Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

8013 Background: Inhibition of PARP and thus Base Excision Repair has been shown to potentiate the cytotoxicity of DNA damaging agents preclinically. A Phase I study of AG014699 + TMZ reported at ASCO 2005 showed that a full dose of TMZ could be given in the presence of profound PARP inhibition. We report the results of a Phase II study of AG014699 12 mg/m(2) and TMZ 200 mg/m(2) 5x daily q 4 weekly in patients with advanced MM. This Phase II study commenced in March 2005 and completed recruitment in December 2005. METHODS: Patients with measurable MM who were chemotherapy naïve, performance status ≤ 2, and had standard blood indices for early trials were recruited. Patients with ocular melanoma or brain metastases were excluded. Treatment was given until progression, with repeat imaging every 2 cycles. A two stage phase II design was used, with the hypothesis to be tested that the response rate to TMZ would be increased to 25%. α and β error rates were set at 0.10. 27 patients were recruited into the first stage with continuation to 40 patients if ≥3 partial responses were observed. Results 40 patients who fulfilled the eligibility criteria were recruited and treated. The required 3 responses were seen at an early stage. More enhancement of TMZ associated myelosuppression by the addition of AG014699 has been observed compared to the phase I study (Grade 4 thrombocytopenia 12% cycles, grade 4 neutropenia 15% to date). There has been one toxic death in cycle 1 (febrile neutropenia), 3 further patients hospitalised with myelosuppression and 12 patients in total requiring dose reduction of TMZ to 150 mg/m(2) (1 to 100 mg/m(2)). All of these patients continued treatment at the reduced dose. Other toxicities have been fatigue and mild nausea. Currently there are 4 confirmed partial responses, 4 prolonged disease stabilisations and 20 patients are too early to evaluate. Conclusions The combination of TMZ and AG014666 shows encouraging activity in MM. Myelosuppression is greater than would be expected with single agent TMZ. PARP expression and activity in blood cells and tumour will be correlated with the mature outcome data from the trial. [Table: see text].


Journal article


J Clin Oncol

Publication Date