This is a phase 0/1 dose-escalation trial to determine the maximum tolerated dose of Mycophenolate Mofetil (MMF) when administered with radiation, in patients with glioblastoma or gliosarcoma.
The goal of the Phase 0 component is to determine if MMF achieves active concentrations in brain tumors. Eight participants in Phase 0 will receive MMF for one week before undergoing an already planned biopsy or re-resection (surgical removal) of glioblastoma or gliosarcoma (GBM/GS). A small portion of the tumor, removed as part of clinical care, will be used for testing in this study. Sixty additional participants will be enrolled in the Phase 1 component of the trial (30 with recurrent GBM/GS and 30 with newly diagnosed GBM/GS). The goal of the Phase 1 component is to find the dose of MMF that works best without causing severe side effects (the maximum tolerated dose) when combined with radiation in recurrent GBM/GS and with radiation and chemotherapy in newly diagnosed GBM/GS. Participants in Phase 0 who meet the eligibility criteria for the Phase 1 component may participate in both phases.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
68
500-2000mg orally twice daily, one week prior to re-resection (2 participants at each of 4 dose levels: 500mg, 1000mg, 1500mg and 2000mg)
40.5 Gy in 15 fractions
Re-resection or biopsy of tumor as part of standard of care
University of Michigan Rogel Cancer Center
Ann Arbor, Michigan, United States
Concentration of Mycophenolic Acid (MPA) in Tumor Tissue in Phase 0 Participants
The concentration of MPA (the active metabolite of mycophenolate mofetil \[MMF\]) in tumor tissue, measured by mass spectrometry on a continuous scale after one week of MMF administration. This measure includes all phase 0 participants.
Time frame: At 1 week
Number of Recurrent Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + radiation therapy (RT). Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only phase 1 participants with recurrent GBM/GS.
Time frame: Up to 28 days following completion of MMF + RT (up to ~9 weeks)
Number of Newly Diagnosed Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level -- DLT1 Period
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced from the start of treatment with MMF and for up to 4 weeks after completion of MMF + RT + TMZ. Assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.
Time frame: Up to 28 days following completion of MMF + RT + TMZ (up to ~11 weeks)
Number of Newly Diagnosed Phase 1 Participants Who Experience Dose-limiting Toxicities (DLTs) at Each Dose Level -- DLT2 Period
DLT will be defined based on the rate of drug related grade 3-5 adverse events experienced during the first 2 cycles (8 weeks) of MMF with adjuvant TMZ. (The first cycle of MMF with adjuvant TMZ begins 28 days post-RT.) These will be assessed using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0. This measure includes only newly diagnosed phase 1 participants.
Time frame: During the first 2 cycles (8 weeks) of MMF with adjuvant TMZ (up to ~19 weeks)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Temozolomide capsules are an approved oral chemotherapeutic drug for the treatment of adult patients with newly diagnosed GBM/GS concomitantly with radiotherapy and then as adjuvant treatment. The dosing and timing of temozolomide therapy will be determined as per standard-of-care for the individual patient by the treating oncologist.
250-2000mg orally twice daily, one week prior to and concurrent with RT.
250-2000mg orally twice daily, one week prior to and concurrent with RT and cyclic chemotherapy with temozolomide.
60 Gy in 30 fractions
Concentrations of Guanosine Triphosphate (GTP) in Tumor Tissue in Phase 0 Participants
The concentrations of GTP in tumor tissue, measured by mass spectrometry on a continuous scale. This measure includes all phase 0 participants.
Time frame: After one week of MMF administration
Adverse Events Associated With Treatment in All Phase 1 Participants
Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes all phase 1 participants.
Time frame: Up to 28 days following completion of MMF + RT (up to ~9 weeks)
Adverse Events Associated With Treatment in Newly Diagnosed Phase 1 Participants
Toxicities at each dose level will be tabulated, categorized by grade and attribution. This measure includes only newly diagnosed phase 1 participants.
Time frame: Up to 28 days following completion of MMF with adjuvant temozolomide (up to ~15 months)
Overall Response Rate in Phase 1 Participants With Recurrent GBM/GS
Determined by modified Response Assessment for Neuro-Oncology (mRANO) criteria. The number and proportion of patients with progressive disease, stable disease, partial and complete response will be calculated for each dose level and overall. This measure includes only phase 1 participants with recurrent GBM/GS.
Time frame: Until study stops or death; up to approximately 3 years.
Median Progression Free Survival (PFS) in Phase 1 Participants With Recurrent GBM/GS
PFS defined as time from date of registration to the date of documented progressive disease, other disease related therapy or death. Determined by mRANO criteria. This measure includes only phase 1 participants with recurrent GBM/GS.
Time frame: Until study stops or death; up to approximately 3 years.
Median Freedom From Local Progression (FFLP) in Phase 1 Participants With Recurrent GBM/GS
FFLP defined as time from date of registration to the date of documented local progressive disease. Determined by mRANO criteria. This measure includes only phase 1 participants with recurrent GBM/GS.
Time frame: Until study stops or death; up to approximately 3 years.
Median Overall Survival (OS) in Phase 1 Participants With Recurrent GBM/GS
OS defined as time from date of registration to date of death or last follow up. Determined by Kaplan Meier method. This measure includes only phase 1 participants with recurrent GBM/GS.
Time frame: Until study stops or death; up to approximately 3 years.