Phase I Study of LY2940680, a Smo Antagonist, in Patients with Advanced Cancer Including Treatment-Naïve and Previously Treated Basal Cell Carcinoma.

Abstract

Purpose: The purpose of this study was to determine a recommended phase II dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer.Experimental Design: This was a phase I, multicenter, open-label study of oral LY2940680. The maximum tolerable dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naïve and previously hedgehog (Hh)-inhibitor-treated patients with basal cell carcinoma (BCC) were enrolled.Results: Eighty-four patients were treated (dose escalation, n = 25; dose confirmation, n = 19; and BCC dose expansion, n = 40). Common treatment-emergent adverse events were dysgeusia [41 (48.8%)], fatigue [40 (47.6%)], nausea [38 (45.2%)], and muscle spasms [34 (40.5%)]. Four patients experienced events (3 were grade 3; 1 was grade 2) that were considered dose-limiting toxicities (DLT). The MTD was determined to be 400 mg because of DLTs and dose reductions. Pharmacokinetic analyses showed no clear relationship between exposure and toxicity. Analysis of Gli1 mRNA from skin biopsies from unaffected areas suggested that all doses were biologically active [inhibition median of 92.3% (80.9% to 95.7%)]. All clinical responses (per RECIST 1.1) were in patients with BCC (n = 47); the overall and estimated response rate was 46.8% (95% confidence interval, 32.1%-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh treatment-naïve (11/16) patients.Conclusions: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced/metastatic cancer. Clinical responses were observed in patients with locally advanced/metastatic BCC who were previously treated with Hh therapy and in Hh treatment-naïve patients. Clin Cancer Res; 24(9); 2082-91. ©2018 AACR.

• Authors: Johanna Bendell, Valerie Andre, Alan Ho, Ragini Kudchadkar, Michael Migden, Jeffrey Infante, Ramon V Tiu, Celine Pitou, Trevor Tucker, Les Brail, Daniel Von Hoff
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 24 Issue 9 Pg. 2082-2091 (05 01 2018) ISSN: 1557-3265 [Electronic] United States
• PMID: 29483143 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• LY2940680
• Phthalazines
• SMO protein, human
• Smoothened Receptor

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Carcinoma, Basal Cell (drug therapy, metabolism, pathology)
• Female
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Staging
• Phthalazines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Retreatment
• Smoothened Receptor (antagonists & inhibitors)