A phase I study of the farnesyltransferase inhibitor Tipifarnib in combination with the epidermal growth factor tyrosine kinase inhibitor Erlotinib in patients with advanced solid tumors

Investigational New Drugs
Khalid JaziehAlex A Adjei

Abstract

Introduction Based on preclinical cytotoxic synergy between tipifarnib and erlotinib, a phase I study of this combination was conducted in patients with advanced solid tumors to evaluate safety, tolerability, maximum tolerated dose (MTD) and preliminary evidence of efficacy. Methods Patient enrollment followed the traditional "3 + 3" dose escalation scheme, through 4 dose levels, ranging from tipifarnib 200 mg twice daily plus erlotinib 75 mg once daily to tipifarnib 300 mg twice daily plus erlotinib 150 mg once daily. After the MTD of the combination was identified, 12 additional patients were treated to better define the pharmacokinetics and pharmacodynamics of these agents. Results A total of 27 patients were enrolled in the study (dose escalation, 15; dose expansion, 12). Dose limiting toxicity was seen in one patient at dose level 4 (grade 3 diarrhea). The MTD was reached at erlotinib 150 mg once daily combined with tipifarnib 300 mg twice daily. The most common side effects of the combination of all grades were diarrhea (85.2%), fatigue (77.8%), rash (70.4%), and anorexia (59.3%). Overall, 2 patients (7.4%; with liver cancer and melanoma, respectively) had partial responses, 10 (37%) had stable disease, 11 had progressive...Continue Reading

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Sep 3, 2019·Current Topics in Medicinal Chemistry·Na YeJia Zhou

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