Theodore C et al. (2005) Multicentre EORTC study 16997: feasibility and phase II trial of farnesyl transferase inhibitor & gemcitabine combination in salvage treatment of advanced urothelial tract cancers. Eur J Cancer 41: 1150–1157

Preclinical studies using xenograft models have shown that SCH66336 (lonafarnib), an orally administered tricyclic farnesyl transferase inhibitor, has significant antitumor activity. A European, multicenter study now demonstrates that combination therapy with SCH66336 and gemcitabine is a feasible second-line treatment in patients with advanced urothelial tract cancers, producing a higher overall response rate than is usually achieved in this setting.

Thirty-four patients were recruited to the study. All had previously received one line of chemotherapy for advanced transitional cell carcinoma of the bladder (n = 28), renal pelvis (n = 4) or ureter (n = 2). With the exception of one patient who withdrew consent, patients received a median of three 28-day cycles of treatment, which consisted of continuous SCH66336 (150 mg each morning and 100 mg each evening, starting on day 2) and gemcitabine (1,000 mg/m2 on days 1, 8 and 15).

The treatment was well tolerated in general. There were no cases of severe hematologic toxicity (grade 4 thrombocytopenia or febrile neutropenia), although grade 3 neutropenia and thrombocytopenia each occurred in six patients and grade 3 anemia was observed in nine patients. The most common nonhematologic grade 3 toxicities were fatigue (eight patients), diarrhea (four patients), and nausea/vomiting (three patients).

Of 31 evaluable patients, one achieved a complete response and nine achieved a partial response. The corresponding overall response rate of 32.3% (95% CI 17–51%) was higher than in most published studies in this setting. An analysis in 11 of the patients showed that SCH66336 did not affect the pharmacokinetics of gemcitabine.

The investigators recommend that the observed activity of this drug combination should now be assessed in randomized trials.