A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer

NSGO AVANOVA1/ENGOT-OV24

Mansoor Raza Mirza, Troels K Bergmann, Morten Mau-Sørensen, René dePont Christensen, Elisabeth Åvall-Lundqvist, Michael J Birrer, Morten Jørgensen, Henrik Roed, Susanne Malander, Flemming Nielsen, Ulrik Lassen, Kim Brøsen, Line Bjørge, Johanna Mäenpää

Research output: Contribution to journalJournal articleResearchpeer-review

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 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.

Original languageEnglish
JournalCancer Chemotherapy and Pharmacology
Volume84
Issue number4
Pages (from-to)791-798
ISSN0344-5704
DOIs
Publication statusPublished - Oct 2019

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Platinum
Angiogenesis Inhibitors
Germ-Line Mutation
Ovarian Neoplasms
Disease-Free Survival
Pharmacokinetics
Poly(ADP-ribose) Polymerase Inhibitors
niraparib
Bevacizumab
Confidence Intervals
Safety

Cite this

Mirza, Mansoor Raza ; Bergmann, Troels K ; Mau-Sørensen, Morten ; Christensen, René dePont ; Åvall-Lundqvist, Elisabeth ; Birrer, Michael J ; Jørgensen, Morten ; Roed, Henrik ; Malander, Susanne ; Nielsen, Flemming ; Lassen, Ulrik ; Brøsen, Kim ; Bjørge, Line ; Mäenpää, Johanna. / A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer : NSGO AVANOVA1/ENGOT-OV24. In: Cancer Chemotherapy and Pharmacology. 2019 ; Vol. 84, No. 4. pp. 791-798.
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title = "A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer: NSGO AVANOVA1/ENGOT-OV24",
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 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.",
author = "Mirza, {Mansoor Raza} and Bergmann, {Troels K} and Morten Mau-S{\o}rensen and Christensen, {Ren{\'e} dePont} and Elisabeth {\AA}vall-Lundqvist and Birrer, {Michael J} and Morten J{\o}rgensen and Henrik Roed and Susanne Malander and Flemming Nielsen and Ulrik Lassen and Kim Br{\o}sen and Line Bj{\o}rge and Johanna M{\"a}enp{\"a}{\"a}",
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doi = "10.1007/s00280-019-03917-z",
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A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer : NSGO AVANOVA1/ENGOT-OV24. / Mirza, Mansoor Raza; Bergmann, Troels K; Mau-Sørensen, Morten; Christensen, René dePont; Åvall-Lundqvist, Elisabeth; Birrer, Michael J; Jørgensen, Morten; Roed, Henrik; Malander, Susanne; Nielsen, Flemming; Lassen, Ulrik; Brøsen, Kim; Bjørge, Line; Mäenpää, Johanna.

In: Cancer Chemotherapy and Pharmacology, Vol. 84, No. 4, 10.2019, p. 791-798.

Research output: Contribution to journalJournal articleResearchpeer-review

TY - JOUR

T1 - A phase I study of the PARP inhibitor niraparib in combination with bevacizumab in platinum-sensitive epithelial ovarian cancer

T2 - NSGO AVANOVA1/ENGOT-OV24

AU - Mirza, Mansoor Raza

AU - Bergmann, Troels K

AU - Mau-Sørensen, Morten

AU - Christensen, René dePont

AU - Åvall-Lundqvist, Elisabeth

AU - Birrer, Michael J

AU - Jørgensen, Morten

AU - Roed, Henrik

AU - Malander, Susanne

AU - Nielsen, Flemming

AU - Lassen, Ulrik

AU - Brøsen, Kim

AU - Bjørge, Line

AU - Mäenpää, Johanna

PY - 2019/10

Y1 - 2019/10

N2 - 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.

AB - 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.

U2 - 10.1007/s00280-019-03917-z

DO - 10.1007/s00280-019-03917-z

M3 - Journal article

VL - 84

SP - 791

EP - 798

JO - Cancer Chemotherapy and Pharmacology

JF - Cancer Chemotherapy and Pharmacology

SN - 0344-5704

IS - 4

ER -