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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 70 Years
Gender	All

More Inclusion & Exclusion 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.

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05095376
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 3
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	NRG Oncology
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Fabio M Iwamoto
Principal Investigator Affiliation	NRG Oncology
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other, NIH
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioblastoma, Gliosarcoma

Additional Details

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.#46;) 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.#46; 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.#46; 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.

Arms & Interventions

Arms

Active Comparator: Arm I (radiation therapy, temozolomide)

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.

Experimental: ARM II (radiation therapy, temozolomide, lomustine)

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.

Interventions

Drug: - Lomustine

Given PO

Radiation: - Photon Beam Radiation Therapy

Undergo radiation therapy

Other: - Quality-of-Life Assessment

Ancillary studies

Other: - Questionnaire Administration

Ancillary studies

Drug: - Temozolomide

Given PO

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Little Rock, Arkansas

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Recruiting

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University of Arkansas for Medical Sciences

Little Rock, Arkansas, 72205

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501-686-8274

Kaiser Permanente-Anaheim, Anaheim, California

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Kaiser Permanente-Anaheim

Anaheim, California, 92806

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