A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours

• Published in: British journal of cancer Vol. 104; no. 5; pp. 750 - 755
• Main Authors: Khan, O A, Gore, M, Lorigan, P, Stone, J, Greystoke, A, Burke, W, Carmichael, J, Watson, A J, McGown, G, Thorncroft, M, Margison, G P, Califano, R, Larkin, J, Wellman, S, Middleton, M R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2011; Nature Publishing Group
• Subjects: 631/92/436/108; 692/699/67/1813/1634; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - pharmacokinetics; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Clinical Study; Dacarbazine - administration & dosage; Dacarbazine - adverse effects; Dermatology; Drug Administration Schedule; Drug Resistance; Epidemiology; Female; Humans; Male; Maximum Tolerated Dose; Medical sciences; Melanoma - drug therapy; Middle Aged; Molecular Medicine; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasms - drug therapy; Neutropenia - chemically induced; Oncology; Phthalazines - administration & dosage; Phthalazines - adverse effects; Piperazines - administration & dosage; Piperazines - adverse effects; Poly(ADP-ribose) Polymerase Inhibitors; Thrombocytopenia - chemically induced; Tumors; Tumors of the skin and soft tissue. Premalignant lesions; melanoma; PARP; chemotherapy; resistance; dacarbazine; Antineoplastic agent; Human; Solid tumor; Enzyme; Transferases; Glycosyltransferases; Olaparib; Malignant tumor; NAD; Resistance; Dacarbazine; Alkylating agent; Chemotherapy; Cancerology; Treatment; Malignant melanoma; Phase I trial; ADP-ribosyltransferase; Advanced stage; Pentosyltransferases; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2011.8

Background:
Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment.
Patients and methods:
Patients with advanced cancer received olaparib (20–200 mg PO) on days 1–7 with dacarbazine (600–800 mg m
−2
IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells.
Results:
The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m
−2
dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma.
Conclusion:
This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses.