Phase I study of the hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors

Antonio Jimeno, Glen J. Weiss, Wilson H. Miller, Scott Gettinger, Bernard J.C. Eigl, Anne Lynne S. Chang, Joi Dunbar, Shannon Devens, Kerrie Faia, Georgios Skliris, Jeff Kutok, Karl D. Lewis, Raoul Tibes, William H. Sharfman, Robert W. Ross, Charles M. Rudin

Research output: Contribution to journalArticlepeer-review

119 Scopus citations


Purpose: To conduct a first-in-human phase I study to determine the dose-limiting toxicities (DLT), characterize the pharmacokinetic profile, and document the antitumor activity of IPI-926, a new chemical entity that inhibits the Hedgehog pathway (HhP). Experimental Design: Patients with solid tumors refractory to standard therapy were given IPI-926 once daily (QD) by mouth in 28-day cycles. The starting dose was 20 mg, and an accelerated titration schedule was used until standard 3 + 3 dose-escalation cohorts were implemented. Pharmacokinetics were evaluated on day -7 and day 22 of cycle 1. Results: Ninety-four patients (32F, 62M; ages, 39-87) received doses ranging from 20 to 210 mg QD. Dose levels up to and including 160 mg administered QD were well tolerated. Toxicities consisted of reversible elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin, fatigue, nausea, alopecia, and muscle spasms. IPI-926 was not associated with hematologic toxicity. IPI-926 pharmacokinetics were characterized by a slow absorption (Tmax = 2-8 hours) and a terminal half-life (t1/2) between 20 and 40 hours, supporting QD dosing. Of those HhP inhibitor-naïve patients with basal cell carcinoma (BCC) who received more than one dose of IPI-926 and had a follow-up clinical or Response Evaluation Criteria in Solid Tumors (RECIST) assessment, nearly a third (8 of 28 patients) showed a response to IPI-926 at doses ≥130 mg. Conclusions: IPI-926 was well tolerated up to 160 mg QD within 28-day cycles, which was established as the recommended phase II dose and schedule for this agent. Single-agent activity of IPI-926 was observed in HhP inhibitor-naïve patients with BCC.

Original languageEnglish (US)
Pages (from-to)2766-2774
Number of pages9
JournalClinical Cancer Research
Issue number10
StatePublished - May 15 2013

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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