ECOG-ACRIN E6293: Phase II Study of Raltitrexed in Advanced Colorectal Cancer

Inhibition of thymidylate synthase (TS) is a common mechanism in the treatment of colorectal cancer (CRC). 5-Fluorouracil is an indirect inhibitor of TS that is commonly used in CRC treatment regimens. Raltitrexed is a direct TS inhibitor that was hypothesized to have better efficacy and toxicity in CRC due to its specific inhibition. To test this, a phase II ECOG-ACRIN trial testing raltitrexed was conducted.

This trial took place from December 1995 to December 1998. Advanced CRC patients were enrolled into three strata: (1) No prior treatment (2) One prior line of 5-FU-based regimen without leucovorin (3) One prior line of 5-FU-based regimen with leucovorin. Raltitrexed 3 mg/m2 was given every 3 weeks. A two-stage design with pre-specified ORR was utilized. Primary endpoints were ORR, toxicity, and prognostic value of TS expression by immunohistochemistry. Secondary endpoints were mPFS and mOS.

One hundred one patients were enrolled. ORR, mPFS, and mOS (months) by stratum were:1. 5-FU Naïve: 3%, 2.1 (95% CI 1.4, 2.7), 14.5 (95% CI 8.0, 19.9),2. 5-FU regimen/no leucovorin: 4.2%, 2.6 (95% CI 1.4, 3.5), 12.5 (95% CI 5.0, 17.0), and3. 5-FU regimen/leucovorin: 3.3%, 1.7 (95% CI 1.4, 2.3), 7.3 (95% CI 4.9, 14.3).Based on low ORR, the trial did not advance to the second stage. One PR occurred in the high TS expression group, none in low TS group.

In this phase II trial, raltitrexed did not show significant response rates in patients with advanced CRC. Due to limited ORR of raltitrexed, value of TS expression as a biomarker was inconclusive. No new safety signals for raltitrexed were demonstrated.