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



      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).


      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.


      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.


      The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients.


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        • Ame J.C.
        • Spenlehauer C.
        • de Murcia G.
        The PARP superfamily.
        Bioessays. 2004; 26: 882-893
        • Ashworth A.
        A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair.
        J Clin Oncol. 2008; 26: 3785-3790
        • McCabe N.
        • Turner N.C.
        • Lord C.J.
        • et al.
        Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition.
        Cancer Res. 2006; 66: 8109-8115
        • Bryant H.E.
        • Schultz N.
        • Thomas H.D.
        • et al.
        Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase.
        Nature. 2005; 434: 913-917
        • Farmer H.
        • McCabe N.
        • Lord C.J.
        • et al.
        Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy.
        Nature. 2005; 434: 917-921
        • Audeh M.W.
        • Carmichael J.
        • Penson R.T.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 245-251
        • Tutt A.
        • Robson M.
        • Garber J.E.
        • et al.
        Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial.
        Lancet. 2010; 376: 235-244
        • Gelmon K.A.
        • Tischkowitz M.
        • Mackay H.
        • et al.
        Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study.
        Lancet Oncol. 2011; 12: 852-861
        • Balmana J.
        • Tung N.M.
        • Isakoff S.J.
        • et al.
        Phase I, open-label study of olaparib plus cisplatin in patients with advanced solid tumors.
        J Clin Oncol. 2012; ([abstr. 1009])
        • Rajan A.
        • Carter C.A.
        • Kelly R.J.
        • et al.
        A phase I combination study of olaparib with cisplatin and gemcitabine in adults with solid tumors.
        Clin Cancer Res. 2012; 18: 2344-2351
        • Dean E.
        • Middleton M.R.
        • Pwint T.
        • et al.
        Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours.
        Br J Cancer. 2012; 106: 468-474
        • Burger R.A.
        • Sill M.W.
        • Monk B.J.
        • Greer B.E.
        • Sorosky J.I.
        Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study.
        J Clin Oncol. 2007; 25: 5165-5171
        • Cannistra S.A.
        • Matulonis U.A.
        • Penson R.T.
        • et al.
        Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer.
        J Clin Oncol. 2007; 25: 5180-5186
        • Matulonis U.A.
        • Berlin S.
        • Ivy P.
        • et al.
        Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer.
        J Clin Oncol. 2009; 27: 5601-5606
        • Miller K.
        • Wang M.
        • Gralow J.
        • et al.
        Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer.
        New Engl J Med. 2007; 357: 2666-2676
        • Mayer E.L.
        • Hamell S.
        • Savoie J.
        • et al.
        AZD2171 for refractory breast cancer: a phase 2 trial.
        Breast Cancer Res Treat. 2007; 106 ([abstr. 6080]): S274
        • Tentori L.
        • Lacal P.M.
        • Muzi A.
        • et al.
        Poly(ADP-ribose) polymerase (PARP) inhibition or PARP-1 gene deletion reduces angiogenesis.
        Eur J Cancer. 2007; 43: 2124-2133
        • Bindra R.S.
        • Gibson S.L.
        • Meng A.
        • et al.
        Hypoxia-induced down-regulation of BRCA1 expression by E2Fs.
        Cancer Res. 2005; 65: 11597-11604
        • Bindra R.S.
        • Schaffer P.J.
        • Meng A.
        • et al.
        Down-regulation of Rad51 and decreased homologous recombination in hypoxic cancer cells.
        Mol Cell Biol. 2004; 24: 8504-8518
        • Chan N.
        • Bristow R.G.
        “Contextual” synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair.
        Clin Cancer Res. 2010; 16: 4553-4560
        • Hegan D.C.
        • Lu Y.
        • Stachelek G.C.
        • et al.
        Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130.
        Proc Natl Acad Sci U S A. 2010; 107: 2201-2206
        • Rustin G.J.
        Use of CA-125 to assess response to new agents in ovarian cancer trials.
        J Clin Oncol. 2003; 21: 187s-193s
        • Fong P.C.
        • Boss D.S.
        • Yap T.A.
        • et al.
        Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers.
        N Engl J Med. 2009; 361: 123-134