953P - A Phase 1 Study to Evaluate the Safety and Tolerability of Bevacizumab-Niraparib Combination Therapy and Determine the Recommended Phase 2 Dose (RP...

Date 09 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Cytotoxic agents
Ovarian Cancer
Gynaecologic Malignancies
Therapy
Biological therapy
Presenter Mansoor Raza Mirza
Citation Annals of Oncology (2017) 28 (suppl_5): v330-v354. 10.1093/annonc/mdx372
Authors M.R. Mirza1, J. Wang2, M. Mau-Sørensen3, M.J. Birrer4, X. Wang2, M. Jørgensen5, Z. Zhang6, H. Roed5, S. Malander7, F. Nielsen8, L. Bjørge9, U. Lassen10, L. Boufercha5, K. Brøsen8, V. Kansra2, J. Mäenpää11
  • 1Oncology, Nordic Society of Gynecologic Oncology (NSGO) and Rigshospitalet, Copenhagen University Hospital, 2200 - Copenhagen/DK
  • 2Clinical Pharmacology, TESARO, Inc., Waltham/US
  • 3Oncology, Rigshospitalet, 2100 - Copenhagen/DK
  • 4Gynecologic Oncology, Massachusetts General Hospital, 2114 - Boston/US
  • 5Oncology, Nordic Society of Gynecologic Oncology (NSGO) and Rigshospitalet, 2200 - Copenhagen/DK
  • 6Clinical Pharmacology, TESARO, Inc., 02451 - Waltham/US
  • 7Oncology, The Nordic Society of Gynecological Oncology (NSGO) & Lund University Hospital, Lund/SE
  • 8Clinical Pharmacology And Pharmacy, Department of Public Health, Environmental Medicine, University of Southern Denmark, Odense/DK
  • 9Clinical Science, University of Bergen, Bergen/NO
  • 10Oncology, Rigshospitalet, 2100   - Copenhagen/DK
  • 11Obstetrics And Gynecology, University of Tampere and Tampere University, Tampere/FI

Abstract

Background

A phase 2 randomized study has indicated that the combination of a poly(ADP-ribose) polymerase inhibitor (PARPi) with an anti-angiogenic drug is superior to PARPi alone.

Methods

Bevacizumab 15 mg/kg IV q 21 days (fixed dose) was administered with escalating dose of niraparib capsules (100, 200, 300 mg daily) in a classic 3 + 3 escalation design. Platinum-sensitive ovarian cancer patients (pts) with high-grade serous/endometrioid carcinoma and with measurable disease (RECIST or GCIG criteria) were eligible. The primary objective was to evaluate the safety and tolerability of the bevacizumab-niraparib combination therapy and determine the RP2D of bevacizumab-niraparib.

Results

Twelve pts (3 + 3+6) were enrolled to three dose levels. Three of 12 pts had gBRCA2 mutation, while the others were non-gBRCAmut. During the first cycle, patients experienced hypertension (G3=5 pts), anemia (G3=3 pts), thrombocytopenia (G3=1 pt), fatigue (G2=1 pt), constipation (G2=1 pt), and nausea (G2=1 pt). One dose-limiting toxicity (Grade 3 thrombocytopenia that persisted for ≥5 days) was observed at the highest dose level, and the RP2D is therefore bevacizumab 15 mg/kg with niraparib capsules 300 mg. Niraparib dose reductions occurred in four pts (cohort 2=1 pt; cohort 3=3 pts), and bevacizumab termination occurred in two pts. Three pts are still on treatment, while nine pts have discontinued treatment (8 progressive disease; 1 withdrawal of consent). Disease control rate was 91%, and response rate was 45% (1 CR; 4 PR). Niraparib pharmacokinetics were consistent with historical data. Overlapping exposure was observed across the dose range tested at both C1D1 and C2D1.

Conclusions

The bevacizumab-niraparib combination has hematologic dose-limiting toxicity and expected, manageable class toxicities with preliminary evidence of efficacy. The PK profiles of niraparib co-administered with bevacizumab are similar to historical data. A phase 2 randomized 2-arm trial is ongoing (AVANOVA2, NCT02354131).

Clinical trial identification

NCT02354131

Legal entity responsible for the study

Nordic Society for Gynaecologic Oncology

Funding

TESARO, Inc.

Disclosure

M.R. Mirza: Advisory board: Tesaro, Roche, AstraZeneca & Clovis Oncology. J. Wang, X. Wang, Z-Y. Zhang, V. Kansra: Employment: Tesaro; Stock: Tesaro. M. Mau-Sørensen: Research grants and support to participate in conferences from Roche. S. Malander: Honoraria: AstraZeneca, Roche. All other authors have declared no conflicts of interest.