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 Anti-Cancer Agents & Biologic Therapy
Ovarian Cancer
Gynaecologic Malignancies
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.