A phase I trial of the Hedgehog inhibitor, sonidegib (LDE225), in combination with etoposide and cisplatin for the initial treatment of extensive stage small cell lung cancer
Introduction
Aberrant activation of the Hedgehog (Hh) pathway has been implicated in the initiation, maintenance and proliferation of SCLC. Hh signaling is essential in early stromal development and branching morphogenesis of the embryonic airways [1]. SCLC appears to be a relatively undifferentiated airway epithelial tumor that may recapitulate aspects of early lung development [2]. Expression of the ligand, Sonic Hh, and transcriptional factor, Gli-1, are upregulated relative to normal airway epithelium in SCLC [3]. Analogous to its role in early lung formation, Hh signaling has been implicated in SCLC initiation [4]. Constitutive activation of the pathway promotes tumor progression, and deletion of Smo, the seven-transmembrane receptor, suppresses initiation and progression in murine models of SCLC [3], [4]. Pharmacologic blockade of Smo inhibits the growth of both mouse and human SCLC [3], [4]. Following chemotherapy, Hh pathway inhibition may delay or prevent recurrence of residual disease in multiple murine SCLC models [4], [5].
Hh signaling has a role in regulating stem cell maintenance and differentiation, which has been suggested to parallel its role in tumorigenesis. Inhibition of Hh signaling in both in vitro and in vivo models has been associated with a loss of tumorigenic potential and improved survival across multiple tumor models [6], [7], [8], [9], [10]. In SCLC cell lines, Hh inhibition reportedly decreases cell growth primarily via a progenitor population [11]. These data support a model in which clonogenic recurrence of SCLC is dependent on a subset of chemotherapy-resistant progenitor cells and which may depend on the Hh developmental pathway.
The addition of a Hh inhibitor to cisplatin and etoposide (EP) may promote a more sustained treatment response and ultimately improve clinical outcomes in SCLC. As a test of this hypothesis, we undertook this phase I study to evaluate sonidegib [LDE225, N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4′-(trifluoromethoxy)-1,1′-[biphenyl]-3-carboxamide diphosphate], an oral Smo antagonist, and to determine its maximum tolerated dose (MTD) in combination with EP in newly diagnosed extensive stage SCLC (ES-SCLC) patients.
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Materials and methods
This was a single institution, open label Phase I study [NCT01579929], reviewed and approved by the Institutional Review Board. All patients provided written informed consent.
Patient characteristics
Between March 2012 and September 2014, 15 patients with untreated ES-SCLC were enrolled on this phase I study. Baseline characteristics are listed in Table 1.
Dose escalation and maximum tolerated dose
The dose escalation scheme is summarized in Fig. 1. At the first dose level, two patients experienced a DLT, including one of grade 3 nausea and one of grade 3 febrile neutropenia. This led to a dose de-escalation to 200 mg daily of sonidegib, as pre-specified in the protocol, with no further DLTs observed in the two patients enrolled in
Discussion
The primary goal of this Phase I study was to establish the safety profile and recommended phase II dose of the Hh inhibitor sonidegib when given with standard of care first-line cisplatin and etoposide in patients with newly diagnosed ES-SCLC, which proved to be cisplatin 60 mg/m2 on day 1 with etoposide 120 mg/m2 daily on days 1–3, and sonidegib 800 mg daily on days 1–21 of a 21-day cycle. Pharmacokinetic analyses did not suggest that EP had a substantial effect on sonidegib exposure. Based on
Conflict of interest
M. Catherine Pietanza—Dr. Pietanza reports employment from Merck. Previously reports personal fees from Genentech, personal fees from CelGene Corp, personal fees from Abbvie, personal fees from Clovis Oncology, grants and personal fees from Novartis, grants and personal fees from Bristol Myers Squibb, grants from Stemcentrx, Inc, grants from OncoMed Pharmaceuticals, Inc.
Lee M. Krug—Dr. Krug reports employment from Bristol-Myers Squibb.
Cami S. Sima—Dr. Sima reports employment from
Funding
This research was funded, in part, through Novartis and the National Institute of Health(NIH)/National Cancer Institute (NCI) Cancer Center Support Grant (P30CA008748).
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Present affiliation: Merck Research Laboratories, Rahway, NJ, United States.