Summary

This phase III trial compares the effect of adding lomustine to standard chemotherapy with temozolomide and radiation therapy versus temozolomide and radiation therapy alone in shrinking or stabilizing newly diagnosed MGMT methylated glioblastoma. MGMT methylated tumors are more likely to respond to temozolomide chemotherapy. Temozolomide and lomustine are chemotherapy drugs and in a class of medications called alkylating agents. They damage the cell’s DNA and may kill cancer cells. Radiation therapy uses high energy x-ray photons to kill tumor cells and shrink tumors. Adding lomustine to standard chemotherapy with temozolomide and radiation therapy may shrink or stabilize glioblastoma.

Objectives

PRIMARY OBJECTIVE:
I. To determine if the regimen with the two alkylating agents temozolomide and lomustine with radiotherapy (RT) significantly prolongs overall survival (OS) versus (vs.) standard chemoradiotherapy with temozolomide in patients with newly diagnosed glioblastoma (GBM) with MGMT promoter methylation.

SECONDARY OBJECTIVES:
I. To determine if the regimen with the two alkylating agents temozolomide and lomustine with radiotherapy (RT) significantly prolongs progression-free survival (PFS) vs. standard chemoradiotherapy with temozolomide in patients with newly diagnosed GBM with MGMT promoter methylation.
II. To compare the two different chemotherapy regimens on patient-reported outcomes (PROs), as measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in patients with newly diagnosed GBM with MGMT promoter methylation.
III. To determine if the regimen with the two alkylating agents temozolomide and lomustine with radiotherapy (RT) is associated with inferior short-term change in PROs as measured by MDASI-BT vs. standard chemoradiotherapy with temozolomide in patients with newly diagnosed GBM with MGMT promoter methylation.
IV. To assess toxicity in the two different chemotherapy regimens.

EXPLORATORY OBJECTIVES:
I. To assess the association between absolute lymphocyte counts and outcomes.
II. To assess the association between CD4+ lymphocyte counts and outcomes.
III. To compare the two different chemotherapy regimens in terms of long-term PROs as measured by MDASI-BT at years 1 and 2.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients undergo radiation therapy 5 days per week and receive temozolomide orally (PO) once daily (QD) for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5 of each cycle. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo magnetic resonance imaging (MRI) throughout the trial.

ARM II: Patients undergo radiation therapy 5 days per week for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients also receive lomustine PO on day 1 of each cycle and temozolomide PO QD on days 2-6 of each cycle. Treatment repeats every 42 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo MRI throughout the trial.

After completion of study treatment, patients are followed up every 3 months for year 1, every 4 months for year 2, and then every 6 months thereafter.

Eligibility

1. STEP 1 REGISTRATION: No known IDH mutation. (If tested before step 1 registration, patients known to have IDH mutation in the tumor on local or other testing are ineligible and should not be registered)
2. STEP 1 REGISTRATION: Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue block and hematoxylin and eosin (H&E) stained slide to be sent for central pathology review for confirmation of histology and MGMT promoter methylation status. Note that tissue for central pathology review and central MGMT assessment must be received by the New York University (NYU) Center for Biospecimen Research and Development (CBRD) on or before postoperative calendar day 30. If tissue cannot be received by postoperative calendar day 30, then patients may NOT enroll on this trial as central pathology review will not be complete in time for the patient to start treatment no later than 8 weeks following surgery. Results of central pathology review and central MGMT analysis will generally be conveyed to NRG Oncology within 10 business days of receipt of tissue. Note: In the event of an additional tumor resection(s), tissue must be received within 30 days of the most recent resection and the latest resection must have been performed within 30 days after the initial resection. Surgical resection is required; stereotactic biopsy alone is not allowed because it will not provide sufficient tissue for MGMT analysis
3. STEP 1 REGISTRATION: Contrast-enhanced brain MRI after surgery and prior to step 2 registration
4. STEP 1 REGISTRATION: Willing to use highly effective method of contraception for participants of childbearing potential (participants who may become pregnant or who may impregnate a partner) during therapy and for 6 months after completing treatment; this inclusion is necessary because the treatment in this study may be significantly teratogenic
5. STEP 1 REGISTRATION: The patient or a legally authorized representative must provide study-specific informed consent prior to study entry and, for patients treated in the United States (U.S.), authorization permitting release of personal health information
6. STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review
7. STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathology review. Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded
8. STEP 2 REGISTRATION: IDH mutation testing by at least one method (such as immunohistochemistry for IDH1 R132H) must be performed as part of standard of care and no mutation must be found (i.e IDH wildtype). (If a mutation is identified then the patient will be ineligible and must be registered as ineligible at step 2.)
9. STEP 2 REGISTRATION: History/physical examination within 28 days prior to step 2 registration
10. STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days prior to step 2 registration
11. STEP 2 REGISTRATION: Neurologic function assessment within 28 days prior to step 2 registration
12. STEP 2 REGISTRATION: Age 18-70 years
13. STEP 2 REGISTRATION: Hemoglobin >= 10 g/dl (Note: the use of transfusion or other intervention to achieve hemoglobin [Hgb] >= 10.0 g/dl is acceptable) (Within 14 days prior to step 2 registration)
14. STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3 (Within 14 days prior to step 2 registration)
15. STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3 (Within 14 days prior to step 2 registration)
16. STEP 2 REGISTRATION: Platelets >= 100,000/mm^3 (Within 14 days prior to step 2 registration)
17. STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN) (Within 14 days prior to step 2 registration)
18. STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN (Within 14 days prior to step 2 registration)
19. STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (Within 14 days prior to step 2 registration)
20. STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula) (Within 14 days prior to step 2 registration)
21. STEP 2 REGISTRATION: For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Note: Known positive test for hepatitis B virus surface antigen (HBV sAg) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy. Patients who are immune to hepatitis B (anti-hepatitis B surface antibody positive) are eligible (e.g. patients immunized against hepatitis B)
22. STEP 2 REGISTRATION: For patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Note: Known positive test for hepatitis C virus ribonucleic acid (HCV ribonucleic acid [RNA]) indicating acute or chronic infection would make the patient ineligible unless the viral load becomes undetectable on suppressive therapy
23. STEP 2 REGISTRATION: Known human immunodeficiency virus (HIV) infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to step 2 registration are eligible for this trial. Testing is not required for entry into protocol
24. STEP 2 REGISTRATION: Negative serum or urine pregnancy test (in persons of childbearing potential) within 14 days prior to step 2 registration * Childbearing potential is defined as any person who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal

Treatment Sites in Georgia