HRAS is a proto-oncogene overexpressed and mutated in head and neck squamous cell carcinomas (HNSCC), bladder, thyroid and salivary gland tumors, among others. Although discovered over 40 years ago, no therapies are yet approved targeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme required for the proper function of HRAS. This Phase 2 study (NCT02383927) was conducted to test the hypothesis that inhibition of HRAS oncogenic activity could translate to objective responses in solid tumors.
The study was designed to enroll patients (pts) into 2 single-arm study cohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a 2-stage design to determine overall response rate (ORR) as the primary objective. This design has 80% power to detect a difference between 10% and 30% ORR at one-sided significance level of 0.087. A study cohort was to be considered positive if at least 4 responses were observed (N = 36, 18 evaluable subjects/cohort). For enrollment, pts must have an HRAS mutation, locally advanced/unresectable and/or metastatic, and RECIST v1.1 measurable disease. Tipifarnib was dosed at 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles.
As of May 1, 2018, 37 pts have been treated, including 11 pts with HRAS mutated HNSCC and 2 pts with HRAS mutated SCC. Tipifarnib was generally well tolerated, with fatigue, myelosuppression, nausea and vomiting constituting the most common adverse events (all grades). 7 HNSCC pts are currently evaluable for efficacy; 5 (71%) achieved a confirmed partial response with a median duration of response of 14.1 months (95% CI: 1.4-17.3 mo), exceeding the pre-specified null hypothesis. Importantly, no HRAS mutated HNSCC pt experienced an objective response on their last therapy prior to receiving tipifarnib (including platinum, immunotherapy and cetuximab +/- chemotherapy regimens).
Encouraging activity of tipifarnib was observed in pts with HRAS mutant HNSCCs. The study met its predefined success criteria and has been amended to continue enrolling HRAS mutant HNSCC pts, as well as pts with SCC, other than HNSCC, with HRAS mutations into a new Cohort 3.
Clinical trial identification
Legal entity responsible for the study
A.L. Ho, N. Chau, J. Bauman, K. Bible, A. Chintakuntlawar, M.E. Cabanillas, D.J. Wong, I. Braña Garcia, M.S. Brose, V. Boni, C. Even, M. Razaq: Clinical investigator for Study KO-TIP-001. V. Mishra, K. Bracken, C. Scholz: Stock ownership and employee: Kura Oncology. D. Wages: Consultant: Kura Oncology. A. Gualberto: Chief Medical Officer and stock ownership: Kura Oncology.