A phase I trial of ABT-751 and carboplatin (C) in patients (pts) with previously treated non-small cell lung cancer (NSCLC)

Abstract

17098 Background: NSCLC is the leading cause of cancer mortality for men and women in the United States. More effective treatments are needed to prolong survival and improve quality of life. Platin-containing chemotherapy doublets are commonly used in NSCLC treatment. ABT-751 is a novel oral anti-microtubule agent targeting the colchicine binding site. As single agent, it was well-tolerated and showed a preliminary signal of activity in previously treated NSCLC. In vivo studies demonstrated additive activity between ABT-751 and cisplatin in a NSCLC xenograft model. Methods: A phase I trial of ABT-751 and C was conducted in pts with advanced previously treated NSCLC. Primary objective - maximum tolerated dose (MTD). Secondary objectives - toxicities, efficacy, and surrogate markers of response (cell cycle changes and cyclin D1 expression) in buccal swabs from pts at the phase II dose. Six dose levels - 1: ABT-751 100mg bid, C AUC 4.5; 2: ABT-751 125 mg bid, C AUC 4.5; 3: ABT-751 125 mg bid, C AUC 6; 4: ABT-751 150 mg bid, C AUC 6; 5: ABT-751 175 mg bid, C AUC 6; 6: ABT-751 200 mg bid, C AUC 6. ABT-751 was taken orally twice a day for 14 days in a 21 day cycle, C was administered intravenously on day 4 during cycle 1 and on day 1 on subsequent cycles. Rapid dose escalation was used for the first 3 dose levels followed by cohorts of at least 3 patients for the remaining dose levels. Results: Eight pts were enrolled, all stage IV NSCLC, 4 women, median age 62 (47–73), all KPS 80, 6 had one and 2 had 2 prior therapies. A median of 3.5 (1–4) cycles was administered. Dose-limiting toxiticies of grade 3 fatigue and grade 4 thrombocytopenia and neutropenia were observed in 2/5 patients on dose level 4. Common grade 2 toxicites were constipation and peripheral sensory neuropathy (levels 2–4). MTD was dose level 3. Seven pts were evaluable for response, 2 had partial responses (levels 2 and 4, both had one prior therapy), 4 had stable disease, 1 had disease progression. Median time to progression was 18.7 weeks (6–24+). Pharmacokinetic analyses and buccal swabs are being performed. Conclusions: The recommended phase II doses are ABT-751 125 mg twice daily for 14 days and carboplatin AUC 6 on a 21-day cycle. This regimen is well tolerated and shows preliminary evidence of activity for previously treated NSCLC. [Table: see text]

Vascular Disrupting Agents: A Novel Mechanism of Action in the Battle Against Non-Small Cell Lung Cancer

“…The recommended doses were 125 mg twice daily for 14 days for ABT-751 and an AUC of 6 on a 21-day cycle for carboplatin. Only seven patients were evaluated for activity, with two partial responses and four cases of stable disease, and the median TTP was 18.7 weeks [45] (Table 2). To date, ABT-751 is being evaluated as second-line therapy in combination with docetaxel or pemetrexed in two ran-domized, placebo-controlled phase II studies in patients with advanced NSCLC [44].…”

Antiangiogenic Agents and Vascular Disrupting Agents for the Treatment of Lung Cancer: A Review

“…Toxicities in a phase I trial included neuropathy, constipation, fatigue, myalgia, anemia, nausea, and vomiting. 137 In the phase I dose-escalation trial of ABT-751 and carboplatin in previously treated NSCLC, dose-limiting toxicities were thrombocytopenia and neutropenia. Of the seven evaluable patients, two had partial response, four had stable disease, and the median TTP was 18.7 weeks.…”