Testing the Addition of the Chemotherapy Drug Lomustine (Gleostine®) to the Usual Treatment (Temozolomide and Radiation Therapy) for Newly Diagnosed MGMT Methylated Glioblastoma

Study Overview
=================
Brief Summary
-----------------
This phase III trial compares the effect of adding lomustine to temozolomide and radiation therapy versus temozolomide and radiation therapy alone in shrinking or stabilizing newly diagnosed MGMT methylated glioblastoma. Chemotherapy drugs, such as lomustine and temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy photons to kill tumor cells and shrink tumors. Adding lomustine to usual treatment of temozolomide and radiation therapy may help shrink and stabilize glioblastoma.

Detailed Description
-----------------
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 patient reported outcomes (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. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. 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 and temozolomide PO QD on days 2-6. Treatment repeats every 42 days for 6 cycles in the absence of disease progression or unacceptable toxicity. 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.

Official Title
-----------------
A Phase III Trial of Gleostine® (Lomustine)-Temozolomide Combination Therapy Versus Standard Temozolomide in Patients With Methylated MGMT Promoter Glioblastoma

Conditions
-----------------
Glioblastoma, Gliosarcoma

Intervention / Treatment
-----------------
* Drug: Lomustine
* Radiation: Photon Beam Radiation Therapy
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration
* Drug: Temozolomide


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 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) 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 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 STEP 1 REGISTRATION: Contrast-enhanced brain MRI after surgery 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 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 STEP 2 REGISTRATION: Histopathologically proven diagnosis of glioblastoma (or gliosarcoma as a subtype of glioblastoma) confirmed by central pathology review STEP 2 REGISTRATION: MGMT promoter with methylation confirmed by central pathology review (See Section 10 for details). Note: Patients with tissue that is insufficient or inadequate for analysis, fails MGMT testing, or has indeterminate or unmethylated MGMT promoter are excluded. 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.) STEP 2 REGISTRATION: History/physical examination within 28 days prior to Step 2 registration STEP 2 REGISTRATION: Karnofsky performance status (KPS) >= 70 within 28 days prior to Step 2 registration STEP 2 REGISTRATION: Neurologic function assessment within 28 days prior to Step 2 registration STEP 2 REGISTRATION: Age 18-70 years Adequate hematologic, renal, and hepatic function within 14 days prior to STEP 2 REGISTRATION defined as follows: 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) STEP 2 REGISTRATION: Leukocytes >= 2,000/mm^3 STEP 2 REGISTRATION: Absolute neutrophil count >= 1,500/mm^3 STEP 2 REGISTRATION: Platelets >= 100,000/mm^3 STEP 2 REGISTRATION: Total bilirubin =< 1.5 x institutional/lab upper limit of normal (ULN) STEP 2 REGISTRATION: Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) =< 2.5 x ULN STEP 2 REGISTRATION: Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN STEP 2 REGISTRATION: Serum creatinine =< 1.5 x ULN OR creatinine clearance (CrCl) >= 50 mL/min (if using the Cockcroft-Gault formula 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) 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 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 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 Exclusion Criteria: STEP 2 REGISTRATION: Prior therapy for tumor, except for resection or prior laser interstitial thermal therapy (LITT). For example, prior chemotherapy, immunotherapy, or targeted therapy for GBM or lower grade glioma is disallowed (including but not limited to temozolomide, lomustine, bevacizumab, any viral therapy, ipilimumab or other CTLA-4 antibody, PD-1 antibody, CD-137 agonist, CD40 antibody, PDL-1 or 2 antibody, vaccine therapy, polio or similar viral injection as treatment for the tumor, and/or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways) as is Gliadel wafer, radiotherapy, radiosurgery, vaccine or other immunotherapy, brachytherapy, or convection enhanced delivery Note: 5-aminolevulinic acid (ALA)-mediated fluorescent guided resection (FGR) photodynamic therapy (PDT) or fluorescein administered prior to/during surgery to aid resection is not exclusionary and is not considered a chemotherapy or intracerebral agent. Prior laser interstitial thermal therapy (LITT) is allowed. STEP 2 REGISTRATION: Current or planned treatment with any other investigational agents for the study cancer STEP 2 REGISTRATION: Definitive clinical or radiologic evidence of metastatic disease outside the brain STEP 2 REGISTRATION: Prior invasive malignancy (except non-melanomatous skin cancer, cervical cancer in situ and melanoma in situ) unless disease free for a minimum of 2 years STEP 2 REGISTRATION: Prior radiotherapy to the head or neck that would result in overlap of radiation therapy fields STEP 2 REGISTRATION: Pregnancy and individuals unwilling to discontinue nursing due to the potential teratogenic effects and potential risk for adverse events in nursing infants STEP 2 REGISTRATION: History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide or lomustine STEP 2 REGISTRATION: History of pulmonary fibrosis STEP 2 REGISTRATION: Uncontrolled intercurrent illness including, but not limited to: Ongoing or active infection requiring IV antibiotics, IV antiviral, or IV antifungal treatment Symptomatic congestive heart failure, defined as New York Heart Association Functional Classification III/IV (Note: Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification) Unstable angina pectoris within 6 months prior to Step 2 registration Uncontrolled cardiac arrhythmia Psychiatric illness/social situations that would limit compliance with study requirements STEP 2 REGISTRATION: No evidence of diffuse leptomeningeal disease that requires whole brain irradiation.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm I (radiation therapy, temozolomide)<br>Patients undergo radiation therapy 5 days per week and receive temozolomide PO QD for 6 weeks in the absence of disease progression or unacceptable toxicity. Patients then receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. | Radiation: Photon Beam Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Radiation, Photon Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|
| Experimental: ARM II (radiation therapy, temozolomide, lomustine)<br>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 and temozolomide PO QD on days 2-6. Treatment repeats every 42 days for 6 cycles in the absence of disease progression or unacceptable toxicity. | Drug: Lomustine<br>* Given PO<br>* Other names: WR-139017;Radiation: Photon Beam Radiation Therapy<br>* Undergo radiation therapy<br>* Other names: Radiation, Photon Beam;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>Drug: Temozolomide<br>* Given PO<br>* Other names: TMZ;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | The Kaplan-Meier method will be used to estimate survival distribution for each treatment arm. | From randomization to death due to any cause, assessed up to 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | Analysis will consist of estimation of the PFS distribution of each treatment arm via the Kaplan-Meier method and a stratified log-rank test. Additional analyses may consist of estimating the hazard ratio (HR) via the Cox proportional hazards model, accounting for other prognostic covariates (and evaluating whether the proportional hazards assumption holds or whether any treatment effect is notably time-varying), and evaluating for potential treatment by prognostic covariate interactions. | From randomization to disease progression or death due to any cause, whichever occurs first, assessed up to 4 years | 
| Incidence of Adverse Events | Adverse events (AEs) will be graded according to Common Terminology Criteria for Adverse Events version 5.0. Comprehensive summaries of all AEs by treatment arm will be generated and examined. | Up to 4 years | 
| Patient reported outcomes for Brain Tumors | Measured by the MD Anderson Symptom Inventory - Brain Tumor (MDASI-BT) in patients with newly diagnosed glioblastoma with MGMT promoter methylation. | Up to 4 years |