Background: Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the US. 5-fluorouracil (5-FU) based chemotherapies in combination with targeted agents remain the standard of care in patients with metastatic or locally advanced disease. It is essential to develop new treatment strategies in metastatic CRC patients with microsatellite stable disease, in whom immune checkpoint blockade is ineffective. Our preclinical studies showed riluzole, an oral medicine for amyotrophic lateral sclerosis, can increase intratumoral CD8⁺ T cells and suppress tumor growth in a syngeneic colon cancer mouse model. Riluzole-mediated tumor growth inhibition depends on the presence of CD8⁺ T cells and activation of cGAS/STING/IFNβ signaling. Methods: This was a single-arm phase I trial of riluzole in combination with mFOLFOX6/bevacizumab for patients with metastatic CRC. The dose of riluzole started from 50 mg twice daily with dose escalation to 100 mg twice daily or dose de-escalation to 50 mg once daily. Patients received riluzole for 16 weeks in combination with mFOLOFX6/bevacizumab for 8 cycles. Then patients either continued mFOLFOX/bevacizumab or switched therapy. The primary objective was adverse events (AE). The secondary objectives were objective response rate (ORR), disease control rate (DCR), and duration of response (DoR). Results: Fourteen patients were enrolled, and twelve patients were evaluable. All patients received FOLFOX in the past; two patients received 2 lines of chemotherapies; one patient received 3 lines and eight patients had ≥ 4 lines before the study. Five patients (41.7%) had disease resistance to FOLFOX. During the study, two patients received only 2 cycles of treatment due to poor PS. Two patients received 7 cycles, and nine patients completed 8 cycles of treatment. The common grade 3 & 4 AEs included neutropenia (46.2%), lymphopenia (30.8%), and abdominal pain (15.4%). No complete response was observed; two patients obtained partial response; nine patients had stable disease, and only one patient had progressive disease. The ORR was 16.7%, and DCR was 91.7%. The median DoR was 5.1 (95% CI 3.2-7.0) months. The maximum tolerated dose for riluzole is 100 mg twice daily. Conclusions: Our study showed that riluzole plus mFOLFOX6/bevacizumab is well tolerated in patients with metastatic CRC and may have clinical activity in patients whose disease is resistant to FOLFOX. Further study is necessary to confirm the immunomodulation effect of riluzole. Clinical trial information: NCT04761614.