A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer

TitleA Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer
Publication TypeJournal Article
Year of Publication2013
AuthorsLiu, JF, Tolaney, SM, Birrer, MJ, Fleming, GF, Buss, MK, Dahlberg, SE, Lee, H, Whalen, C, Tyburski, K, Winer, E, Ivy, P, Matulonis, UA
JournalEur J Cancer
Volume49
Pagination2972-8
KeywordsAdministration, Drug Drug Administration Schedule Fatigue/chemically induced Female Humans Middle Aged Nausea/chemically induced Neoplasm Recurrence, erbB-2/metabolism Receptors, Estrogen/metabolism Receptors, Glandular and Epithelial/*drug therapy/pathology Ovarian Neoplasms/*drug therapy/pathology Phthalazines/administration & dosage/adverse effects Piperazines/administration & dosage/adverse effects Poly(ADP-ribose) Polymerases/antagonists & inhibitors Quin, Local Neoplasms, Oral Adult Aged Antineoplastic Combined Chemotherapy Protocols/adverse effects/*therapeutic use Breast Neoplasms/*drug therapy/metabolism/pathology Capsules Diarrhea/chemically induced Dose-Response Relationship, Progesterone/metabolism Receptors, Vascular Endothelial Growth Factor/antagonists & inhibitors Tablets Treatment Outcome
Abstract

BACKGROUND: Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). METHODS: Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. RESULTS: 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia >/= 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks. INTERPRETATION: The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients.