Abstract B32: LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC)
Authors: Bendell Johanna , Andre Valerie , Ho Alan , Kudchadkar Ragini , Migden Michael , Infante Jeffrey , Tiu Ramon , Pitou Celine , Tucker Trevor , Brail Les , Von Hoff Daniel 
Published: May 2016

Abstract
We previously reported interim dose escalation results from this multi-center, open-label Phase 1 clinical trial (NCT01226485) (Bendell et al, EJC 2012). Here, we report the final aggregate safety results and the anti-tumor activity demonstrated by LY2940680, a novel Hh pathway inhibitor, in locally advanced (la) and metastatic (m) BCC.
Methods: The primary objective of this study was to determine a recommended Phase 2 dose and regimen of LY2940680 that could be safely administered to patients with advanced cancer, including BCC. Patients deemed eligible for experimental therapy were enrolled in the study and dosed once daily (QD) for 28 day cycles until discontinuation. The maximum tolerated dose (MTD) was determined using a 3+3 dose escalation design. Based on initial anti-tumor activity, a cohort of la/m BCC patients was enrolled. Safety, PK/PD, and tumor response data were collected and analyzed.
Results: A total of 84 advanced cancer patients were dosed, including 47 patients with la/m BCC. Median age was 62.5 years (range: 29-89). Advanced cancer patients received escalating doses ranging from 50 mg to 600 mg QD resulting in a MTD of 400 mg QD. The most commonly reported treatment-emergent adverse events (TEAE) possibly related to study drug (&gt;20%) were dysgeusia (Gr 1-2: 46.4%, Gr 3: 2.4%), fatigue (Gr 1-2: 44.0%, Gr 3: 3.6%), nausea (Gr 1-2: 42.9%, Gr 3: 2.4%), muscle spasms (Gr 1-2: 35.7%, Gr 3: 4.8%), decreased appetite (Gr 1-2: 35.7%, Gr 3: 0%), vomiting (Gr 1-2: 29.7%, Gr 3: 2.4%), alopecia (Gr 1-2: 33.3%, Gr 3: 0%), and weight decrease (Gr 1-2: 26.2%, Gr 3: 1.2%). PK analysis showed no clear relationship between exposure (PK) and toxicity. PD marker analysis of Gli-1 mRNA from unaffected skin biopsies suggested all doses were biologically active (inhibition median of 91.7% with interquartile range (80.9-95.7%) in all patients with available pre- and post-treatment biopsies). The most common reasons for treatment discontinuation were progression of disease (n = 43), adverse event (n = 10) and withdrawal by subject (n = 10). All reported clinical responses (per RECIST 1.1) were in patients with la/m BCC. Overall response rate (ORR) for patients with la/m BCC (n = 47) was 46.8% (95% CI: 32.1-61.9%) and clinical benefit rate (CR+PR+SD) was 93.6% (95% CI: 82.5-98.7%). The median duration of response was estimated at 10.2 months (95% CI: 5.6- not estimable). Responses were observed in patients who were Hh treatment naïve (11/16) but also in patients who previously failed Hh therapy (11/31).
Conclusion: LY2940680 treatment resulted in an acceptable safety profile in patients with advanced cancer including la/m BCC. Clinical responses were observed in la/m BCC patients naïve to Hh inhibitor treatment and also in those who had failed treatment with other Hh inhibitor agents. This phase 1 study supports further clinical development of LY2940680 in advanced BCC and potentially in other malignancies
Citation Information: Bendell J. et al. European Journal of Cancer (EJC) 2012 48(6 Suppl) Abstract 594.
Citation Format: Johanna Bendell, Valerie Andre, Alan Ho, Ragini Kudchadkar, Michael Migden, Jeffrey Infante, Ramon Tiu, Celine Pitou, Trevor Tucker, Les Brail, Daniel Von Hoff. LY2940680, a hedgehog (Hh) pathway inhibitor, demonstrates anti-tumor activity in patients with advanced basal cell carcinoma (BCC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B32.