A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors

Abstract

Purpose: This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies.

Experimental design: This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75-125 mg po BID) with gemcitabine (750-1,000 mg/m(2) on days 1, 8, 15) and fixed cisplatin (75 mg/m(2) day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered "heavily pre-treated" and the protocol was amended to limit prior therapy and re-escalate lonafarnib in "less heavily pre-treated patients" on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed.

Results: Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer.

Conclusion: Lonafarnib 75 mg BID, gemcitabine 750 mg/m(2) days 1, 8, 15, and cisplatin 75 mg/m(2) day 1 on a 28-day schedule was established as the MTD. Lonafarnib did not demonstrate FTPase inhibition at these doses. Despite the observed efficacy, substantial toxicity and questionable contribution of anti-tumor activity of lonafarnib to gemcitabine and cisplatin limits further exploration of this combination.

Fig. 1

a Chest CT at baseline and after two cycles of therapy, demonstrating complete resolution of a lung lesion in a breast cancer patient. b Chest CT at baseline and after two cycles of therapy, demonstrating partial resolution (72% reduction) of axillary adenopathy in another breast cancer patient

Fig. 2

Mean plasma concentrations of lonafarnib versus time profiles following twice daily oral administration of lonafarnib in combination with intravenous gemcitabine and cisplatin

Fig. 3

a Mean gemcitabine plasma concentrations versus time profiles following weekly 30 min intravenous infusion of gemcitabine without (day 1) and with (day 8) oral administration of lonafarnib and cisplatin. b Individual gemcitabine area under the curve (AUC) values following weekly 30 min intravenous infusion of gemcitabine without (day 1) and with (day 8) oral administration of lonafarnib and intravenous cisplatin. c Mean Plasma cisplatin concentrations of versus time profiles following day 1 60 min intravenous infusion of cisplatin in every cycle without (cycle 1) and with (cycle 2) administration of lonafarnib and gemcitabine. d Individual cisplatin area under the curve (AUC) values following day 1 60 min intravenous infusion of cisplatin in every cycle without (cycle 1) and with (cycle 2) administration of lonafarnib and gemcitabine

Fig. 4

a Farnesyltransferase activity for patients treated with lonafarnib 75 mg po BID at baseline, cycles 1 and 2. b Farnesyltransferase activity for patients treated with lonafarnib 100 po BID at baseline, cycles 1 and 2