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• W2793851382 abstract "HRAS is a proto-oncogene that is overexpressed and mutated in head and neck, bladder, thyroid, and salivary gland tumors, among others. While discovered over 40 years ago, no specific therapies have yet been developed targeting mutant HRAS. Tipifarnib is a potent and highly selective inhibitor of farnesyltransferase, a critical enzyme requisite for HRAS activation. Over 5,000 patients (pts) have been treated with tipifarnib; although responses have been documented in several tumor indications, the mechanisms of response are still poorly understood. Tipifarnib has demonstrated robust activity in HRAS-mutant patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and squamous non-small cell lung cancer that are resistant to standard therapies. This Phase 2 study (NCT02383927) was conducted to test the hypothesis that inhibition of mutant HRAS oncogenic activity with tipifarnib could translate to objective responses in HNSCC pts driven by the HRAS oncogene. The study was originally designed to enroll pts into 2 single-arm study cohorts: Cohort 1 (thyroid cancer) and Cohort 2 (other solid tumors), each one with a 2-stage design (11+7 evaluable pts). Two objective responses needed to be observed in the first stage for each cohort to proceed to stage 2. The prespecified activity goal for the first stage of accrual in Cohort 2 was met. Based on data observed in the first stage of this Cohort, enrollment to the second stage of Cohort 2 has been limited to HRAS-mutant HNSCC since August 2016. For enrollment, pts must have an HRAS-mutant, locally advanced/unresectable and/or metastatic solid tumor malignancy and RECIST v1.1 measurable disease. Tipifarnib is given at 900 mg orally twice daily on days 1-7 and 15-21 of 28-day cycles. Response assessments are conducted every 8 weeks. As of August 30, 2017, 7 pts with HNSCC have been enrolled. Tipifarnib was generally well-tolerated with fatigue, myelosuppression, nausea, and vomiting constituting the most common adverse events (all grades). Six pts are currently evaluable for efficacy. Four (67%, 3 confirmed, 1 unconfirmed) pts achieved a partial response, 3 of whom remain on treatment currently in cycle 3, cycle 5, and cycle 19. One subject discontinued in Cycle 21. Two (33%) pts had disease stabilization as best response (4 cycles, ongoing and 7 cycles). Four of these pts were refractory to prior therapies, including immunotherapy and cetuximab +/- chemotherapy regimens. Encouraging activity of tipifarnib was observed in pts with HRAS-mutant HNSCC. Trial enrollment continues." @default.
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• W2793851382 date "2018-04-01" @default.
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• W2793851382 title "Preliminary Results From a Phase 2 Trial of Tipifarnib in HRAS-Mutant Head and Neck Squamous Cell Carcinomas" @default.
• W2793851382 doi "https://doi.org/10.1016/j.ijrobp.2017.12.156" @default.
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