Phase 1 trial of olaparib and oral cyclophosphamide in BRCA breast cancer, recurrent BRCA ovarian cancer, non-BRCA triple-negative breast cancer, and non-BRCA ovarian cancer

Chee Khoon Lee,Chee Khoon Lee,Geoffrey J Lindeman,Geoffrey J Lindeman,Geoffrey J Lindeman,Edmond Michael Kwan,Lauren Macnab,Robin Paterson,Robin Paterson,Emma Gibbs,Elizabeth Lieschke,Anne Hamilton,Prudence A Francis,Rebecca Asher,Heath Badger,Heath Badger,Michael Friedlander,Michael Friedlander,Frances Boyle,Frances Boyle,Frances Boyle,Frances Boyle,Clare Scott,Clare Scott,Clare Scott

doi:10.1038/s41416-018-0349-6

Abstract

BackgroundWe conducted a Phase 1 study to evaluate safety and activity of olaparib tablets and oral cyclophosphamide.MethodsPatients had metastatic breast cancer (BC) or recurrent high-grade serous ovarian cancer (HGSOC), performance status 0–2, and ≤3 lines of prior therapy. Patients were treated using a dose escalation strategy with cohort expansion once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1): olaparib 300 mg bid, cyclophosphamide 50 mg on days 1, 3, and 5, weekly. DL2: olaparib 300 mg bid, cyclophosphamide 50 mg, days 1–5 weekly.ResultsOf 32 patients, 23 had HGSOC (germline BRCA mutation [gBRCAm] 70%) and 9 had BC (gBRCAm 67%). Four were treated at DL1 and 28 at DL2, the MTD. Haematological adverse events (AEs) were most common: grade 3/4 AEs: lymphopenia 75%, anaemia 31%, neutropenia 37%, thrombocytopenia 47%. Two permanently discontinued treatment due to haematological AEs. In BC, no objective response was reported. Unconfirmed objective response was 48% and 64% for all HGSOC and gBRCAm subset, respectively. CA125 responses were 70% (all HGSOC) and 92% (gBRCAm).ConclusionsIn HGSOC and BC, olaparib 300 mg bid and cyclophosphamide 50 mg on days 1–5 weekly were tolerable and active, particularly in gBRCAm, and is worthy of further investigation.

Highlights

Olaparib is a first-in-class potent oral poly (ADP-ribose) polymerase (PARP) inhibitor
Dose optimisation and treatment-related adverse events We have identified the recommended Phase 2 dose (RP2D) as olaparib tablets 300 mg twice daily, and cyclophosphamide tablets 50 mg on days 1–5 each week
Despite no dose-limiting toxicity (DLT)’s being observed with olaparib plus cyclophosphamide during the first 6 weeks of therapy at DLs 1 and 2, patients did not proceed to DL3 due to recurrent haematological adverse events (AEs) observed beyond 6 weeks (Table 1)

Summary

Introduction

Olaparib is a first-in-class potent oral poly (ADP-ribose) polymerase (PARP) inhibitor. Monotherapy studies have demonstrated acceptable toxicity and activity in metastatic breast cancer[1,2,3,4,5], and recurrent ovarian cancer[1,2,3,4,6,7] in patients with germline BRCA mutations (gBRCAm). Response rates varied from 0 to 60% and 26 to 41% for gBRCAm breast and ovarian cancer patient cohorts, respectively. METHODS: Patients had metastatic breast cancer (BC) or recurrent high-grade serous ovarian cancer (HGSOC), performance status 0–2, and ≤3 lines of prior therapy. CONCLUSIONS: In HGSOC and BC, olaparib 300 mg bid and cyclophosphamide 50 mg on days 1–5 weekly were tolerable and active, in gBRCAm, and is worthy of further investigation

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Conclusion