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.