A phase I pharmacodynamic and pharmacokinetic study of a Ras inhibitor, PRLX 93936, in patients with advanced solid tumors.

Abstract

e13042 Background: The primary study objectives are to identify a maximum tolerated dose (MTD) for PRLX 93936 and a dose for further studies. PRLX 93936 is a structurally novel quinazolinone with broad spectrum, high order of activity in vitro and in explant models, including many with Ras mutations. PRLX 93936 is derived from a molecule identified in a screen against isogenic cell lines engineered to differentially express several genes including activated RasV12 (Dolma et.al, Cancer Cell 3: 285-296, 2003). Potent and selective activity has been observed against tumor cell lines derived from breast, colon, lung, melanoma, ovary, kidney and pancreas. PRLX 93936 causes sensitive cells to undergo caspase dependent apoptosis, necrosis, cell cycle arrest, ion flux and cell shrinkage leading to tumor cell death and tumor growth inhibition. Selective activation of Mapk and Jnk pathway members correlates with compound sensitivity in treated cells. Cardiotoxicity in monkeys was dose limiting at 2 mg/m2 IVx5days; 1 mg/m2 IVx5days was tolerated. Methods: 27 adult ECOG 0-1 patients with RECIST measureable histologically confirmed nonhematologic malignancies that have progressed despite standard therapy have been treated to date. A one stage, 3+3 design is being used, with dosing according to a modified Fibonacci escalation scheme, starting with a human equivalent dose of 1/6 of the monkey MTD (i.e., 2 mg/m2 IV×5days). Results: Doses are administered IV×5days every three weeks. Observation for adverse events, including protocol-defined dose limiting toxicities is ongoing, while tumor response is assessed after Cycle 1 and every two cycles thereafter. Pharmacokinetic assessments are made on Days 1 and 5 of Cycle 1. Blood samples are collected for selected biomarkers including changes in gene or protein expression or protein modifications. Conclusions: The observation of toxicities consistent with cytokine release, including fever, chills and transient hematologic abnormalities at 15 mg/m2 has prompted modification of the study to include pharmacologic pretreatment in order to abrogate these effects. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Prolexys Prolexys