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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

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Summary

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 disease (40.7%) and 4 stopped treatment prematurely for assessment. Conclusion The combination of tipifarnib and erlotinib was well tolerated. Erlotinib 150 mg once daily for 28 days combined with tipifarnib 300 mg twice daily for 21 days was identified as the recommended phase 2 dose. Tipifarnib is currently being evaluated in HRAS mutant tumors, providing a potential opportunity to further test this combination.

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Acknowledgements

This study was funded by the National Cancer Institute P30CA015083 and U01CA069912 grants.

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  1. Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA

    Khalid Jazieh, Julian Molina, Jacob Allred, Jun Yin, Joel Reid, Matthew Goetz, Vun-Sin Lim, Scott H. Kaufmann & Alex Adjei

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MG is consultant for Pfizer Inc., Eli Lilly and Company, and Novartis. KJ, JM, JA, JY, JR, V-SL, SHK, and AA have no conflict of interest to report.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Jazieh, K., Molina, J., Allred, J. et al. 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. Invest New Drugs 37, 307–314 (2019). https://doi.org/10.1007/s10637-018-0662-1

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