P18.13.A DE-NOVO PURINE METABOLISM CAN BE TARGETED SAFELY IN GLIOBLASTOMA TREATMENT TO OVERCOME CHEMORADIATION RESISTANCE: AN INTERIM RESULT OF PHASE 0/1 CLINICAL TRIAL

Abstract BACKGROUND Mycophenolate mofetil (MMF) is a commonly used oral immunosuppressant, which exerts its effect by its antimetabolite mechanism. Contrary to normal brain preferring to salvage purines, which is resource-efficient, glioblastoma tumor cells prefer to make new purine via de-novo purine pathway. The de-novo purine metabolism can be disrupted using MMF which inhibits IMPDH, a key enzyme in this pathway. There are pre-clinical evidence of MMF improving radiation and temozolomide efficacy in glioblastoma mouse models, which 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. MATERIAL AND METHODS In the phase 0 study, eight recurrent glioblastoma patients received MMF at doses ranging 500-2000mg BID for one-week before planned surgery. The tissues were analyzed using mass spectrometry for drug accumulation and purine synthesis inhibition. In the phase 1 study, adult patients were given MMF starting at 1000mg PO BID, with the possible dose ranging 500-2000 PO BID using TITE-CRM. Nineteen recurrent glioblastoma patients (target N=30) received MMF one-week prior to and concurrently with re-irradiation (40.5 Gy). 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. RESULTS Both enhancing and non-enhancing tumor from phase 0 subjects 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), indicating effective target engagement and inhibition of purine synthesis. In the Phase 1 study, no dose limiting toxicities (DLTs) have been observed at the interim analysis at MMF 1000-1500mg BID combined with chemoradiation. At 2000mg BID, there was no DLT combined with temozolomide alone, however, there were four DLTs noted (hemiparesis, cognitive disturbance, fatigue, thrombocytopenia) when combined with radiotherapy and temozolomide together, though all were reversible. 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 promising evidence of brain tumor target engagement and drug accumulation in gliobla