3533 Background: AT7519M is a structure-based rationally designed Nan molar small molecular Cyclin-dependent Kinase (CDK) inhibitor (CDK 1, 2, 4, 5). It has been evaluated in a first in human trial for primary endpoints of safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD). Methods: AT7519 was administered in a dose escalation format according to observed toxicity using 3–6 evaluable patients per cohort. Eligible patients had refractory solid tumors with adequate bone marrow, hepatic and renal function. AT7519M was administered as a 1-hour intravenous infusion on days 1 through 5 of a 21 day cycle (starting dose 1.8 mg/m2/day). Patients were monitored closely for hematologic, non-hematologic and symptoms of dose limiting toxicities (DLT). Pre- and post-treatment PK and PD (serum and skin biopsies) were obtained for each patient. Results: At dose level 6 (34mg/m2/day) DLT was reached due to fatigue (grade 4), mucositis (grade 3) and neutropenia (grade 4) that occurred on day 2 but recovered by day 4 (grade 2). Several patients treated at the 28.8mg/m2/day dose experienced nausea/vomiting, fatigue and reversible thrombocytopenia (grade 2). Dose dependent QTc-prolongation was observed, which manifested as a fatal SAE in one patient at dose level 6. Four patients have received treatment for at least six months including one partial response of 80% (lung adenocarcinoma). The PK profile of AT7519M revealed only modest inter-patient variation (<3-fold) with exposure increasing linearly with dose. Significant changes in PCNA levels in skin biopsies were observed in a number of patients across all dose levels, perhaps reflecting a direct effect of CDK inhibition on this cell cycle marker. All samples processed for cohort 5 exhibited a reduction in PCNA staining but also an increase in the apoptosis marker cleaved cytokeratin in serum samples. A reduction in Ki-67 expression was also observed in 66% of samples at this dose level. Conclusions: AT7519M shows evidence of clinical and PD activity but the appearance of QTc prolongation precludes further exploration of this dose schedule. Alternative administration schedules are being investigated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Astex Therapeutics Ltd Astex Pharmaceuticals, Inc.
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Mahadevan et al. (2008) studied this question.