Cancer Chemotherapy and Pharmacology

, Volume 62, Issue 4, pp 631–646

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

  • Laura Q. M. Chow
  • S. Gail Eckhardt
  • Cindy L. O’Bryant
  • Mary Kay Schultz
  • Mark Morrow
  • Stacy Grolnic
  • Michele Basche
  • Lia Gore
Original Article

DOI: 10.1007/s00280-007-0646-x

Cite this article as:
Chow, L.Q.M., Eckhardt, S.G., O’Bryant, C.L. et al. Cancer Chemother Pharmacol (2008) 62: 631. doi:10.1007/s00280-007-0646-x

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/m2 on days 1, 8, 15) and fixed cisplatin (75 mg/m2 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/m2 days 1, 8, 15, and cisplatin 75 mg/m2 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/m2 days 1, 8, 15, and cisplatin 75 mg/m2 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.

Keywords

Lonafarnib SCH66336 Cisplatin Gemcitabine Farnesyltransferase Phase I Pharmacokinetics 

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Laura Q. M. Chow
    • 1
  • S. Gail Eckhardt
    • 1
  • Cindy L. O’Bryant
    • 1
  • Mary Kay Schultz
    • 1
  • Mark Morrow
    • 1
  • Stacy Grolnic
    • 1
  • Michele Basche
    • 1
  • Lia Gore
    • 1
    • 2
    • 3
  1. 1.University of Colorado Cancer CenterAuroraUSA
  2. 2.The Children’s HospitalDenverUSA
  3. 3.University of Colorado Health Sciences Center at FitzsimonsAuroraUSA

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