The PROOV study is an open-label, monocenter, single-arm, prospective phase I/II trial with a safety lead-in, evaluating the feasibility of combining PARPi with HIPEC in stage III EOC patients. Phase I is a dose-finding phase with a time-to-event Bayesian Optimal Interval (TITE-BOIN) design, in which three doses of olaparib are evaluated to identify the optimal dose for the phase II part and future trials. The recommended phase II dose (RP2D) will be determined based on the experienced DLTs per dose level and the level of intra-tumor and systemic enzymatic PARP inhibition. During Phase II, the safety profile of the RP2D will be assessed in a total cohort of 40 patients. To provide a proof-of-concept, efficacy will be explored in both translational analyses and survival data.
Signed and written informed consent
At least 18 years of age and able to understand patients' information
FIGO stage III primary high-grade serous ovarian, fallopian tube, or extra-ovarian cancer.
Resectable stage IV desease, such as local bowel involvement, iatrogenic abdominal wall metastases or umbilical lesions
History of previous malignancy treated with chemotherapy
Opting for fertility-sparing surgery
Concurrent use of potent inducers or inhibitors of CYP3A4 as assessed with the KNMP "G-standaard" that cannot be stopped temporarily
Single group
Olaparib
Drugseven days of PARPi (olaparib, Lynparza®) twice a day. The dosage will be either 100mg, 150mg or 300mg, depending on the phase of the trial.
Safety and toxicity of combining PARP-inhibitors with HIPEC
Safety lead in phase 1 part: evaluation of dose limiting toxicities by CTCAE v.5 and Clavien dindo from start PARP inhibition until 28 days postoperatively. Evaluated dosages are 100mg, 150mg and 300mg BID of olaparib. Further toxicity will be evaluated in phase 2, in which an additional number of patients will be treated with recommended phase 2 dose.
The degree of PARP (enzymatic) inhibition
Blood and intracellular PARP activity will be measured, and the extent of PARP inhibition will be quantified as percentage reduction (%) from baseline activity levels in all enrolled patients.
Overall survival (OS)
Recurrence-free survival (RFS)
Tumor cell proliferation (Ki67)
DNA damage (yH2AX foci assay)
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