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Clinical Trial
. 2011 Mar 1;104(5):750-5.
doi: 10.1038/bjc.2011.8. Epub 2011 Feb 15.

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

O A Khan  1 , M Gore, P Lorigan, J Stone, A Greystoke, W Burke, J Carmichael, A J Watson, G McGown, M Thorncroft, G P Margison, R Califano, J Larkin, S Wellman, M R Middleton
Affiliations
Clinical Trial

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

O A Khan et al. Br J Cancer. .

Abstract

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.

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Figures

Figure 1
Figure 1
Chronological flow chart of implemented study design cohorts.
Figure 2
Figure 2
Pharmacokinetic data: (A) Activity of N-methylpurine-DNA glycosylase (MPG) during course of sampling after olaparib administration. (B) Mean MPG activity for 21 available patients. (C) Effect of MPG activity on 7-methylguanine (7-meG) levels.
See this image and copyright information in PMC

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