Phase 2 randomized study evaluating safety, efficacy, and optimal dose of ABBV-400 in combination with fluorouracil, folinic acid, and bevacizumab in previously treated patients with metastatic colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer. In the metastatic (m) setting, the 5-year relative overall survival is approximately 15%. Conventional treatment comprises fluorouracil (5-FU)–based chemotherapy. Recently, targeted therapies have been studied for specific molecular subtypes. c-Met overexpression frequently occurs in a variety of tumors, including CRC. ABBV-400 is a c-Met–directed antibody-drug conjugate composed of the monoclonal antibody telisotuzumab conjugated to a potent topoisomerase 1 inhibitor payload. Preliminary data from the first-in-human study of ABBV-400 in patients with advanced solid tumors indicate encouraging efficacy of ABBV-400 monotherapy in patients with third-line or later mCRC. This phase 2 randomized study evaluates the safety, efficacy, and optimal dose of ABBV-400 in combination with 5-FU, folinic acid (FA), and bevacizumab (bev) in patients with mCRC with progression after first line (1L) treatment. Global, open-label, phase 2 randomized controlled study (NCT06107413). Eligible patients (≥18 years) have confirmed unresectable mCRC and measurable disease per RECIST v1.1, are microsatellite stable or mismatch repair proficient, V600E wild type, and have progression after 1L combination chemotherapy ± an anti-vascular endothelial growth factor or anti-epidermal growth factor receptor antibody. Primary objectives are (a) optimize ABBV-400 dose in combination with 5-FU, FA, and bev; (b) evaluate the efficacy of the combination, using objective response and progression-free survival as dual primary endpoints; (c) evaluate the safety and tolerability of the combination. Approximately 206 patients planned for enrollment in 2 stages: safety lead-in dose escalation (stage 1; n=30) and dose optimization (stage 2; n=176). In stage 1, patients receive escalating doses of ABBV-400 either every 2 weeks (Q2W; 0.8–2.4 mg/kg) or every 4 weeks (Q4W; 1.6–3.0 mg/kg) in combination with Q2W 5-FU (2400 mg/m infusion), FA (200 mg/m ), and bev (5 mg/kg) in 28-day cycles. Dose escalation of ABBV-400 uses a Bayesian optimal interval design, with target toxicity rate of 30%. Dose-limiting toxicities (DLT) are assessed during cycle 1, with ≥6 DLT evaluable patients required to declare a dose safe for the dose-optimization stage. In stage 2, patients are randomized to up to 4 ABBV-400 dose cohorts (2 with Q2W and 2 with Q4W ABBV-400 schedule; all in combination with Q2W 5-FU, FA, and bev) and a comparator cohort (irinotecan [180 mg/m ] + 5-FU [400 mg/m bolus and 2400 mg/m infusion] + FA [200 mg/m ] + bev [5 mg/kg]; all Q2W). Patients are treated until progression, unacceptable toxicity, or other discontinuation criteria are met. Enrollment was initiated in November 2023, with 3 patients enrolled as of January 4, 2024. .

Duke Scholars

Author John Strickler Medicine, Medical Oncology