Phase II Dose Escalation Study of Oral Capecitabine Substitution for 5‑FU in Perioperative FLOT Regimen for Resectable Gastric and Esophageal Adenocarcinoma

Primary objective: determine the MTD and recommended dose of perioperative capecitabine within the DOC regimen in patients with oesophageal, gastro‑oesophageal junction (GEJ) and gastric adenocarcinoma, to establish a dosing framework that could replace 5‑fluorouracil in the perioperative FLOT protocol. Secondary objectives:

• Assess the pharmacokinetic profile of capecitabine in the DOC regimen pre‑operatively and post‑operatively, providing data on systemic exposure and metabolism.
• Evaluate the feasibility of implementing the DOC regimen in the target patient population, including adherence to treatment schedules and completion rates.
• Characterize the toxicity profile of capecitabine within the DOC regimen, documenting safety markers relevant to perioperative management.

The trial enrolled adult patients of both sexes, aged 18 years and older, with histologically confirmed esophageal cancer, gastro‑oesophageal junction or gastric adenocarcinoma for which peri‑operative FLOT chemotherapy was indicated. Eligible individuals required a WHO performance status of 0–1, indicating full activity or slight restriction. Selection was based on confirmed pathology and the ability to provide written informed consent in accordance with ICH‑GCP and local regulations. The sponsor did not provide the total number of participants. No specific lifestyle restrictions such as diet or physical activity were stipulated in the available description.

The study is a phase I dose‑finding investigation within a perioperative FLOT regimen that replaces 5‑fluorouracil with oral capecitabine for patients with histologically confirmed esophageal cancer, gastro‑esophageal junction or gastric cancer indicated for perioperative chemotherapy; eligibility requires WHO performance status 0–1, age ≥18 years, and written informed consent. The trial employs a standard 3+3 design with a dose‑escalation approach to determine the maximum tolerated dose (MTD) of capecitabine administered at 1300 mg/m² per cycle, with dose‑limiting toxicities guiding escalation. Participants undergo a screening visit, followed by baseline assessments, then receive neoadjuvant chemotherapy cycles, undergo surgery, and subsequently receive adjuvant cycles; each treatment phase is accompanied by scheduled follow‑up visits for safety monitoring, pharmacokinetic sampling, and efficacy assessments, concluding with an end‑of‑study visit after completion of all planned therapy. The overall study period spans from the estimated start of recruitment on 1 July 2026 to the projected end date of 1 April 2028, with individual participant involvement lasting from screening through the final follow‑up, approximately 12 months. Early discontinuation may occur if a participant experiences a treatment‑related adverse event meeting the predefined criteria for dose‑limiting toxicity, develops a serious adverse event, or withdraws consent.

The experimental arm utilizes Capecitabine 500 mg film‑coated tablets administered orally at a total dose of 1300 mg/m² per treatment cycle; the tablets are taken according to the study‑specified schedule and divided as directed by the protocol.

The second formulation consists of Capecitabine 150 mg film‑coated tablets, also given orally at a total dose of 1300 mg/m² per cycle and administered in accordance with the protocol‑defined dosing schedule.

In the control context, the standard perioperative FLOT regimen—which normally incorporates 5‑fluorouracil as the fluoropyrimidine component—is modified by substituting the oral capecitabine regimen described above while maintaining the remaining chemotherapeutic agents at their conventional doses. Administration of oral capecitabine is overseen by study staff, with participant adherence assessed through pill counts and documented dosing records.

Efficacy will be evaluated by analyzing the pharmacokinetic exposure of capecitabine metabolites. The area under the concentration‑time curve (AUC) for each metabolite will be determined in both the preoperative and postoperative settings for each patient. These individual AUC values will be used to calculate an AUC ratio, allowing comparison of drug exposure before and after surgery.

Additional efficacy indicators include treatment adherence metrics. The proportion of patients who discontinue treatment because of treatment‑related adverse events, as well as the percentages of patients completing all planned neoadjuvant and adjuvant treatment cycles, will be recorded and summarized.