Phase 1b/2 trial of taladegib (LY2940680), a Hh/Smo inhibitor, in combination with carboplatin and etoposide followed by taladegib maintenance in extensive-stage small-cell lung cancer

• Published in: European journal of cancer (1990) Vol. 69; pp. S131 - S132
• Main Authors: Schaefer, E, Braiteh, F, Forster, M, Talbot, D, Chandler, J, Richards, D, Andre, V, Estrem, S, Pitou, C, Tiu, R, Brail, L, Nikolinakos, P
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science Ltd 01-12-2016
• Subjects: Alopecia; Anemia; Anorexia; Cancer; Carboplatin; Clinical trials; Decision analysis; Emergence; Enterocolitis; Etoposide; Exposure; Fatigue; Females; Gene expression; Graphical user interface; Hedgehog protein; Hematology, Oncology and Palliative Medicine; Inhibitor drugs; Inhibitors; Lung cancer; Lungs; Males; Medical treatment; Nausea; Neutropenia; Pathogenesis; Patients; Placebo effect; Proteins; Safety; Skin; Small cell lung carcinoma; Smoothened protein; Thrombocytopenia; Toxicity; Vomiting; Xenografts; Xenotransplantation
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/S0959-8049(16)32990-2

Background: Small-cell lung cancer (SCLC) is the most aggressive form of lung cancer, and carboplatin (C) and etoposide (E), the standard treatment for extensive-stage disease (ED-SCLC), has only modest efficacy. Activation of Type II and Ill Hedgehog (Hh) pathways (ligand dependent) and the Smoothened protein (Smo) have been implicated in ED-SCLC pathogenesis, with Gill overexpression reported in ∼`50% of SCLC patients (pts). Precilnical studies found that SCLC cell lines increased expression of both Hh hgand and G1i2 following exposure to C/E, and that C/E followed by Hh inhibitor (LDE-225) prolonged survival of mice bearing SCLC human xenografts, suggesting that CIE treatment precedes an emergence of cells upregulating the Hh pathway to survive and proliferate. Materials and Methods: This Phase lb/2 study (NCT01722292; 14J-MC- HHBE; Eli Lilly and Co) evaluated the safety and tolerability of Rh/Smo inhibitor taladegib in chemo-nalve pts with ED-SCLC, ECOG ~1, and at least 1 measurable lesion by RECIST 1.1. The Phase lb dose-escalation portion assessed safety, PK, and PD of taladegib (100mg, 200mg, and 400mg/d) plus IV C (AUC5, dl)IE (100mg/rn2, dl-3) every 21 d for 6 cycles, followed by taladegib alone until disease progression. The Phase 2 portion was intended to compare C/E + taladegib followed by maintenance taladegib versus C/F + placebo followed by placebo. Results: A total of 26 pts(lOOmg: 6,200mg: 6,400mg: 14), 13 females and 13 males, median age 63.5 yrs (range: 43-84), received at least one dose, with a median of 6 cycles (range: 1-13). There were 4 DLTs (100mg: enterocolitis; 200mg: dysgeusia; 400mg: neutropenia, febrile neutropenia) and 15 deaths (4 on study, 3 tC3Od and 8 >30d post- Tx discontinuation) due to disease progression (11), AEs deemed to be related to study drug treatment (1), and AEs not deemed to be related to study drug treatment (3). Overall response rate (au PRs) was 53.8% (90% Ci: 37.8-69.9%). The most frequent TEAEs deemed possibly related to therapy were dysgeusia (53.8%), fatigue (50.0%), neutropenia (46.2%), nausea (42.3%), alopecia (30.8%), vomiting (30.8%), anorexia (30.8%), anemia (30.8%), and thrombocytopenia (26.9%). The primary reasons for discontinuation were progressive disease (61.5%), patient decision (15.4%), TEAE (11.5%), and death (11.5%). PK analysis showed no clear relationship between exposure and toxicity. Gui inhibition (measured in skin) was high (>70%) across all doses, indicating a robust PD effect. Due to limited enrollment and the emergence of clinical data from another agent in the same class, the study was discontinued prior to Phase 2. Conclusions: The recommended Phase 2 dose for taladegib in combination with C/E is 400 mg/d. The type and frequency of TEAEs observed in this combination are comparable to those seen with another Hh/Smo antagonist given in combination with CIE.