ECOG 6293: Phase II Study of Raltitrexed in Advanced Colorectal Cancer.

[BACKGROUND] Inhibition of thymidylate synthase (TS) is a common mechanism in the treatment of colorectal cancer (CRC). 5-Flurouracil 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.

[METHODS] This trial took place from December 1995 to December 1998. Advanced CRC patients were enrolled into 3 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.

[RESULTS] 101 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.

[CONCLUSION] 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.