The PROOV Study: Exploiting the Synergistic Effect of PARP Inhibition With Cisplatin and Hyperthermia During Interval Cytoreductive Surgery and HIPEC in Ovarian Cancer (PROOV)

March 5, 2026 updated by: The Netherlands Cancer Institute
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Peritoneal recurrence is common in patients with advanced epithelial ovarian cancer (EOC) despite cytoreductive surgery (CRS) and platinum-based chemotherapy. Novel therapeutic strategies have emerged, such as Hyperthermic Intra PEritoneal Chemotherapy (HIPEC) added to interval CRS and maintenance therapy with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors (PARPi). While these treatment strategies effectively delay recurrences, long-term survival for patients with advanced EOC remains poor.

It has been demonstrated that PARP inhibition synergizes with platinum compounds, but concurrent treatment with systemically administered platinum is considered too (myelo-)toxic. On the other hand, hyperthermia induces a transient state of homologous recombination deficiency (HRD) that is required for a therapeutic effect of PARP inhibition. Hence, we hypothesize that administering HIPEC when PARP is inhibited could optimally exploit the synergistic effect of local cisplatin and hyperthermia at the peritoneal surface without adding systemic toxicity.

The study population will consist of min. 40 to max. 55 patients with histologically proven FIGO stage III and operable stage IV high-grade serous ovarian cancer, peritoneal cancer, or fallopian tube carcinoma eligible for interval CRS with HIPEC, meaning that only patients with a response or stable disease after neo-adjuvant chemotherapy (NACT) will be eligible.

The study participants enrolled in the PROOV will receive seven days of PARPi (olaparib, Lynparza®) twice a day. The dosage will be either 100mg, 150mg or 300mg, depending on the phase of the trial. The treatment with olaparib will start 7 days before the scheduled CRS, with the final dose administered in the morning prior to the surgery. Following achievement of optimal or complete interval CRS, HIPEC will be performed by administering cisplatin intraperitoneally (either 100 mg/m2 with a maximum of 220 mg, or 40 mg/L) and sodium thiosulphate intravenously. Blood samples and peritoneal tissue samples (before and after HIPEC) will be collected for the translational analyses. Whenever possible, tissue at recurrence will also be collected.

Study Type

Interventional

Enrollment (Estimated)

55

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • In order to be eligible to participate in this study, a subject must meet all of the following criteria:

    • 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.

    • FIGO stage IV is allowed in the following situations:

      • Resectable stage IV desease, such as local bowel involvement, iatrogenic abdominal wall metastases or umbilical lesions
      • Stage IV based on cardiophrenic lymph nodes <1cm
    • The diagnosis should be confirmed with either histology or cytology. If the diagnosis of ovarian carcinoma is based on cytology only, immunohistochemistry, including keratin 7, keratin 20, p53, PAX8 should be considered for confirmation of the diagnosis (at the discretion of the pathologist)

    • Eligible and planned for interval cytoreductive surgery with HIPEC

      • Neo-adjuvant chemotherapy consists of at least 3 courses of carboplatin/paclitaxel
      • Patients should have response or stable disease after NACT; no progression should occur
      • Operability has been evaluated in a multidisciplinary team (MDT) meeting via CT scan, MRI or diagnostic laparoscopy and an optimal or complete interval CRS is deemed feasible
    • Fit for major surgery, WHO performance status 0-2
    • Adequate bone marrow function (hemoglobin level >5.5 mmol/L, leukocytes >3 x10^9/L, platelets > 100 x10^9/L)
    • Adequate hepatic function (ALT, AST, and bilirubin < 2.5 times the upper limit of normal)
    • Adequate renal function (creatinine clearance ≥ 60 ml/min using Cockcroft-Gault formula or 24-hour measurement or ml/min/1,73 m2 using MDRD or CKD-EPI)

Exclusion Criteria:

  • A potential subject who meets any of the following criteria will be excluded from participation in this study:

    • 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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: PARPi (olaparib, Lynparza®)
Drug: Olaparib
seven days of PARPi (olaparib, Lynparza®) twice a day. The dosage will be either 100mg, 150mg or 300mg, depending on the phase of the trial.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Safety and toxicity of combining PARP-inhibitors with HIPEC
Time Frame: 4 years

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.
4 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The degree of PARP (enzymatic) inhibition
Time Frame: 4 years
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.
4 years

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall survival (OS)
Time Frame: 10 years
10 years
Recurrence-free survival (RFS)
Time Frame: 10 years
10 years
Tumor cell proliferation (Ki67)
Time Frame: 4 years
4 years
DNA damage (yH2AX foci assay)
Time Frame: 10 years
10 years
○ Apoptosis (cl-Casp3)
Time Frame: 4 years
4 years
Functional homologous recombination (RAD51 foci assay)
Time Frame: 10 years
10 years
The establishment of patient-derived organoids/explants cultures from tumor tissue collected intraoperatively
Time Frame: 4 years
Tumor tissue obtained during cytoreductive surgery will be used to generate PDOs and/or short-term explant cultures. These ex vivo models will be used to mimic the cellular response of patient tumors after clinical exposure to PARP inhibitors (PARPi) and HIPEC, allowing evaluation of treatment effects over time.
4 years
Treatment effects in the tumor microenvironment
Time Frame: 4 years
Spatial proteomics analyses (CODEX) comparing the baseline tumor microenvironment with the on post treatment tumor microenvironment.
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

The Netherlands Cancer Institute

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2025

Primary Completion (Estimated)

May 1, 2027

Study Completion (Estimated)

May 1, 2032

Study Registration Dates

First Submitted

November 27, 2025

First Submitted That Met QC Criteria

March 5, 2026

First Posted (Actual)

March 10, 2026

Study Record Updates

Last Update Posted (Actual)

March 10, 2026

Last Update Submitted That Met QC Criteria

March 5, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • M23PRV

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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