Results from phase 1 study of mycophenolate mofetil with chemoradiation in newly diagnosed glioblastoma to target de-novo purine metabolism to overcome treatment resistance.

Abstract

2015 Background: Mycophenolate mofetil (MMF) inhibits IMPDH and disrupts de novo purine synthesis which is preferred by glioblastoma (GBM) whilst normal brain prefers resource efficient salvage pathway. A phase 0 study demonstrated the active drug metabolite reaching both enhancing and non-enhancing GBM tissues in humans, and effective target engagement, noted by reduced GTP/IMP ratio. This phase 1 trial assessed the tolerability of MMF with chemoradiation in newly diagnosed GBM patients (NCT04477200). Methods: Thirty adult patients with newly diagnosed GBM were given MMF, dosed BID, 1 week prior to and concurrently with standard of care (SOC) radiotherapy (RT) of 60 Gy in 30 fractions with concomitant temozolomide (TMZ) 75mg/m2, followed by MMF 1 day before + 5 days of each SOC TMZ 150-200mg/m2 x 5/28-day cycle up 12 cycles. Optune was optional. Primary endpoint was dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of MMF combined with SOC GBM chemoradiation. Time-to-event continual reassessment method was used to determine MMF dosing, with MTD defined as estimated rate of dose-limiting toxicity (DLT) closest to but not exceeding 30%. DLT periods were during and up to 4 weeks after concurrent chemoradiation (DLT1), and first two 28-day cycles of MMF with temozolomide (DLT2). Transient grade 4 neutropenia x < 7 days and asymptomatic grade 4 lymphopenia were excluded from DLT. Kaplan Meier method was used to estimate overall survival (OS). Results: The median age was 57 (range 20-75). The majority had KPS > 80 (67%) at baseline, and unmethylated MGMT (70%). During DLT1 period, 5 DLT1 was noted out of 16 subjects on 2000mg BID (grade 3 hemiparesis, cognitive disturbance, fatigue, and grade 4 thrombocytopenia x2), and none at 1500mg (N = 10) and 1000mg (N = 4). During DLT2 period, 1/6 subjects at 1500mg BID experienced DLT of grade 3 fatigue, and none at 1000mg (N = 4) and 2000mg (N = 16). All DLTs were reversible. Four patients did not receive MMF during DLT2 period due to withdrawal from the study (N = 2) and progression of disease (N = 2). The most common treatment related adverse events were fatigue (77%), leukopenia (67%), and nausea (53%). Of the dose levels studied, the MTD for DLT1 and DLT2 were both 2000mg BID (posterior probability of DLT1: 18.5%, posterior probability of DLT2: 7.5%), however, due to frequent fatigue and nausea, DLT1 period starting dose was lowered to 1500mg BID for the last 7 subjects. The recommended phase 2 dose is 1500mg BID combined with concurrent RT+TMZ followed by TMZ. Median OS was 16.8 months with 25.5 months median follow up duration (NR & 25.5 months in MGMT methylated, 14.2 & 24.9 months in MGMT unmethylated respectively). Conclusions: MMF can penetrate enhancing and non-enhancing GBM with evidence of successful inhibition of de-novo purine synthesis in humans, and is reasonably well tolerated when combined with chemoradiation newly diagnosed GBM patients. These promising results have led to a planned phase 2/3 randomized controlled trial through Alliance for Clinical Trials in Oncology. Clinical trial information: NCT04477200 .