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

Abstract

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 (T(max) = 2-8 hours) and a terminal half-life (t(1/2)) 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.

• Authors: Antonio Jimeno, Glen J Weiss, Wilson H Miller Jr, 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
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 19 Issue 10 Pg. 2766-74 (May 15 2013) ISSN: 1557-3265 [Electronic] United States
• PMID: 23575478 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2013 AACR

Chemical References

• Hedgehog Proteins
• IPI-926
• Veratrum Alkaloids
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• Adult
• Aged
• Aged, 80 and over
• Alanine Transaminase (metabolism)
• Alopecia (chemically induced)
• Area Under Curve
• Aspartate Aminotransferases (metabolism)
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Fatigue (chemically induced)
• Female
• Follow-Up Studies
• Hedgehog Proteins (metabolism)
• Humans
• Male
• Metabolic Clearance Rate
• Middle Aged
• Nausea (chemically induced)
• Neoplasms (drug therapy, metabolism, pathology)
• Signal Transduction (drug effects)
• Spasm (chemically induced)
• Treatment Outcome
• Veratrum Alkaloids (adverse effects, pharmacokinetics, therapeutic use)