Phase I lead-in to a 2x2x2 factorial trial of dose-dense temozolomide, memantine, mefloquine, and metformin as postradiation adjuvant therapy of glioblastoma (GBM)

TPS2106 Background: Treatment for GBM is an area of unmet need. Despite optimal therapy, survival is poor and 2nd line therapies are scarce. There is an urgent need to find better treatments for recurrence, but also more effective 1st line therapies. Dose-dense temozolomide (ddTMZ) using the 7/14-day regimen has shown promising preliminary results in combination with cytostatic agents. Memantine (MEM) is a glutamate receptor (NMDA) blocker with antiproliferation properties and possibly neuroprotective effect. Mefloquine (MFQ) induces autophagy and apoptosis. Metformin (MFM) has mTOR inhibitor properties. Methods: Trial Design: Phase I/II trial to evaluate adjuvant ddTMZ with MEM MFQ and MFM. Primary objective Phase I: MTDs of ddTMZ with MEM/MFQ/MFM, 3+3 design. MTDs will be the recommended Phase II doses for a subsequent randomized factorial Phase II trial (ddTMZ alone and single, double and triple combinations). Accrual of about 55 eligible patients was calculated for Phase I (48-144). Clinical trial registry number is NCT01430351. Treatment planned: Patients accrued sequentially to ddTMZ with 1, 2, or 3 drugs. Arm 1 (ddTMZ alone) will be enrolled in Phase II only. Patients were first accrued to 1-drug Arms 2-4. Once MTDs were determined, accrual started to 2-drug Arms 5-7. Once completed, accrual to Arm 8 will start. Arms 2-4 were started at a predetermined target dose, and deescalated if excessive toxicity. Treatment in Arms 5-8 will be escalated for each drug to reach MTDs of Arms 2-4. Major eligibility criteria: Adults (≥ 18) with supratentorial GBM, KPS ≥60, adequate bone marrow and organ function. Post chemoradiation MRI ≤14 days before enrollment on stable/decreasing steroids and no progression; registration ≤5 weeks of chemoradiation. Patients on MFQ: no EIAED, EKG without prolonged QTc or arrhythmia. Pregnancy not allowed; adequate contraception required. Informed consent in keeping with IRB policies. Current enrollment: To date, 49 patients started treatment and 18 are still active. Enrollment to Arms 2-4 and 6 is completed and MTDs determined. Accrual is ongoing in Arms 5 and 7, and pending in Arm 8. Clinical trial information: NCT01430351.