CTNI-19. MYCOPHENOLATE MOFETIL TARGETS GLIOBLASTOMA DE-NOVO PURINE METABOLISM TO OVERCOME CHEMORADIATION RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA

Abstract

Abstract Glioblastoma prefer de-novo purine synthesis while normal brain prefers resource-efficient salvage pathway. Mycophenolate mofetil (MMF) disrupts de-novo purine metabolism by inhibiting a key enzyme, IMPDH. The pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma models led to this first-in-human phase 0/1 trial (NCT04477200) to assess the tolerability of MMF with chemoradiation in glioblastoma, MPA accumulation, and purine synthesis inhibition in tumor. Tissues from eight phase 0 recurrent glioblastoma subjects, receiving MMF ranging 500-2000mg BID one-week pre-operatively, were analyzed using mass spectrometry. Both enhancing and non-enhancing tumor yielded >1µM 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). In phase 1 study, adult patients were given MMF ranging 1000-2000mg PO BID using TITE-CRM dosing. Twenty-one recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy) with no dose-limiting toxicities (DLTs). Thirty newly diagnosed glioblastoma patients received MMF one-week prior to and concurrently with chemoradiation, followed by MMF one-day before and during 5 days of each adjuvant temozolomide cycles. In the newly diagnosed cohort, there was no DLT with temozolomide and MMF, however, with both temozolomide and radiation, there were five DLT instances noted at 2000mg BID (G3 hemiparesis, G3 cognitive disturbance, G3 fatigue, G4 thrombocytopenia x2): all were reversible. Interim phase 1 median overall-survival in recurrent MGMT-methylated and unmethylated subjects were 16.1 (N=10) and 6.1 (N=11) months, and in newly diagnosed subjects, 27.2 (N=8) and 14.2 months (N=22) respectively. Median follow ups were 7.4 (recurrent) and 23.2 months (new diagnosis). MMF combined with chemoradiation is reasonably well tolerated in glioblastoma patients with promising evidence of drug accumulation in glioblastoma, effective target engagement and inhibition of purine synthesis, leading to a recommended phase 2 dose of MMF 1500mg BID.