Phase 1 study of LY2940680, a Smo antagonist, in patients with advanced cancer including treatment naive and previously treated basal cell carcinoma

Purpose: To determine a recommended Phase 2 dose and schedule of LY2940680 (taladegib) for safe administration to patients with locally advanced/metastatic cancer. Experimental Design: This was a Phase 1, multicenter, open-label study of oral LY2940680. The maximum tolerated dose (MTD) was determined using a 3+3 design, the dose was confirmed, and then treatment-naive 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 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% CI: 32.1-61.9%). Responses were observed in patients previously treated with Hh therapy (11/31) and in Hh-treatment-naive (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-naive patients.

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