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Updated: May 12, 2026
Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor
Published on: September 13, 2018
Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors
Antonio Jimeno1, Glen J Weiss, Wilson H Miller
1University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado 80045, USA. antonio.jimeno@ucdenver.edu
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.
Insights
This phase I study found that IPI-926, a Hedgehog pathway inhibitor, was well tolerated up to 160 mg daily. Promising antitumor activity was observed in patients with basal cell carcinoma naive to Hedgehog pathway inhibitors.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- The Hedgehog pathway (HhP) is implicated in various cancers.
- IPI-926 is a novel Hedgehog pathway inhibitor.
- Understanding its safety and efficacy is crucial for therapeutic development.
Purpose of the Study:
- To determine dose-limiting toxicities (DLT) of IPI-926.
- To characterize the pharmacokinetic profile of IPI-926.
- To assess the antitumor activity of IPI-926 in patients with solid tumors.
Main Methods:
- A first-in-human phase I study involving patients with solid tumors refractory to standard therapy.
- IPI-926 was administered orally once daily in 28-day cycles.
- Dose escalation followed an accelerated titration schedule, then a standard 3+3 design; pharmacokinetics were assessed.
Main Results:
- Ninety-four patients received doses from 20 to 210 mg QD; doses up to 160 mg QD were well tolerated.
- Common toxicities included reversible elevations in liver enzymes, fatigue, nausea, alopecia, and muscle spasms; no hematologic toxicity was observed.
- Pharmacokinetics showed slow absorption and a terminal half-life supporting once-daily dosing. Single-agent activity was noted in nearly a third of Hedgehog pathway inhibitor-naïve basal cell carcinoma patients at doses ≥130 mg.
Conclusions:
- IPI-926 is well tolerated up to 160 mg QD, establishing this as the recommended phase II dose and schedule.
- Single-agent activity of IPI-926 was observed in Hedgehog pathway inhibitor-naïve patients with basal cell carcinoma.
- IPI-926 represents a potential new therapeutic option for specific cancer types.
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