Mycophenolate Mofetil in Combination With Standard of Care for the Treatment of Glioblastoma

PRIMARY OBJECTIVE: I. To evaluate the recommended phase 2 dose (RP2D) for mycophenolate mofetil (MMF) in combination with radiation therapy as well as in combination with temozolomide (TMZ). II. Phase 1b (Groups 3 and R): To estimate median and corresponding 95% CI for progression-free survival (PFS) and overall survival (OS). III. Phase 0 (Group S; Sub-Group S1 and Sub-Group S2): To evaluate drug uptake and target effect in the brain. SECONDARY OBJECTIVES: I. To evaluate the safety profile of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ). II. To estimate progression free survival (PFS) per Response Assessment in Neuro-Oncology Criteria (RANO). III. To estimate overall survival (OS). IV. To estimate the overall response rate (ORR) per RANO criteria. V. To evaluate quality of life per Functional Assessment of Cancer Therapy Scale-Brain (FACT-Br) for patients treated with mycophenolate mofetil and/or temozolomide. EXPLORATORY OBJECTIVES: I. To investigate the relationship between the molecular signature of individual glioblastoma multiforme (GBM) with clinical outcome, by measuring levels of serum mycophenolic acid in patient's plasma post MMF administration. Ia. Perform molecular characterization of all GBM tissues by ribonucleic acid sequencing (RNAseq) analysis. Ib. Perform bulk metabolomics for GBM tissue. Ic. Measure plasma and serum concentration of mycophenolic acid, the MMF's primary active metabolite, during and after combination therapy. Id. Measure IMPDH activity assay in patients' peripheral blood mononuclear cells (PBMCs) as well as in GBM tissue. Ie. Analyze relevant gene mutations from standard of care next generation sequencing (NGS) tumor gene mutation data, if available. II. Group R only: To assess early efficacy of mycophenolate mofetil (MMF) in combination with temozolomide (TMZ) in recurrent GBM. OUTLINE: This is a dose-escalation study of MMF (Part 1), followed by a dose-expansion study (Part 2). PART 1: Patients are assigned to 1 of 3 groups. GROUP 1: Patients who have already undergone surgery or biopsy followed by chemoradiation receive TMZ orally (PO) once daily (QD) on days 1-5 of each cycle and MMF PO twice daily (BID). Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. GROUP 2: Patients with unmethylated glioblastoma who have already undergone surgery or biopsy receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting at the same time as TMZ and MMF administration, patients also receive radiation therapy daily, 5 days per week, for 6 weeks. GROUP S: Patients planning to undergo surgery receive MMF PO BID and TMZ PO QD for 5 days prior to surgery in the absence of disease progression or unacceptable toxicity. PART 2: Patients are assigned to Group 3 or enrolled to Group R. GROUP 3: Patients who have already undergone surgery or biopsy receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Starting at the same time as TMZ and MMF administration, patients also receive radiation therapy daily, 5 days per week, for 6 weeks. After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 18 months. Group R (Recurrent): MMF + TMZ at MTD. Enrollment to begin concurrently with Group 3.Group R will be given the MTD for temozolomide + MMF via the same schedule and dosing as the adjuvant group (Group 1) and will open once the RP2D from Group 1 has been determined. Patients receive TMZ PO QD on days 1-5 of each cycle and MMF PO BID. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.