Phase I study to assess the safety and tolerability of olaparib in combination with bevacizumab in patients with advanced solid tumours

• Published in: British journal of cancer Vol. 106; no. 3; pp. 468 - 474
• Main Authors: Dean, E, Middleton, M R, Pwint, T, Swaisland, H, Carmichael, J, Goodege-Kunwar, P, Ranson, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 31.01.2012; Nature Publishing Group
• Subjects: 631/92/436/108; 631/92/436/1729; 692/699/67; 692/700/565/1436/1437; Administration, Oral; Adult; Aged; Angiogenesis Inhibitors - administration & dosage; Angiogenesis Inhibitors - pharmacokinetics; Antibodies, Monoclonal, Humanized - administration & dosage; Antibodies, Monoclonal, Humanized - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bevacizumab; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Breast Neoplasms - blood; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cancer Research; Cancer therapies; Chemotherapy; Clinical Studies; clinical-study; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; DNA damage; Drug Resistance; Epidemiology; Female; Humans; Hypoxia; Infusions, Intravenous; Male; Medical research; Medical sciences; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Oncology; Ovaries; Phthalazines - administration & dosage; Phthalazines - adverse effects; Phthalazines - pharmacokinetics; Piperazines - administration & dosage; Piperazines - adverse effects; Piperazines - pharmacokinetics; Poly(ADP-ribose) Polymerase Inhibitors; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Toxicity; Treatment Outcome; Tumors; Vascular endothelial growth factor; Young Adult; United Kingdom > UK; bevacizumab; phase 1; AZD2281; olaparib; Antineoplastic agent; Human; AZD228 1; Solid tumor; Drug combination; Olaparib; Monoclonal antibody; Malignant tumor; Bevacizumab; Cancerology; Vascular endothelium growth factor; Treatment; Phase I trial; Advanced stage; phase I; Antiangiogenic agent; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.555

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.