Olaparib (Lynparza) is a potent, oral PARP inhibitor that induces synthetic lethality in tumours deficient in homologous recombination repair. Durvalumab is a selective, high-affinity, engineered, human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80, preventing PD-L1-mediated inhibition of T-cell activation, and promoting antitumour immune responses. In a Phase I study (NCT02484404), olaparib plus durvalumab was tolerable, and a recommended combination dose was determined (Lee et al, ASCO 2016). MEDIOLA (NCT02734004) is using this combination dose to assess olaparib and durvalumab, which may have complementary mechanisms of action, in pts selected using criteria that predict sensitivity to olaparib.
MEDIOLA has four pt cohorts: pts with platinum-sensitive recurrent ovarian cancer (OC) who have received ≥2 lines of platinum-based therapy and have a known/suspected deleterious germline BRCA1/2 mutation (gBRCAm); pts with unresectable, advanced, gBRCAm, HER2-negative breast cancer (BC) who have received anthracycline/taxane therapy; pts with small-cell lung cancer (SCLC) that has relapsed >12 weeks (wks) after platinum-based therapy; and pts with advanced ATM-negative gastric cancer (GC) that has progressed after first-line chemotherapy. Pts will receive olaparib monotherapy (300 mg bid, tablets) for 4 wks, then olaparib (300 mg bid) plus durvalumab (1500 mg IV q4w) until disease progression. Disease will be assessed by CT/MRI at baseline, after olaparib monotherapy and every 8 wks during the combination phase. Primary objectives are disease control rate (DCR) at 12 wks (includes pts with complete/partial response or stable disease) by modified RECIST 1.1 (using a post-progression scan), safety and tolerability. Secondary endpoints include pharmacokinetics, DCR at 28 wks, objective response rate, progression-free survival and overall survival. Cohorts will be considered as individual Bayesian predictive probability designs. Initially, 10 pts/cohort will be enrolled across ∼17 centres worldwide, with expansion to n = 30 (OC), n = 38 (BC), n = 34 (SCLC) and n = 37 (GC) after interim assessment. Enrolment began in Q1 2016.
Clinical trial identification
Legal entity responsible for the study
S. Domchek: The University of Pennsylvania has received research funding from AbbVie, and Clovis. Dr. Domchek has received an honorarium from EMD Serrano. Y-J. Bang: Research funds from AstraZeneca (through institution), and consulted for AstraZeneca. G. Coukos: Commercial research grants: Celgene, Boehringer-Ingelheim. Honoraria from Speakers Bureau: Roche, Genentech. Consultant or Advisory Roles: Genentech, Roche, Novartis, Sanofi-Aventis. K. Kobayashi, N. Baker, E. McMurtry, W. Song: AstraZeneca employee and AstraZeneca stock ownership. B. Kaufman: Participation in an advisory board for AstraZeneca.