Background: Adding P to gemcitabine (GEM) for platinum-resistant ovarian cancer improved progression-free survival (PFS) in a subset of patients (pts) with low tumor HER3 mRNA expression [Makhija 2010]. PENELOPE (NCT01684878) comprises a safety run-in (Part 1, complete) and PLA-controlled randomized assessment of CT ± P (Part 2, below). Methods: Eligible pts have: measurable/non-measurable recurrent platinum-resistant epithelial ovarian, primary peritoneal or fallopian tube cancer (progression during or within 6 mo of completing ≥4 platinum cycles); centrally tested low HER3 mRNA expression (concentration ratio ≤2.81 by qRT-PCR on cobas z480); and have received ≤2 prior lines of CT. The primary Part 2 objective is to determine if PFS (assessed by independent review committee; IRC) is superior with P + CT vs PLA + CT. The key secondary endpoint is overall survival (OS). Both endpoints are part of a closed testing procedure. Additional endpoints include investigator-assessed PFS, objective response rate (RECIST v1.1), safety (NCI CTCAE v4.0), quality of life (including EORTC QLQ-C30 and QLQ-OV28) and pharmacokinetic parameters. Translational studies aiming to scrutinize and validate the preselection concept by correlating markers of signal pathway activation with efficacy have been implemented. Additional exploratory analyses will include gene expression profiling. Investigators select CT (topotecan, paclitaxel or GEM) before 1:1 randomization to P or PLA. Treatment is continued until progression or unacceptable toxicity. Stratification factors are: selected CT; prior anti-angiogenic therapy; and platinum-free interval (<3 vs 3–6 mo). The planned Part 2 enrollment is 154 pts. Recruitment to each CT cohort is capped at 1/3 of the total sample size. Primary PFS analysis will be done after 109 IRC-assessed PFS events, providing 95% power to detect a PFS hazard ratio (HR) of 0.50 (median PFS 1.4→2.8 mo) with 2-sided log-rank at α=0.05. Final OS analysis is planned after 129 deaths in Part 2, providing 80% power to detect an OS HR of 0.61 (median OS 8.4→13.8 mo); 2-sided log-rank at α=0.05. By 27 Jan 2014, 62 pts were randomized. Clinical trial information: NCT01684878.