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

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

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.

Study Overview

• Status: Completed
• Conditions: Glioblastoma Multiforme; Brain and Central Nervous System Tumors
• Intervention / Treatment: Drug: Temozolomide; Drug: Thalidomide; Drug: Isotretinoin; Drug: Celecoxib

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.

• Study Type: Interventional
• Enrollment (Actual): 178
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Fort Smith, Arkansas, United States, 72913
      • Hembree Mercy Cancer Center at St. Edward Mercy Medical Center
  • Florida
    • Orlando, Florida, United States, 32806-2134
      • University of Texas MD Anderson Cancer Center at Orlando
  • Georgia
    • Atlanta, Georgia, United States, 30342-1701
      • CCOP - Atlanta Regional
  • Illinois
    • Decatur, Illinois, United States, 62526
      • CCOP - Central Illinois
  • Kansas
    • Wichita, Kansas, United States, 67214-3882
      • CCOP - Wichita
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • CCOP - Grand Rapids
    • Kalamazoo, Michigan, United States, 49007-3731
      • CCOP - Kalamazoo
  • Missouri
    • Kansas City, Missouri, United States, 64131
      • CCOP - Kansas City
    • Springfield, Missouri, United States, 65804
      • Cancer Research for the Ozarks
  • Ohio
    • Columbus, Ohio, United States, 43210-1240
      • Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at Ohio State University Comprehensive Cancer Center
  • South Carolina
    • Spartanburg, South Carolina, United States, 29303
      • CCOP - Upstate Carolina
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas MD Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: FACTORIAL
• Masking: TRIPLE

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Arm I: TMZ; Oral Temozolomide (TMZ) 150 mg/m^2 once daily on days 1-7 and 15-21.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar
EXPERIMENTAL: Arm II: TMZ + Thalidomide; Temozolomide as in arm I and oral Thalidomide (Thal) once daily on days 1-28 (starting dose 200 mg).	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: 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); Other Names: Thalomid
EXPERIMENTAL: Arm III: TMZ + Isotretinoin; Temozolomide as in Arm I and oral Isotretinoin 40 mg/m^2 twice daily on days 1-21.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: Isotretinoin; 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.; Other Names: Accutane; 13-Cis-Retinoic Acid
EXPERIMENTAL: Arm IV: TMZ + Celecoxib; Temozolomide as in arm I and oral Celecoxib 400 mg twice daily on days 1-28.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: Celecoxib; 400 mg orally twice a day continuous dosing; Other Names: Celebrex
EXPERIMENTAL: Arm V: TMZ + Thalidomide + Isotretinoin; Temozolomide as in arm I, Thalidomide as in arm II, and Isotretinoin as in arm III.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: 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); Other Names: Thalomid; Drug: Isotretinoin; 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.; Other Names: Accutane; 13-Cis-Retinoic Acid
EXPERIMENTAL: Arm VI: TMZ + Thalidomide + Celecoxib; Temozolomide as in Arm I, Thalidomide as in Arm II, and Celecoxib as in Arm IV.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: 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); Other Names: Thalomid; Drug: Celecoxib; 400 mg orally twice a day continuous dosing; Other Names: Celebrex
EXPERIMENTAL: Arm VII: TMZ + Isotretinoin + Celecoxib; Temozolomide as in Arm I, Isotretinoin as in Arm III, and Celecoxib as in Arm IV.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: Isotretinoin; 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.; Other Names: Accutane; 13-Cis-Retinoic Acid; Drug: Celecoxib; 400 mg orally twice a day continuous dosing; Other Names: Celebrex
EXPERIMENTAL: Arm VIII: TMZ + Thalidomide + Isotretinoin + Celecoxib; Temozolomide as in Arm I, Thalidomide as in Arm II, Isotretinoin as in Arm III, and Celecoxib as in Arm IV.	Drug: Temozolomide; 150 mg/m2 orally daily, 7 days on treatment, 7 days off.; Other Names: Temodar; Drug: 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); Other Names: Thalomid; Drug: Isotretinoin; 40 mg/m^2 orally twice a day (total daily dose = 80 mg/m^2) days 1-21 of a 28 day cycle.; Other Names: Accutane; 13-Cis-Retinoic Acid; Drug: Celecoxib; 400 mg orally twice a day continuous dosing; Other Names: Celebrex

What is the study measuring?

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.

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Marta Penas-Prado, MD, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Gilbert MR, Gonzalez J, Hunter K, Hess K, Giglio P, Chang E, Puduvalli V, Groves MD, Colman H, Conrad C, Levin V, Woo S, Mahajan A, de Groot J, Yung WK. A phase I factorial design study of dose-dense temozolomide alone and in combination with thalidomide, isotretinoin, and/or celecoxib as postchemoradiation adjuvant therapy for newly diagnosed glioblastoma. Neuro Oncol. 2010 Nov;12(11):1167-72. doi: 10.1093/neuonc/noq100. Epub 2010 Aug 20.
• Penas-Prado M, Hess KR, Fisch MJ, Lagrone LW, Groves MD, Levin VA, De Groot JF, Puduvalli VK, Colman H, Volas-Redd G, Giglio P, Conrad CA, Salacz ME, Floyd JD, Loghin ME, Hsu SH, Gonzalez J, Chang EL, Woo SY, Mahajan A, Aldape KD, Yung WK, Gilbert MR; MD Anderson Community Clinical Oncology Program; Brain Tumor Trials Collaborative. Randomized phase II adjuvant factorial study of dose-dense temozolomide alone and in combination with isotretinoin, celecoxib, and/or thalidomide for glioblastoma. Neuro Oncol. 2015 Feb;17(2):266-73. doi: 10.1093/neuonc/nou155. Epub 2014 Sep 19.

Helpful Links

• University of Texas (UT) MD Anderson Cancer Center Official Website

Study record dates

Study Major Dates

• Study Start: September 1, 2005
• Primary Completion (ACTUAL): September 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: June 2, 2005
• First Submitted That Met QC Criteria: June 2, 2005
• First Posted (ESTIMATE): June 3, 2005

Study Record Updates

• Last Update Posted (ACTUAL): October 18, 2021
• Last Update Submitted That Met QC Criteria: September 21, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: adult glioblastoma; adult giant cell glioblastoma; adult gliosarcoma
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Nervous System Neoplasms; Central Nervous System Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Leprostatic Agents; Cyclooxygenase 2 Inhibitors; Thalidomide; Temozolomide; Celecoxib; Isotretinoin
• Other Study ID Numbers: 2004-0662; MDA-ID-02586; NCI-6636; MDA-2004-0662; CDR0000432954 (OTHER: NCI); NCI-2009-00076 (REGISTRY: NCI CTRP)