Mansoor Raza Mirza1,2, Troels K Bergmann3, Morten Mau-Sørensen4, René dePont Christensen5,6, Elisabeth Åvall-Lundqvist5,7, Michael J Birrer8, Morten Jørgensen5,4, Henrik Roed5,4, Susanne Malander5,9, Flemming Nielsen10, Ulrik Lassen4, Kim Brøsen10, Line Bjørge5,11,12, Johanna Mäenpää5,13. 1. Nordic Society of Gynecological Oncology (NSGO), Copenhagen, Denmark. mansoor@rh.regionh.dk. 2. Department of Oncology, Copenhagen University Hospital, 5073, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. mansoor@rh.regionh.dk. 3. Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, Denmark. 4. Department of Oncology, Copenhagen University Hospital, 5073, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark. 5. Nordic Society of Gynecological Oncology (NSGO), Copenhagen, Denmark. 6. Research Unit of General Practice, Institute of Public Health, University of Southern Denmark, Odense, Denmark. 7. Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. 8. Comprehensive Cancer Center, The University of Alabama, Birmingham, USA. 9. Lund University Hospital, Lund, Sweden. 10. Clinical Pharmacology and Pharmacy, Department of Public Health, Environmental Medicine, University of Southern Denmark, Odense, Denmark. 11. Department of Clinical Science, Center for Cancer Biomarkers CCBIO, University of Bergen, Bergen, Norway. 12. Department of Gynecology and Obstetrics, Haukeland University Hospital, Bergen, Norway. 13. Department of Obstetrics and Gynecology, Tampere University Hospital, University of Tampere, Tampere, Finland.
Abstract
BACKGROUND: Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial. MATERIALS AND METHODS: In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer receivedbevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D). RESULTS: Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21. CONCLUSIONS: There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.
RCT Entities:
BACKGROUND: Combining poly(ADP-ribose) polymerase (PARP) inhibitors with antiangiogenic agents appeared to enhance activity vs PARP inhibitors alone in a randomized phase II trial. MATERIALS AND METHODS: In AVANOVA (NCT02354131) part 1, patients with measurable/evaluable high-grade serous/endometrioid platinum-sensitive ovarian cancer received bevacizumab 15 mg/kg every 21 days with escalating doses of niraparib capsules (100, 200, or 300 mg daily) in a 3 + 3 dose-escalation design. Primary objectives were to evaluate safety and tolerability and to determine the recommended phase II dose (RP2D). RESULTS: Three of 12 enrolled patients had germline BRCA2 mutations. In cycle 1, nine patients experienced grade 3 toxicities: five with hypertension, three with anemia, and one with thrombocytopenia. There was one dose-limiting toxicity (grade 4 thrombocytopenia with niraparib 300 mg), thus the RP2D was bevacizumab 15 mg/kg with niraparib 300 mg. The response rate was 50%; disease was stabilized in a further 42%. Median progression-free survival was 11.6 (95% confidence interval 8.4-20.1) months. Niraparib pharmacokinetics were consistent with historical single-agent data. Overlapping exposure was observed across the dose ranges tested on days 1 and 21. CONCLUSIONS: There was one dose-limiting toxicity; other adverse events were typical PARP inhibitor and antiangiogenic class effects. Niraparib-bevacizumab showed promising activity; Part 2 (vs bevacizumab) was recently reported and phase III comparison with standard-of-care therapy is planned.