Phase I Study to Assess the Safety and Tolerability of Olaparib in Combination with Bevacizumab in Patients with Advanced Solid Tumours

Overview

Journal Br J Cancer

Specialty Oncology

Date 2012 Jan 7

PMID 22223088

Citations 56

Authors

E Dean

M R Middleton

T Pwint

H Swaisland

J Carmichael

P Goodege-Kunwar

M Ranson

Affiliations

Soon will be listed here.

Abstract

Background: Olaparib (AZD2281) is a potent oral poly(ADP-ribose) polymerase inhibitor with anti-tumour activity and acceptable toxicity as monotherapy in patients with BRCA-deficient cancers. The vascular endothelial growth factor receptor inhibitor bevacizumab has been incorporated into standard of care with chemotherapy in various tumours. This phase I study established the safety, tolerability and clinical pharmacokinetics of olaparib alone and in combination with bevacizumab.

Methods: Patients with advanced solid tumours received increasing doses of continuous oral olaparib (100, 200 and 400 mg b.i.d. capsule formulation) in combination with bevacizumab (10 mg kg(-1) intravenous q2w).

Results: In all, 12 patients enrolled and received treatment. The most common adverse events (AEs) related to olaparib were grade 1/2 nausea and fatigue. No haematological parameters were reported as AEs. No serious AEs related to olaparib or dose-limiting toxicities (DLTs) were reported. Three patients discontinued due to AEs, two patients discontinued both olaparib and bevacizumab and one patient discontinued olaparib. Five patients received combination treatment for over 6 months. There was no evidence that bevacizumab affected olaparib.

Conclusion: The combination of olaparib 400 mg b.i.d. with bevacizumab 10 mg kg(-1) q2w was generally well tolerated with no DLTs. This combination could be considered for future clinical investigation.

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References

Khan O, Gore M, Lorigan P, Stone J, Greystoke A, Burke W . A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. Br J Cancer. 2011; 104(5):750-5. PMC: 3048218. DOI: 10.1038/bjc.2011.8. View

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(22):3785-90. DOI: 10.1200/JCO.2008.16.0812. View

Tutt A, Robson M, Garber J, Domchek S, Audeh M, Weitzel J . 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(9737):235-44. DOI: 10.1016/S0140-6736(10)60892-6. View

Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda S . Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010; 28(13):2144-50. DOI: 10.1200/JCO.2009.26.7849. View

Farmer H, McCabe N, Lord C, Tutt A, Johnson D, Richardson T . Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434(7035):917-21. DOI: 10.1038/nature03445. View

Fong P, Boss D, Yap T, Tutt A, Wu P, Mergui-Roelvink M . Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009; 361(2):123-34. DOI: 10.1056/NEJMoa0900212. View

Bergers G, Hanahan D . Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer. 2008; 8(8):592-603. PMC: 2874834. DOI: 10.1038/nrc2442. View

Bryant H, Schultz N, Thomas H, Parker K, Flower D, Lopez E . Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005; 434(7035):913-7. DOI: 10.1038/nature03443. View

Samol J, Ranson M, Scott E, Macpherson E, Carmichael J, Thomas A . Safety and tolerability of the poly(ADP-ribose) polymerase (PARP) inhibitor, olaparib (AZD2281) in combination with topotecan for the treatment of patients with advanced solid tumors: a phase I study. Invest New Drugs. 2011; 30(4):1493-500. DOI: 10.1007/s10637-011-9682-9. View

10.

Virag L, Szabo C . The therapeutic potential of poly(ADP-ribose) polymerase inhibitors. Pharmacol Rev. 2002; 54(3):375-429. DOI: 10.1124/pr.54.3.375. View

11.

Kwon J, Daniels M, Sun C, Lu K . Preventing future cancers by testing women with ovarian cancer for BRCA mutations. J Clin Oncol. 2009; 28(4):675-82. DOI: 10.1200/JCO.2008.21.4684. View

12.

Menear K, Adcock C, Boulter R, Cockcroft X, Copsey L, Cranston A . 4-[3-(4-cyclopropanecarbonylpiperazine-1-carbonyl)-4-fluorobenzyl]-2H-phthalazin-1-one: a novel bioavailable inhibitor of poly(ADP-ribose) polymerase-1. J Med Chem. 2008; 51(20):6581-91. DOI: 10.1021/jm8001263. View

13.

Turner N, Tutt A, Ashworth A . Hallmarks of 'BRCAness' in sporadic cancers. Nat Rev Cancer. 2004; 4(10):814-9. DOI: 10.1038/nrc1457. View

14.

Sandler A, Gray R, Perry M, Brahmer J, Schiller J, Dowlati A . Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006; 355(24):2542-50. DOI: 10.1056/NEJMoa061884. View

15.

Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W . Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004; 350(23):2335-42. DOI: 10.1056/NEJMoa032691. View

16.

Nguewa P, Fuertes M, Valladares B, Alonso C, Perez J . Poly(ADP-ribose) polymerases: homology, structural domains and functions. Novel therapeutical applications. Prog Biophys Mol Biol. 2004; 88(1):143-72. DOI: 10.1016/j.pbiomolbio.2004.01.001. View

17.

Hegan D, Lu Y, Stachelek G, Crosby M, Bindra R, Glazer P . 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(5):2201-6. PMC: 2836641. DOI: 10.1073/pnas.0904783107. View

18.

Fong P, Yap T, Boss D, Carden C, Mergui-Roelvink M, Gourley C . Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010; 28(15):2512-9. DOI: 10.1200/JCO.2009.26.9589. View

19.

Audeh M, Carmichael J, Penson R, Friedlander M, Powell B, Bell-McGuinn K . 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(9737):245-51. DOI: 10.1016/S0140-6736(10)60893-8. View

20.

Chan N, Bristow R . "Contextual" synthetic lethality and/or loss of heterozygosity: tumor hypoxia and modification of DNA repair. Clin Cancer Res. 2010; 16(18):4553-60. DOI: 10.1158/1078-0432.CCR-10-0527. View