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

Eur J Cancer. 2013 Sep;49(14):2972-8. doi: 10.1016/j.ejca.2013.05.020. Epub 2013 Jun 27.

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: Anti-angiogenic; Breast; Cediranib; Olaparib; Ovarian; PARP-inhibitor; Phase 1.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Capsules
  • Carcinoma, Ovarian Epithelial
  • Diarrhea / chemically induced
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fatigue / chemically induced
  • Female
  • Humans
  • Middle Aged
  • Nausea / chemically induced
  • Neoplasm Recurrence, Local
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / pathology
  • Phthalazines / administration & dosage
  • Phthalazines / adverse effects
  • Piperazines / administration & dosage
  • Piperazines / adverse effects
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolines / administration & dosage
  • Quinazolines / adverse effects
  • Receptor, ErbB-2 / metabolism
  • Receptors, Estrogen / metabolism
  • Receptors, Progesterone / metabolism
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Tablets
  • Treatment Outcome

Substances

  • Capsules
  • Phthalazines
  • Piperazines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolines
  • Receptors, Estrogen
  • Receptors, Progesterone
  • Tablets
  • Receptor, ErbB-2
  • Receptors, Vascular Endothelial Growth Factor
  • cediranib
  • olaparib

Associated data

  • ClinicalTrials.gov/NCT01116648