Phase I/II dose escalation trial of patupilone every 3 weeks in patients with non-small cell lung cancer

Abstract

7110 Background: Patients (pts) with newly diagnosed advanced non-small cell lung cancer (NSCLC) usually receive a platinum-containing doublet. However, these regimens do not produce a marked improvement in survival and many are associated with cumulative toxicity. Patupilone, a natural epothilone, is a microtubule-targeting cytoxic agent that causes cell death and is active in a variety of tumors, including those that are resistant to taxanes. In a phase I/II study, we are investigating the safety, efficacy, and maximum tolerated dose (MTD) of patupilone in pts with stage IIIB/IV NSCLC. Methods: Pts who have relapsed after 1 prior platinum-containing regimen and did not have symptomatic brain metastases have been enrolled. During the phase I study, pts receive patupilone at a starting dose of 6.5 mg/m2 via 10- to 20-min IV infusion once every 3 weeks with dose escalation in 0.5-mg/m2 increments and proactive diarrhea management. Severe toxicities occurring in cycle 1 were considered dose-limiting toxicities (DLTs). Results: To date, 39 pts have been enrolled in 10 cohorts receiving 6.5 (n = 3), 7.0 (n = 3), 7.5 (n = 6), 8.0 (n = 6), 8.5 (n = 6), 9.0 (n = 3), 9.5 (n = 3), 10.0 (n = 3), 10.5 (n = 3), and 11.0 (n = 3) mg/m2 patupilone. Median age was 57 years (range, 38 to 77 years) and median performance status was 1. DLTs were not observed until the 7.5 mg/m2 cohort wherein 1 pt reported grade 3 asthenia. The 8.0- and 8.5-mg/m2 cohorts had 1 pt each with grade 3 diarrhea. No other DLTs have been reported up to 11.0 mg/m2 and pts are currently being enrolled in the 11.5 mg/m2 cohort. The most common adverse events were diarrhea (54%), abdominal pain (36%), fatigue (31%), and nausea (31%). Only 9 (26%) pts had grade 3 adverse events of any kind; 5 pts with grade 3 diarrhea. Alopecia (grade 1) occurred in only 3 pts and 11 pts had grade 1 or 2 peripheral neuropathy. Grade 3 hematologic toxicity was uncommon (< 10%) and there were no grade 4 adverse events. According to RECIST, 4 pts had a partial response and 9 pts had stable disease; median duration of stable disease was 4.2 months (95% CI: 4.0 to 5.4). Conclusions: The MTD has not yet been reached. Preliminary results suggest that patupilone is safe and there is evidence of antitumor activity in pts with advanced NSCLC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Novartis Pharmaceuticals, AG Novartis Novartis, Novartis Pharmaceuticals, AG Novartis