Phase I Study of Perioperative Intraperitoneal Irinotecan and Systemic FLOT Combination Therapy for Curative Gastric and Gastroesophageal Junction Cancer

Trial ID: 2025-522864-34-00
Sponsor: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

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Diseases & Conditions

Gastric cancer

Objectives

The primary objective is to determine the maximum tolerated dose and the recommended phase II dose of perioperative intraperitoneal irinotecan combined with systemic FLOT in patients with gastric cancer or gastroesophageal junction cancer undergoing gastrectomy. Secondary objectives include:

Assessment of the toxicity profile associated with combined intraperitoneal and systemic therapy.
Evaluation of the feasibility of perioperative intraperitoneal administration in conjunction with surgery and systemic treatment.
Analysis of the pharmacokinetic profile of the administered agents within the peritoneal cavity.
Investigation of the impact of the UGT1A1 genotype on the pharmacokinetics of irinotecan.

Participants

The sponsor did not provide information regarding the total number of participants. The study population consists of adult patients, aged 18 years or older, diagnosed with histologically confirmed gastric cancer or gastroesophageal junction cancer. Eligible individuals are those scheduled to undergo (sub)total gastrectomy in conjunction with perioperative systemic FLOT chemotherapy. Participants must possess a WHO performance status of 0–1 and a life expectancy of at least three months. Both males and females are included in the study.

Plans and Procedures

This phase I study utilizes a 3+3 dose escalation design to evaluate the curative treatment of gastric cancer and gastroesophageal junction cancer. The primary objective is to determine the maximum tolerated dose and the recommended phase II dose of perioperative intraperitoneal irinotecan combined with systemic FLOT chemotherapy in patients undergoing gastrectomy. The methodology focuses on identifying dose-limiting toxicities to establish safety parameters. Secondary endpoints include the assessment of adverse events, serious adverse events, postoperative complications, and pharmacokinetic parameters. Evaluation of the peritoneum/plasma ratio and the influence of UGT1A1 genotype will also be conducted. Inclusion requires histologically confirmed adenocarcinoma, a WHO performance score of 0-1, and a life expectancy of at least three months.

Treatment

The experimental treatment consists of irinotecan hydrochloride trihydrate, provided as an irinotecan 20 mg/ml solution for infusion. The administered dose is 75 mg via the intraperitoneal route. This substance is utilized as part of a perioperative intraperitoneal chemotherapy regimen.

The study protocol involves the administration of systemic FLOT as a non-experimental or concurrent therapeutic component. The investigation aims to evaluate the maximum tolerated dose and the recommended phase II dose when combining the experimental agent with this systemic therapy in patients with gastric cancer or gastroesophageal junction cancer undergoing gastrectomy.

Efficacy

The primary objective of this study is to establish the maximum tolerated dose (MTD) and the recommended phase II dose of perioperative intraperitoneal irinotecan combined with systemic FLOT in patients with gastric cancer or gastroesophageal junction cancer undergoing gastrectomy. The MTD will be determined through a 3+3 dose escalation design based on the frequency of dose-limiting toxicities (DLTs).

Secondary assessments include the evaluation of treatment safety via the following parameters:

All treatment-related adverse events (AEs) as categorized by the Common Terminology Criteria for Adverse Events (CTCAE).
All serious adverse events (SAEs).
All postoperative complications.
The percentage of patients discontinuing treatment due to treatment-related AEs.
The percentage of patients undergoing resection following preoperative chemotherapy.

Efficacy and pharmacological profiles will be evaluated using pharmacokinetic parameters and the peritoneum/plasma ratio during the second treatment cycle. Additionally, UGT1A1 genotype will be compared with pharmacokinetic parameters within the peritoneal cavity.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Histologically confirmed GC or GEJ adenocarcinoma planned to (sub)total gastrectomy in combination with perioperative systemic FLOT chemotherapy
WHO-performance score 0 -1 with a life expectancy greater than or equal to three months
Aged 18 years or older
Written informed consent according to the ICH-GCP and national/local regulations.

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Exclusion Criteria

Any contra-indication for the (planned) systemic chemotherapy (e.g. active infection, serious concomitant disease, severe allergy, persistent neurologic toxicity after (neo-)adjuvant oxaliplatin based systemic therapy), as determined by the treating medical oncologist;
Inadequate organ functions (defined as a hemoglobin <5.0 mmol/L (before transfusion), an absolute neutrophil count <1.5 x 109/l, platelet count <100 x 109/l, creatinine clearance <30 mL/min, bilirubin >2x ULN and liver transaminases >2.5x ULN)
Pregnant or lactating women
Concomitant participation in any clinical study that could modify the outcomes relevant to this study
Unwillingness or inability to comply with the study protocol.