Testing the Addition of an Anti-Cancer Drug, Mycophenolate Mofetil, to the Usual Treatment (Radiation Therapy and Temozolomide) for Advanced Brain Cancer

Mycophenolate Mofetil to Overcome Glioblastoma Resistance to Radiotherapy and Temozolomide

This phase II/III trial tests how well adding mycophenolate mofetil, to the usual treatment with intensity-modulated radiation therapy and temozolomide works for the treatment of glioblastoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). Mycophenolate mofetil blocks enzyme activity which can disrupt tumor activity and may make the tumor more sensitive to radiation and/or temozolomide. Intensity modulated radiation therapy is a type of 3-dimensional radiation therapy that uses computer-generated images to show the size and shape of the tumor. Thin beams of radiation of different intensities are aimed at the tumor from many angles. This type of radiation therapy reduces the damage to healthy tissue near the tumor. Temozolomide is a chemotherapy drug and in a class of medications called alkylating agents. It damages the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. Giving mycophenolate mofetil with intensity-modulated radiation therapy and temozolomide may be more effective than intensity-modulated radiation therapy and temozolomide alone for the treatment of advanced glioblastoma.

Study Overview

• Status: Not yet recruiting
• Conditions: Advanced Glioblastoma
• Intervention / Treatment: Procedure: Magnetic Resonance Imaging; Radiation: Intensity-Modulated Radiation Therapy; Drug: Mycophenolate Mofetil; Radiation: Hypofractionated Radiation Therapy; Drug: Temozolomide (TMZ); Procedure: Biospecimen Collection

Detailed Description

The primary and secondary objectives of the study:

PRIMARY OBJECTIVE:

I. To compare the overall survival (OS) (phase III) and progression-free survival (PFS) (phase II) between the experimental arm (mycophenolate mofetil [MMF] + standard of care [SOC]) and the control arm (SOC).

SECONDARY OBJECTIVES:

I. To compare the proportion of patients with an objective tumor response (ORR), measured with Response Assessment in Neuro-Oncology (RANO) 2.0 criteria, between the two treatment arms.

II. To determine the adverse event profiles for each arm (using the current latest version of Common Terminology Criteria for Adverse Events [CTCAE]).

III. To determine if there is an association between OS and PFS between treatment arms.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients under 70 years undergo intensity modulated radiation therapy (IMRT), Monday-Friday for 30 treatments and patients greater than or equal to 70 years undergo hypofractionated radiation therapy, Monday-Friday for 15 treatments in the absence of disease progression or unacceptable toxicity. Starting 24 hours prior to radiation, patients also receive temozolomide orally (PO) once daily (QD) until the day of the last radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients then undergo a 4-week rest period. Patients then receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo magnetic resonance imaging (MRI) and blood sample collection throughout the study.

ARM II: Patients under 70 years undergo IMRT, Monday-Friday for 30 treatments and patients greater than or equal to 70 years undergo hypofractionated radiation therapy, Monday-Friday for 15 treatments in the absence of disease progression or unacceptable toxicity. Starting 24 hours prior to radiation, patients also receive temozolomide PO QD until the day of the last radiation treatment, and, starting on the first day of radiation, patients also receive mycophenolate mofetil PO twice daily (BID) in the absence of disease progression or unacceptable toxicity. Patients then undergo a 4-week rest period. Patients then receive temozolomide PO QD on days 1-5 and mycophenolate mofetil PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI and blood sample collection throughout the study.

After completion of study treatment, patients are followed up every 10 weeks until 2 years then every 6 months until 5 years.

• Study Type: Interventional
• Enrollment (Estimated): 422
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Amanda Clark; Phone Number: (773) 702-9171; Email: neurooncologyprotocols@alliancenctn.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Newly diagnosed primary glioblastoma by World Health Organization (WHO) 2021 criteria
• No spinal cord glioblastoma
• No leptomeningeal disease
• No extracranial metastatic disease
• Patient is a candidate for first-line standard of care chemoradiation per treating physician(s)
• No prior treatment for glioblastoma other than resection (i.e. prior chemotherapy, radiation therapy, or other therapies such as laser ablation are not allowed)
• Prior biopsy and/or resection of glioblastoma must be completed at least 14 days prior to registration with adequate wound healing
• Age ≥ 18 years
• Karnofsky performance status (KPS) ≥ 60
• Absolute neutrophil count (ANC) ≥ 1,500/mm^3
• Platelet count ≥ 100,000 cells/mm^3
• Hemoglobin (Hg) ≥ 9.0 g/dL

• Calculated (Calc.) creatinine clearance (CrCl) ≥ 25 mL/min

  * Calculated using the Cockcroft-Gault equation

• Bilirubin ≤ 1.5 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 3.0 x ULN
• Not pregnant and not nursing, because this study involves an agent that has known genotoxic, mutagenic and teratogenic effects.

Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 14 days prior to registration is required.

Women and men of reproductive potential must agree to use a highly effective method of birth control throughout their participation in this study and for at least 6 weeks (women) or 90 days (men) after last dose of treatment. Reproductive status and discussions about birth control measures should be documented in the patient's record. Appropriate methods of birth control include, but are not limited to: abstinence, oral contraceptives, implantable hormonal contraceptives or double barrier method (diaphragm plus condom)

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• HIV-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• 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
• No known history of allergic reaction or hypersensitivity to mycophenolate mofetil (MMF), mycophenolic acid (MPA), or any component of the drug product
• No known history of hypersensitivity reactions to temozolomide (TMZ) or other ingredients in TMZ
• No known medical condition causing an inability to swallow oral formulations of agents
• No active systemic or central nervous system (CNS) infection
• No grade 4 lymphopenia (if absolute lymphocyte count [ALC] < 0.5, then patient must be on prophylaxis for Pneumocystis jirovecii)
• No known history of organ transplantation
• No known hypoxanthine-guanine phosphoribosyl-transferase deficiency
• No known serious intercurrent illness that limits participation in the trial
• No known immunosuppressive condition from autoimmune disease, immune deficiency syndrome, or chronic immunosuppressive therapy
• Patient must be able to undergo MRI brain with and without contrast
• No known phenylketonuria
• No known medical contraindication for mycophenolate mofetil (MMF) per treating physician(s)
• Patients on steroids must be on stable or decreasing dose within 7 days of registration (no more than 8 mg dexamethasone/day or equivalent)

Exclusion Criteria:

-

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (radiation, temozolomide); Patients under 70 years undergo IMRT, Monday-Friday for 30 treatments and patients greater than or equal to 70 years undergo hypofractionated radiation therapy, Monday-Friday for 15 treatments in the absence of disease progression or unacceptable toxicity. Starting 24 hours prior to radiation, patients also receive temozolomide PO QD until the day of the last radiation treatment, in the absence of disease progression or unacceptable toxicity. Patients then undergo a 4-week rest period. Patients then receive temozolomide PO QD on days 1-5 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI and blood sample collection throughout the study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Radiation: Hypofractionated Radiation Therapy; Undergo hypofractionated radiation therapy; Drug: Temozolomide (TMZ); Given PO; Procedure: Biospecimen Collection; undergo Biospecimen Collection
Experimental: Arm II (radiation, temozolomide, mycophenolate mofetil); Patients under 70 years undergo IMRT, Monday-Friday for 30 treatments and patients greater than or equal to 70 years undergo hypofractionated radiation therapy, Monday-Friday for 15 treatments in the absence of disease progression or unacceptable toxicity. Starting 24 hours prior to radiation, patients also receive temozolomide PO QD until the day of the last radiation treatment, and, starting on the first day of radiation, patients also receive mycophenolate mofetil PO twice daily (BID) in the absence of disease progression or unacceptable toxicity. Patients then undergo a 4-week rest period. Patients then receive temozolomide PO QD on days 1-5 and mycophenolate mofetil PO BID on days 1-28 of each cycle. Cycles repeat every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo MRI and blood sample collection throughout the study.	Procedure: Magnetic Resonance Imaging; Undergo MRI; Radiation: Intensity-Modulated Radiation Therapy; Undergo IMRT; Other Names: IMRT; Drug: Mycophenolate Mofetil; Given PO; Drug: Temozolomide (TMZ); Given PO; Procedure: Biospecimen Collection; undergo Biospecimen Collection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS) (phase II)	PFS will be calculated from randomization until disease progression according to RANO 2.0 criteria or death due to any cause, censoring patients at their last disease evaluation. The Kaplan-Meier method will be used to estimate PFS for each arm and a stratified log-rank test will be used to compare distributions	From randomization to the disease progression according to Response Assessment in Neuro-Oncology (RANO) 2.0 criteria or death due to any cause, up to 5 years
Overall survival (OS) (phase III)	OS will be calculated from randomization until death due to any cause, censoring patients at their last disease evaluation. The Kaplan-Meier method will be used to estimate OS for each arm and a stratified log-rank test will be used to compare distributions.	From randomization until death due to any cause, up to 5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tumor response	Defined as a complete response or partial response as determined using RANO 2.0.	Up to 5 years
Incidence of adverse events	Determined by the most recent version of Common terminology Criteria for Adverse Events.	Up to 5 years
Overall survival (OS)	Kaplan Meier methods will be used to estimate key aspects of the OS distributions for each of the treatment arms, and log rank tests will be used to compare these distributions between arms.	From randomization until death due to any cause, up to 5 years
Progression free survival (PFS)	Kaplan-Meier methods will be used to estimate key aspects of the PFS distributions for each of the treatment arms, and log-rank tests will be used to compare these distributions between arms.	From randomization to the disease progression according to RANO 2.0 criteria or death due to any cause, up to 5 years

Collaborators and Investigators

• Sponsor: Alliance for Clinical Trials in Oncology
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Priya Kumthekar, MD, Alliance for Clinical Trials in Oncology; Study Chair: Yoshie Umemura, MD, MS, Alliance for Clinical Trials in Oncology

Study record dates

Study Major Dates

• Study Start (Estimated): June 10, 2026
• Primary Completion (Estimated): September 30, 2029
• Study Completion (Estimated): January 5, 2031

Study Registration Dates

• First Submitted: May 19, 2026
• First Submitted That Met QC Criteria: May 19, 2026
• First Posted (Actual): May 26, 2026

Study Record Updates

• Last Update Posted (Actual): May 26, 2026
• Last Update Submitted That Met QC Criteria: May 19, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Investigative Techniques; Therapeutics; Fatty Acids; Lipids; Azoles; Acids, Acyclic; Carboxylic Acids; Dacarbazine; Triazenes; Imidazoles; Chemistry Techniques, Analytical; Spectrum Analysis; Radiotherapy; Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Caproates; Temozolomide; Mycophenolic Acid; Magnetic Resonance Spectroscopy; Radiotherapy, Intensity-Modulated
• Other Study ID Numbers: A072402

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No