Background: p53 mutations are associated with increased chemoresistance. APR-246 is a small molecule that restores mutant p53 to wild type conformation and function(Lambert et al., Cancer Cell. 2009; 15(5):376-88). APR-246 also increases reactive oxygen species levels and ER stress; acts synergistically with DNA damaging drugs in vitro; resensitizes ovarian cancer cells to cisplatin and doxorubicin in vitro and reduces glutathione levels thereby decreasing cellular drug efflux. APR-246 showed no end-organ toxicity in the non-clinical toxicity studies but C_max related reversible CNS effects were identified. In a previous single agent dose finding study recommended phase II dose and safety profile was determined and signs of clinical activity and p53-dependent biological effects were observed in several patients (Lehmann et al., J Clin Oncol. 2012; 30(29):3633-9). As in animals dose limiting toxicity (DLT) was mainly C_max related reversible CNS effects. PK was linear and displayed no accumulation. APR-246 was concluded to have a safety and PK profile suitable for further development in combination with chemotherapeutic drugs. The rationale for this study was that p53 mutation occurs in > 97% of HGSOC, thus identifying an appropriate study population for targeted therapy. Methods: Patients with relapsed platinum sensitive HGSOC and positive p53 immunostaining were treated with APR-246 in combination with carboplatin AUC 5 and pegylated liposomal doxorubicin 30 mg/m²every 4 weeks for 6 cycles. APR-246 was dosed as a 6h IV infusion on 4 consecutive days; on day 4, chemotherapy was given concomitantly with APR-246. A 3+3 dose escalation design with 3 dose levels (35, 50 and 67.5 mg/kg) was used. Endpoints include determination of the appropriate combination APR-246 dose, safety, PK, progression free survival, response rate, overall survival and multiple translational readouts (transcriptomic and proteomic). Matched pre-treatment and on-treatment radiologically guided biopsies are mandatory. The first two dose cohorts have been recruited with one DLT (GI perforation) in cohort 2. Recruitment to cohort 3 commenced in December 2014. Clinical trial information: NCT02098343