Phase 2 study of ABT-751 in patients with refractory metastatic colorectal carcinoma (CRC)

Abstract

3537 Background: ABT-751, an oral antimitotic agent that binds to the colchicine site of β-tubulin and prevents microtubule polymerization, has shown antitumor activity in CRC in xenograft models, including HCT-15, a human colon carcinoma-derived cell line in which paclitaxel and vincristine were ineffective. Minor responses to ABT-751, including one partial response, were seen in CRC patients in phase 1 studies. Methods: This phase 2, multi-center study evaluated the safety and efficacy of ABT-751 in patients with metastatic CRC (N = 49) refractory to irinotecan or oxaliplatin [single refractory (SR) arm, n = 14], or irinotecan and oxaliplatin [double refractory (DR) arm, n = 35]. For each cycle, patients received 200 mg ABT-751 orally once daily for 21 days followed by a 7-day break. Time to disease progression (TTP) was analyzed using Kaplan-Meier Methods: CT scans were obtained every 2 cycles. Patient response was evaluated using RECIST. Results: The median duration of therapy was 2 cycles (range 1–8). 57% of patients experienced Grade 3 or 4 toxicities. 18/49 (37%) subjects experienced Grade 3 or 4 toxicities considered probably or possibly related to study drug, including 15/35 in the DR arm and 3/14 in the SR arm [most common = asthenia (12%), anorexia (10%), neuropathy (8%), and constipation (6%)]. Median TTP was 2.1 months (95% CI = 1.9–2.6). Median TTP by study arm was 2.0 months for the DR arm (95% CI = 1.8–2.3) and 3.8 months for the SR arm (95% CI = 2.0–3.9). Three patients remain on study in the SR arm, including 1 patient in Cycle 6. One patient discontinued after exhibiting stable disease through 8 cycles. No complete or partial responses have been observed to date. Conclusions: ABT-751 was well tolerated in CRC patients. Despite preclinical and phase 1 data suggesting activity, ABT-751 was not active as a single-agent in patients with multiple refractory metastatic CRC. Phase 2 studies in patients with renal, breast, and lung carcinoma are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Abbott Laboratories Abbott Laboratories