Background: P53 is ubiquitously mutated in HGSOC. APR-246 is a novel agent which stabilises mutant P53 in the wild-type conformation, increasing cancer cell chemo-sensitivity. Our aim was to establish the recommended phase II dose (RPTD) of APR-246 in combination with C and PLD. Methods: A 3+3 dose escalation of APR-246 (35, 50 and 67.5 mg/kg given IV days 1-4) in combination with C AUC 5 and PLD 30mg/m2 given day 4 in a 28 day schedule was performed in patients with platinum sensitive relapsed HGSOC whose archival tumour specimen demonstrated mutant P53 IHC staining. After the three cohorts were fully recruited (3+6+6) further patients were included in the high and low cohorts to allow a better evaluation of the possible dose dependency of safety and efficacy. Patients were followed with CA-125 after each cycle and by CT scan every two cycles. Results: All three dose cohorts were fully recruited with expansion of middle (DLT) and high (RPTD) cohort. One DLT (ruptured diverticulum) occurred at dose level 2. No difference in dose dependent activity or toxicity was demonstrated. In the expanded cohorts (9 in lower and 11 in higher) two additional DLT events (myelosuppression and fatigue) occurred. The main toxicity attributable to APR-246 rather than chemotherapy was dizziness, which occurred in 20 out of 28 patients (71%; 18 grade 1/2, 2 grade 3). This was self-limiting, resolving within 24 hours of APR-246 infusion. Pharmacokinetic analysis revealed no interaction between APR-246 and C or PLD. In the 17 patients evaluable for GCIG response that had received at least 2 cycles (11 partially platinum sensitive; PPS) 14 responded (9 PPS). Response rate was 7/8 (88%) in the high dose cohort. Of 20 patients evaluable for best response by RECIST 1.1, 3 had a CR, 9 had a PR (4 await confirmatory scan), 8 had SD and 0 had PD. Overall response rate (GCIG or RECIST) was 17/23 (74%), 11/16 (69%) in PPS patients. Conclusions: An APR-246 dose of 67.5 mg/kg has been selected for use in combination with C and PLD for phase 2 evaluation. The combination activity in the phase 1b study is encouraging, particularly in patients with partially platinum sensitive disease. Clinical trial information: 2013-001472-38.