Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small-cell lung cancer.

BACKGROUND: R115777 (tipifarnib, Zarnestra) is a farnesyl transferase inhibitor that blocks the farnesylation of proteins involved in signal transduction pathways critical for cell proliferation and survival. This multicenter phase II study was conducted to determine the efficacy, tolerability and pharmacokinetics of R115777 in patients with relapsed small-cell lung cancer (SCLC). PATIENTS AND METHODS: Patients who had a partial or complete response to their initial chemotherapy regimen, followed by at least 3 months off treatment before relapse (sensitive relapse) were eligible. R115777 was administered in 3-week cycles at a dose of 400 mg orally twice daily for 14 consecutive days followed by 7 days off treatment. RESULTS: Twenty-two patients were enrolled. The median progression-free survival was 1.4 months and median overall survival was 6.8 months. Non-hematological toxicities were predominantly grade 1-2 and included nausea (64%) and fatigue (60%). Grade 3-4 granulocytopenia and thrombocytopenia occurred in 27% and 23% of patients, respectively. Febrile neutropenia was not observed. Pharmacokinetic studies demonstrated peak plasma concentrations of R115777 2.6-4.5 h after oral dosing and no significant drug accumulation. The trial was terminated because no objective responses were observed in 20 patients evaluable for response. CONCLUSIONS: R115777 showed no significant antitumor activity as a single agent in sensitive-relapse SCLC.

Weekly irinotecan and cisplatin in advanced non-small cell lung cancer: a multicenter phase II study.

The combination of weekly irinotecan (CPT-11) and monthly cisplatin has shown promising activity in advanced non-small cell lung cancer (NSCLC) in previous Phase I and II studies. However, same-day administration of these agents may better exploit their therapeutic synergy and minimize toxicities. This multicenter Phase II study was undertaken to evaluate the efficacy and safety of a combination of weekly CPT-11 and weekly cisplatin in patients with advanced NSCLC. Patients with chemotherapy-naive stage IIIB or IV NSCLC were treated with repeated cycles of therapy comprising weekly treatment with both cisplatin and CPT-11 for 4 weeks, followed by a 2-week rest. The starting doses of CPT-11 and cisplatin were 65 and 30 mg/m2, respectively. Treatment was continued until the occurrence of disease progression, unacceptable toxicity, or a maximum of six cycles. Fifty patients were enrolled. The median age was 59 years (range, 44-79 years). Eastern Cooperative Oncology Group performance status was 0 in 22 patients, 1 in 19 patients, and 2 in 9 patients. Seven and 43 patients had stages IIIB and IV disease, respectively. Five patients had brain metastasis. Patients received a median of three 6-week cycles (range, 1-6). The objective response rate was 36% (18 of 50; 95% confidence interval, 24-54%) and included 18 partial responses. Median time to tumor progression was 6.9 months (range, 0.6-15.2). The median survival was 11.6 months (range, 0.16-21.9 months), and the 1-year survival rate was 46%. Grade 3/4 nonhematological toxicities included vomiting (12%) and diarrhea (26%). Grade 3/4 hematological toxicities included anemia (14%), neutropenia (26%), and thrombocytopenia (14%). Relative dose intensities for CPT-11 and cisplatin were 89 and 62%, respectively. Weekly combined administration of CPT-11 and cisplatin achieved a promising overall response rate, median time to tumor progression, and median survival in patients with stage IIIB/IV NSCLC. The regimen was well tolerated, and the planned dose intensity was well maintained. Further evaluation of this combination in NSCLC is warranted.