A first-in-human, phase I study of an oral hedgehog (HH) pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors.

2501 Background: Aberrant HH pathway signaling has been suggested to play a role in the development of multiple solid tumors and hematological malignancies. BMS-833923 is a potent, oral, small molecule antagonist of the HH signaling component Smoothened. Methods: The trial is designed to identify a maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics. All subjects receive a single dose 1 week prior to continuous daily dosing, which allows for single dose PK collection for 1 week. To identify the pharmacologically active dose range, skin samples are collected prior to day 1 and again on day 22 of the first cycle to assess GLI1 protein expression levels. Results: As of October 21, 2009, eighteen subjects (mean age of 56 [range 21-78]; ECOG performance 0--1) have been treated at four dose levels: 30 mg (n=5), 60 mg (n=3), 120 mg (n=3), and 240 mg (n=7). No subjects in the first three dose cohorts experienced drug-related CTCAE adverse events greater than grade 2. One subject with medulloblastoma in the 30 mg dose cohort continues on study for >11 months with stable disease. Treatment of subjects in the fourth cohort at 240 mg is ongoing. In this cohort, a 50 year old female subject with Gorlin Syndrome, caused by germline mutation in the HH pathway gene Patched, experienced an ongoing confirmed partial response. This subject experienced drug-related CTCAE grade 2 lipase elevation and pancreatitis that quickly resolved when drug was withheld. The subject is currently receiving a single 60 mg dose every other week. BMS-833923 PK properties showed dose proportionality between the 30, 60, and 120 mg dose cohorts and greater than dose proportionality between the 120 mg and 240 mg dose cohorts. All dose cohorts show a prolonged terminal half-life of >7 days with drug accumulation of 3-6 fold between days 1 and 22 as measured by changes in the Cmax. Measurement of GLI1 protein expression in the skin biopsies shows a decrease at all dose levels. Conclusions: BMS-833923 is generally well tolerated at the dose levels tested, which include dose levels that are clinically active. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb, Merck, Millennium Bristol-Myers Squibb Bayer, Bristol-Myers Squibb, Cyclacel Pharmaceuticals, GlaxoSmithKline, Merck, Novartis, Pfizer, Regeneron, Roche Bristol-Myers Squibb Bristol-Myers Squibb