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Overall Survival (OS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | 20.2 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Overall Survival (OS) Comparison of Celecoxib Arms Versus no Celecoxib Arms | 17.1 months |
95% CI: [0.5, 1.2]
Secondary
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).
Time frame: Every 3 months from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Overall Survival (OS) Comparison of Doublet Versus Triplet Therapy | 17.0 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Overall Survival (OS) Comparison of Doublet Versus Triplet Therapy | 20.1 months |
95% CI: [0.5, 1.1]
Secondary
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).
Time frame: Every 3 months from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Overall Survival (OS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | 17.1 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Overall Survival (OS) Comparison of Isotretinoin Arms Versus no Isotretinoin Arms | 19.9 months |
95% CI: [0.8, 1.8]
Secondary
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).
Time frame: Every 3 months from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Overall Survival (OS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | 18.3 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Overall Survival (OS) Comparison of Thalidomide Arms Versus no Thalidomide Arms | 17.4 months |
95% CI: [0.7, 1.5]
Secondary
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).
Time frame: Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Progression-Free Survival (PFS) Comparison of Doublet Versus Triplet Therapy | 8.3 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Progression-Free Survival (PFS) Comparison of Doublet Versus Triplet Therapy | 8.2 months |
95% CI: [0.6, 1.3]
Secondary
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).
Time frame: Every 2 cycles (1 cycle = 28 days) from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Median Progression-Free Survival (PFS) of Individual Arms | 10.5 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Median Progression-Free Survival (PFS) of Individual Arms | 7.7 months |
| Arm III: TMZ + Celecoxib | Median Progression-Free Survival (PFS) of Individual Arms | 13.4 months |
| Arm IV: TMZ + Isotretinoin | Median Progression-Free Survival (PFS) of Individual Arms | 6.5 months |
| Arm V: TMZ + Isotretinoin + Celecoxib | Median Progression-Free Survival (PFS) of Individual Arms | 11.6 months |
| Arm VI: TMZ + Thalidomide + Celecoxib | Median Progression-Free Survival (PFS) of Individual Arms | 7.9 months |
| Arm VII: TMZ + Thalidomide + Isotretinoin | Median Progression-Free Survival (PFS) of Individual Arms | 6.2 months |
| Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib | Median Progression-Free Survival (PFS) of Individual Arms | 5.8 months |
Secondary
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).
Time frame: Every 3 months from randomization until progression of disease, death or last follow-up.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Thalidomide: Arm II, Arm VI, Arm VII and Arm VIII | Overall Survival of Individual Arms | 21.2 months |
| No Thalidomide: Arm I, Arm III, Arm IV and Arm V | Overall Survival of Individual Arms | 17.4 months |
| Arm III: TMZ + Celecoxib | Overall Survival of Individual Arms | 18.1 months |
| Arm IV: TMZ + Isotretinoin | Overall Survival of Individual Arms | 11.7 months |
| Arm V: TMZ + Isotretinoin + Celecoxib | Overall Survival of Individual Arms | 23.1 months |
| Arm VI: TMZ + Thalidomide + Celecoxib | Overall Survival of Individual Arms | 20.2 months |
| Arm VII: TMZ + Thalidomide + Isotretinoin | Overall Survival of Individual Arms | 17.9 months |
| Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib | Overall Survival of Individual Arms | 18.5 months |