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.
Keywords
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Article Info
Publication History
Published online: July 01, 2013
Identification
Copyright
© 2013 Elsevier Ltd. Published by Elsevier Inc. All rights reserved.
