Epithelial Cancer, Fallopian Tube Cancer, Ovarian Cancer
Conditions
Keywords
safety, efficacy, PARP inhibitor, HIPEC, Hyperthermic intraperitoneal Chemotherapy
Brief summary
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.
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.
Interventions
DRUGOlaparib
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.
Sponsors
The Netherlands Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety and toxicity of combining PARP-inhibitors with HIPEC | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The degree of PARP (enzymatic) inhibition | 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. |
Countries
Netherlands
Contacts
CONTACTmadelief schreuder-goedheijt
CONTACTleah frenkel
Outcome results
None listed