A phase 2 trial of TAS-102 with or without celecoxib in ctDNA-defined minimal residual disease (MRD) in colorectal cancer after completion of adjuvant chemotherapy.

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TPS270 Background: Multiple studies demonstrate that circulating tumor DNA (ctDNA) captures radiographically occult micrometastases and predicts colorectal cancer (CRC) recurrence with a positive predictive value approaching 100%. The average lead-time of ctDNA positivity to radiographic recurrence is 6-9 months, which provides a window of opportunity to investigate novel MRD-directed therapies. Arm A of this trial evaluated TAS-102 monotherapy for 6 months in CRC patients with ctDNA defined MRD. The study met its primary end point with a 33% ctDNA clearance rate at 6 months and 47% at 3 months, however, 60% of patients had radiographic recurrence at median follow up of 14.8 months. (Pellatt et al., JCO PO, 2025). These findings highlight the need for combination approaches to enhance the durability of response. Celecoxib has been studied as a chemo preventive agent in CRC and shown to be synergistic with cytotoxic therapies in multiple preclinical studies. A retrospective ctDNA analysis from the phase III CALGB 80702 study demonstrated a significant disease-free survival (DFS) benefit with the addition of celecoxib to FOLFOX in ctDNA+ patients (41% vs 22.6%, HR 0.55). Given the activity of TAS-102 noted in 5-FU refractory patients and the promising signals of TAS-102 from the ALTAIR and INTERCEPT trials, arm B of this study investigates whether TAS-102 with celecoxib will be synergistic in eradicating MRD. Methods: This is a single-center investigator initiated non-randomized open-label phase 2 study investigating the efficacy of TAS-102 (35mg/m2 on D1-5 and D8-12 every 28 days) in combination with celecoxib (400mg daily) in CRC patients with ctDNA defined MRD. Key eligibility criteria include patients with stages II-IV CRC and detectable ctDNA levels (Signatera) without radiographic evidence of disease on imaging in last 30 days following curative intent therapies that must include ≥ 3 months of oxaliplatin containing chemotherapy. In arm B of this study, 15 patients will receive TAS-102 with celecoxib for 6 months. Celecoxib may be continued up to 12 months if well tolerated. The primary objective is to determine the 6-month ctDNA clearance rate. With a null hypothesis of 5% and alternative of 30% ctDNA clearance, 15 patients per cohort provide 85% power. Secondary objectives include evaluating the 3-month ctDNA clearance rate, DFS, OS, and safety and tolerability. As of August 2025, arm B is open to patient enrollment at MD Anderson Cancer Center. Trial Identification: NCT05343013. Clinical trial information: NCT05343013 .

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