A multinomial Phase II study of lonafarnib (SCH 66336) in patients with refractory urothelial cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Protein farnesylation by farnesyltransferase (FTase) is crucial for G-protein signaling, including Ras, impacting cell growth.
• Dysregulated Ras signaling pathways are implicated in the development of transitional cell carcinoma (TCC).
• Lonafarnib is an FTase inhibitor with demonstrated preclinical and clinical antitumor effects.

Purpose of the Study:

• To evaluate the antitumor activity of lonafarnib as a single agent in patients with previously treated advanced or metastatic transitional cell carcinoma (TCC).
• To assess the safety and tolerability of lonafarnib in this patient population.

Main Methods:

• A National Cancer Institute of Canada Clinical Trials Group Phase II trial enrolled 19 patients with advanced TCC who had received at least one prior chemotherapy regimen.
• Lonafarnib was administered orally at 200 mg twice daily continuously, with 4-week cycles.
• Patients were monitored for response, toxicity, and treatment discontinuation.

Main Results:

• The median treatment duration was 7.1 weeks.
• Grade 3 toxicities, including fatigue, anorexia, nausea, confusion, dehydration, muscle weakness, depression, headache, and dyspnea, were observed.
• Five patients discontinued treatment due to toxicity.
• No objective responses were observed in the 10 evaluable patients.
• Five of nine non-evaluable patients experienced symptomatic progression, leading to early study termination.

Conclusions:

• Single-agent lonafarnib demonstrated no observable antitumor activity in patients with aggressive TCC who had failed prior chemotherapy.
• The observed toxicities limited treatment duration and efficacy in this study population.