CTNI-61. MYCOPHENOLATE MOFETIL INHIBITS GLIOBLASTOMA PURINE METABOLISM IN HUMANS: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Abstract

Abstract BACKGROUND Mycophenolate mofetil (MMF), a purine synthesis inhibitor, improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) is the first-in-human study to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. METHODS Adult patients meeting eligibility are given MMF 500-2000 PO BID using TITE-CRM dose assignment. Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly-diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with chemoradiation and followed for 28 days for DLT1-period. During the adjuvant temozolomide (days 1-5/28-day cycle) period, MMF is given days 0-5 on a separate dose-escalation (DLT2 period = cycles 1-2). Tissues from phase-0 recurrent glioblastoma patients (N = 8) receiving MMF 500-2000mg BID one-week pre-operatively are analyzed using mass spectrometry. RESULTS Enhancing and non-enhancing tumor from phase 0 subjects yielded above 1 µM active drug metabolite, and the GTP/IMP ratio was decreased by 75% in enhancing tumor in MMF-treated patients compared to untreated controls (p = 0.009), indicating effective target engagement and inhibition of purine synthesis. No DLT has been observed with adjuvant cyclic temozolomide in phase 1 newly-diagnosed group (N = 26), nor in the recurrent-disease group (N = 18) with re-irradiation. In newly diagnosed arm, 3 subjects experienced DLT1 at 2000mg BID; grade-3 hemiparesis and cognitive disturbance, and grade-4 thrombocytopenia. Other main toxicities are mild nausea and fatigue. Interim median overall survival in recurrent phase 1 is 15.6 months, and not reached yet in newly diagnosed phase 1. CONCLUSION MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary promising evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.