Combination therapy with DNAdamaging agents

The intravenous PARPi PF-1367338 has been investigated in the clinic for several years, and recently a Phase II study coupling PF-1367338 with cisplatin was initiated in TNBC patients [46]. A Phase II study with combination therapy of PF-1367338 and TMZ in metastatic malignant melanoma patients has been reported [47]. In this melanoma clinical trial, there was an increase in both the partial response rate and disease stabilization compared to the use of TMZ monotherapy alone. This improved response was accompanied by an increased frequency of myelosuppression.

Arguably, the most clinically advanced PARPi is BSI-201 and this agent is currently being investigated in Phase III studies in TNBC as a combination with both gemcitabine and carboplatin [48]. The results of a randomized Phase II studies have been reported, where TNBC patients were treated with both gemcitabine and carboplatin and BSI-201 was given to one group of patients [49]. Interim results showed clinical benefit in 62% of patients on the BSI-201 combination, compared to 21% on chemotherapy alone. Improvements in survival were also noted, with median overall survival of 9.2 months compared with 5.7 months, respectively. The BSI-201 combination was well tolerated; common severe side effects included neutropenia, thrombocytopenia, and anemia.

Combination studies of olaparib are being explored clinically with a number of agents, including irinotecan, dacarbazine, carboplatin, gemci-tabine, doxorubicin, cisplatin, and topotecan.

A Phase 0 clinical trial was conducted using ABT-888 [50] to determine a dose range and time course that would inhibit PARP activity. The compound was rapidly absorbed, with the target Cmax exceeded at a 10 mg dose. Statistically significant PARP inhibition was observed in PBMC and tumor biopsies following single 25 and 50 mg doses. Currently, ABT-888 is being used in combination with several chemother-apeutics, and results of a Phase I study of ABT-888 combined with TMZ in patients with nonhematological malignancies and metastatic melanoma have been reported [51]. Of 20 patients evaluated, one had a partial response, and 10 had stable disease. Finally, Phase I clinical trials with the PARPi CEP-9722 were initiated in 2009 [52].

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