Phase I Trial Results Demonstrate Safe Administration of Niraparib/Bevacizumab Combo in Relapsed Ovarian Cancer

Mansoor Raza Mirza, MD

Mansoor Raza Mirza, MD

Results of a phase I trial demonstrate that the combination of niraparib and bevacizumab (Avastin) can be safely administered to patients with platinum-sensitive relapsed ovarian cancer. The findings were presented during the 2016 ASCO Annual Meeting¹and included data from the 12 patients enrolled on the trial.

“This is part 1 of a 2-stage study. Part 2 is a phase II randomized trial,” said lead author Mansoor Raza Mirza, MD, medical director of the Nordic Society of Gynaecologic Oncology, and chief oncologist at Rigshospitalet, Copenhagen, Denmark. “Niraparib was not given with bevacizumab before so we had to do the feasibility [study]. So these 12 patients’ data are of the feasibility, and we reached the defined dose easily. We are already randomizing patients in the phase II part.”

The primary objective of part 1 was the safety and tolerability of the combination of the PARP inhibitor niraparib with the VEGF inhibitor bevacizumab. Secondary objectives included determining the recommended phase II dose of the combination, and describing preliminary antitumor responses.

Part 1 enrolled patients with recurrent platinum-sensitive epithelial ovarian cancer, defined as no recurrence within 6 months of the last dose of a platinum-based chemotherapy regimen. Patients must have received platinum-based therapy for primary disease, without limit to the number of platinum-based therapies, and up to 1 non-platinum-based line of therapy for recurrent disease.

Bevacizumab and niraparib were administered on day 1 of 21-day cycles. Bevacizumab was administered first followed by niraparib. Niraparib was administered on days 2 to 21. In cohorts 1 to 3, the dose of bevacizumab was fixed at 15 mg/kg, once every 3 weeks. The dose of niraparib was escalated in each cohort: 100 mg daily in cohort 1200 mg daily in cohort 2, and 300 mg daily in cohort 3.

There were 12 women enrolled, 3 each in cohorts 1, 2, and 3. Cohort 3 had 3 additional women enrolled. The median age was 63.5 years, and mean prior treatment regimen was 2.5.

The median treatment duration was 41.7 weeks. During that time, no patients in cohort 1 required dose reductions. Dose reductions and interruptions occurred in cohorts 2 and 3 for both agents. Two patients discontinued treatment: 1 patient in cohort 1 withdrew consent due to unrelated pancreatitis, and 1 patient had progressive disease.

The objective response rate was 41.6% (5 of the 12 evaluable patients); there was 1 patient with a complete response (CR, 8.3%), 4 patients with partial responses (PR, 33.3%), 6 patients with stable disease (SD, 50%), and 1 patient with progressive disease (PD, 8.3%). The disease control rate (CR+PR+SD) was 91.6%.

Patients were tested for BRCA somatic mutations, BRCA germline mutations, and homologous recombination deficiency (HRD) score, which have previously been reported to be associated with response to niraparib. In this study, the patient with CR was positive for HRD and somatic mutation.

There were 3 additional patients positive for HRD: 2 had BRCA2 positive germline mutations, and of these, 1 had a PR, 1 had SD; the third patient had no somatic BRCA mutations, a wild-type germline BRCA, and PR. BRCA/HRD results were pending for 1 patient. The patient with PD had negative HRD and BRCA somatic mutations, and a wild-type germline BRCA.

Dose-limiting toxicities (DLT) did not occur in patients in cohorts 1 and 2; in cohort 3, 1 patient had a DLT of grade 4 thrombocytopenia. Based on these results, the maximum tolerated dose was not reached and the recommended phase II dose was determined to be 300 mg daily of niraparib plus 15 mg/kg of bevacizumab once every 3 weeks.

Toxicities other than DLT included grade 3 muscle pain and hypertension in cohort 1, and grade 2 fatigue and grade 3 anemia in cohort 2. In cohort 3, patients experienced grade 2 nausea and fatigue, as well as grade 3 hypertension, thrombocytopenia, anemia, and proteinuria.

The phase II portion of the study (NCT02354131) will enroll 132 patients with platinum-sensitive ovarian cancer with positive HRD scores. Patients will be randomly assigned to 1 of 3 arms comprised of bevacizumab 15 mg/kg every 3 weeks, niraparib 300 mg daily on days 1 to 21, or a combination of both drugs.

Patients will be treated until PD or toxicity. Patients on the bevacizumab arm will cross over to niraparib. Patients in the other 2 arms will receive the investigator’s choice but not niraparib.

References:

1. Mirza RM, Mortensen CR, Christensen R, et al. A phase I study of bevacizumab in combination with niraparib in patients with platinum-sensitive epithelial ovarian cancer: The ENGOT-OV24/AVANOVA1 trial.J Clin Oncol. 2016;34 (suppl; abstr 5555).