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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.
Jazieh, Khalid; Molina, Julian; Allred, Jacob; Yin, Jun; Reid, Joel; Goetz, Matthew; Lim, Vun-Sin; Kaufmann, Scott H; Adjei, Alex.
Afiliação
  • Jazieh K; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Molina J; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Allred J; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Yin J; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Reid J; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Goetz M; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Lim VS; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Kaufmann SH; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA.
  • Adjei A; Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN, 55905, USA. adjei.alex@mayo.edu.
Invest New Drugs ; 37(2): 307-314, 2019 04.
Article em En | MEDLINE | ID: mdl-30171497
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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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Regulação Neoplásica da Expressão Gênica / Terapia de Salvação / Farnesiltranstransferase / Neoplasias Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Invest New Drugs Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Protocolos de Quimioterapia Combinada Antineoplásica / Regulação Neoplásica da Expressão Gênica / Terapia de Salvação / Farnesiltranstransferase / Neoplasias Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Invest New Drugs Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Estados Unidos