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

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.

Poly(ADP-ribose) Polymerase 1 Modulates the Lethality of CHK1 Inhibitors in Mammary Tumors

“…1, A-C) (Donawho et al, 2007;Riches et al, 2008;Zabludoff et al, 2008;Fong et al, 2009;Khan et al, 2011). Of particular note was the finding that the cell death response of tumor cells lacking PTEN function (BT549 and HCC38) was not significantly different from that of cells expressing wild-type PTEN (HCC1187 and HCC1954).…”

PARP and CHK inhibitors interact to cause DNA damage and cell death in mammary carcinoma cells

“…33,34 PARP1 inhibitor trials in other malignancies are still on-going. 35,36 CHK and PARP inhibitors interacted to cause single strand and double strand DNA breaks. PARP is known to regulate base excision repair whereas CHK signaling plays a role in regulating the G 1 and G 2 checkpoints as well as homologous recombination repair.…”

Synthesis and Evaluation of a Radioiodinated Tracer with Specificity for Poly(ADP-ribose) Polymerase-1 (PARP-1) in Vivo

“…However, a number of early phase clinical trials have reported severe bone marrow toxicity with such therapeutic combinations [5][6][7][8][9][10] which could in part be attributed to suboptimal dosing schedules. 8 Non-invasive in vivo imaging of PARP-1 using a radiolabeled PARPi and techniques such as Positron Emission Tomography (PET) or Single-Photon Emission Tomography (SPECT) could be used to assess the duration of PARP-1 inhibition in different tissues.…”