Reference Detail

Ref Type

Journal Article

PMID

(29483143)

Authors

Bendell J, Andre V, Ho A, Kudchadkar R, Migden M, Infante J, Tiu RV, Pitou C, Tucker T, Brail L, Von Hoff D

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	24	9	2018 05 01	2082-2091	Clin Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Taladegib	Taladegib	0	3

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Taladegib		LY2940680\|LY-2940680\|ENV-101	SMO Inhibitor 16	Taladegib (LY-2940680) inhibits Smo, thereby inhibiting Hedgehog signaling and subsequent cell proliferation (Cancer Res 2011;71(8 Suppl):Abstract nr 2819, PMID: 29483143, PMID: 29453627).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References