A first-in-human, phase I study of an oral hedgehog (HH) pathway antagonist, BMS-833923 (XL139), in subjects with advanced or metastatic solid tumors.

Management of Cutaneous and Extracutaneous Side Effects of Smoothened Inhibitor Therapy for Advanced Basal Cell Carcinoma

“…In a phase II trial of sonidegib, 33% of patients treated with the 200-mg daily dosage experienced nausea (12,13). Only 3 of 28 patients exposed to varying doses of BMS-833923 in a phase I study reported nausea (17). No formal studies to date have examined the efficacy of currently available antiemetics for SI-induced nausea or vomiting.…”

“…A number of cutaneous and extracutaneous side effects of SIs have been reported (12,(14)(15)(16)(17)19), although few studies have been conducted on the mechanisms of the clinical side effects in humans. Nevertheless, data on the function of the Hh pathway from preclinical animal models and the limited clinical trials in humans lend insight into how SIs may exert their toxicities (8,(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

“…Aberrant activation of this pathway results in tumorigenesis and is associated with BCCs and medulloblastoma (2-4, 6, 7). SIs block Hh signaling, leading to suppression of tumor growth and tumor regression (12)(13)(14)(15)(16)(17). Although there are many potential targets within this pathway, most compounds in clinical development that block Hh signaling target SMO, including vismodegib (GDC-0449), which is already commercially available (18).…”

“…Other SIs currently being studied in clinical trials include sonidegib (LDE225), saridegib (IPI-926), and BMS-833923 (XL139; refs. [12][13][14][15]17).…”

Targeting the Hedgehog Pathway in Cancer: Can the Spines Be Smoothened?

“…For other malignancies that are not driven by mutational activation of the Hh pathway, patient selection is challenged by the absence of predictive biomarkers that signify effective targeting of the tumor-stroma interaction or eradication of CSCs. Adverse events such as muscle cramps, dysgeusia, and alopecia, which have been commonly observed among Hh pathway inhibitors, may represent on-target modulation of normal tissues (1,11,12), but the value of these events as systemic biomarkers of activity is yet to be explored. The combination of Hh pathway inhibitors with cytotoxic chemotherapy or targeted agents should be based on preclinical rationale, as in the example of improved drug delivery when this class of agent is combined with gemcitabine in a mouse pancreatic cancer model (13).…”