PISARRO: A EUTROC phase 1b study of APR-246 with carboplatin (C) and pegylated liposomal doxorubicin (PLD) in relapsed platinum-sensitive high grade serous ovarian cancer (HGSOC)

TP53 mutations are ubiquitous in HGSOC. APR-246 stabilises mutant p53 into wild-type conformation and through its active moiety MQ, also depletes glutathione and inhibits thioredoxin reductase. These mechanisms of action potentiate chemosensitivity of cancer cells. This study aimed to establish the recommended phase II dose (RPTD) of APR-246 in combination with C and PLD. A 3 + 3 dose escalation study of APR-246 (35, 50 and 67.5mg/kg IV on days 1-4) in combination with C AUC5 and PLD 30mg/m2 given on day 4 in a 28-day schedule. Eligible patients had platinum sensitive relapsed HGSOC with archival tumour specimens demonstrating cytoplasmic mutant p53 staining. Following recruitment to the three dose cohorts (3 + 6 + 6) further patients were included in dose level (DL) 1 and DL3 cohorts to evaluate possible dose dependency of safety and efficacy. CA-125 was tested at each cycle, and CT scans performed every two cycles. All 3 dose escalation cohorts have completed recruitment with expansion of DL2 (due to one dose limiting toxicity (DLT) of ruptured diverticulum) and DL3 (RPTD). No dose dependent signals in activity or toxicity were established. The main toxicity attributable to APR-246 was dizziness in 20 out of 28 patients (71%; 18 grade 1/2, 2 grade 3). There were no pharmacokinetic interactions between APR-246 and C/PLD. To date, of 17 patients evaluable for CA125 response (GCIG Intergroup criteria) after at least 2 cycles, 14 showed response. Nine of these responders were previously partially platinum sensitive, of whom 8 out of 9 were treated at DL3. Of 18 patients evaluable for radiological response, 3 had a CR (2 confirmed), 11 had a PR, 4 had SD and 0 had PD. Overall response rate (GCIG or RECIST) was 18/23 (78%). APR-246 at a dose of 67.5mg/kg in combination with C and PLD has been selected as RPTD. Efficacy data for the combination regimen in the phase 1b study is encouraging and a multi-centre randomised phase II study is being opened in 2016. Updated efficacy and translational data will be presented.