163TiP - Single-institution, single-arm, open-label phase II basket study of mutation and/or elevated hedgehog (Hh) expression-directed smoothened inhibitor sonidegib in patients with advanced solid malignancies

Background

Patients with advanced solid malignancies progressing through several lines of therapy have limited treatment options, typically latter-line chemotherapy with modest benefits. With precision medicine, targeted therapies result in better outcomes with less toxicity. The hedgehog (Hh) pathway is highly conserved and regulates embryogenesis and tissue homeostasis. Aberrant Hh pathway signalling (SMO or PTCH1 mutation, or elevated Hh expression) has been implicated in malignancy including cancer stem cell self-renewal, chemotherapy resistance, epithelial-mesenchymal transition, and metastasis, and is reported in a variety of malignancies. Sonidegib, a potent small molecule inhibitor of the Hh pathway demonstrates significant activity in patients with advanced basal cell carcinoma where Hh pathway activation is a hallmark. Activity has also been observed in other malignancies though many prior studies have not selected patients specifically with SMO or PTC1 mutations.

Trial Design

This single-institution, single-arm, open-label phase II basket study will explore safety and initial efficacy of sonidegib in patients with advanced solid malignancies and limited further treatment options who exhibit aberrant Hh pathway expression. The study will be performed in 2 parts with the primary endpoint of ORR by RECIST v1.1. Key secondary endpoints include DCR, PFS, toxicity, and incidence of SMO/PTCH1 mutations as a proportion of total patients screened. Part A: eligible patients will undergo biomarker screening for aberrant Hh pathway expression. Whole exome sequencing will be performed on archival tumour tissue and a contemporary blood sample (for ctDNA + patients). Part B: biomarker-positive patients via Part A or a prior commercially available NGS panel will receive sonidegib at 200mg daily with potential dose-escalation until disease progression by RECIST v1.1 or unacceptable toxicity. Enrolment has commenced at Royal North Shore Hospital, Sydney. Sixteen patients have enrolled in Part A and 1 (of 35 planned) has enrolled in Part B.

Editorial acknowledgement

Clinical trial identification

ANZCTR: ACTRN12623001216606; Registered 27/11/2023.

Legal entity responsible for the study

Department of Medical Oncology Royal North Shore Hospital - Northern Sydney Local Health District.

Funding

Sun Pharma and philanthropic donations.

Disclosure

A. Guminski: Financial Interests, Personal, Advisory Board: Regeneron, MSD, Pfizer, Merck KGaA; Financial Interests, Personal, Invited Speaker: BMS; Financial Interests, Institutional, Other, Supply of drug for an investigator initiated clinical trial: AstraZeneca; Financial Interests, Institutional, Other, Drug and genomic testing support for an investigator initiated clinical trial: Sun Pharma; Non-Financial Interests, Personal, Advisory Role, Clinical Trial Steering Committee: Shasqi. All other authors have declared no conflicts of interest.