Concomitant Intraperitoneal and Systemic Chemotherapy in Patients With Extensive Peritoneal Carcinomatosis of Gastric Origin

Study Overview
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Brief Summary
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Gastric cancer with peritoneal carcinomatosis has a poor prognosis, with little treatment options available. The current treatment strategy consists of palliative systemic chemotherapy. However, previous research suggests that systemic chemotherapy is less effective against peritoneal carcinomatosis than against metastases that spread hematogenously. Several studies suggested that in patients with peritoneal carcinomatosis, intraperitoneal chemotherapy (IP) may be superior compared to intravenous chemotherapy. Intraperitoneal chemotherapy could lead to higher concentrations of chemotherapy in the peritoneal cavity for a longer period of time, resulting in an increased cumulative exposure to the peritoneal metastases. A few Asian studies have shown promising results with intraperitoneal chemotherapy in patients with peritoneal carcinomatosis of gastric origin. However, intraperitoneal chemotherapy combined with systemic chemotherapy has not been investigated in Western patients with peritoneal carcinomatosis of gastric origin yet. The objective of this trial is to establish the maximum tolerated dose (MTD) of intraperitoneal administration of irinotecan, added to systemic capecitabine/oxaliplatin (CAPOX) in patients with peritoneal carcinomatosis of gastric origin.

Official Title
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Concomitant Intraperitoneal and Systemic Chemotherapy in Patients With Extensive Peritoneal Carcinomatosis of Gastric Origin

Conditions
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Gastric Cancer, Peritoneal Metastases

Intervention / Treatment
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* Drug: Irinotecan
* Drug: CAPOX


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a histologically confirmed diagnosis of HER2-negative gastric cancer. A histologically confirmed diagnosis of peritoneal carcinomatosis. Age ≥ 18 years old. Written informed consent according to the ICH-GCP and national/local regulations. A peritoneal cancer index (PCI) ≥7 evaluated by laparoscopy or laparotomy before inclusion in this trial. Patients must be ambulatory: World Health Organisation (WHO) performance status 0 or 1. Life expectancy of at least 3 months. Ability to return to the Erasmus MC for adequate follow-up as required by this protocol. Patients must have normal organ function and adequate bone marrow reserve as assessed by the following laboratory requirements: absolute neutrophil count >1.5 * 10^9/l; platelet count >100*10^9/l; Hb>6.0mmol/l; Bilirubin < 1.5x upper limit of normal (ULN); Serum aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) < 2.5 x ULN; Glomerular Filtration Rate (GFR) >45 and Creatinine clearance <2 x ULN. Exclusion Criteria: Medical or psychological impediment to probable compliance with the protocol. Serious concomitant disease or active infections. Distant metastasis other than peritoneal metastasis or metastatic lymph nodes. No sufficient oral food intake. Polyneuropathy grade 2 or worse according to CTCAE version 5.0. History of auto-immune disease or organ allografts, or with active or chronic infection, including HIV and viral hepatitis. Serious intercurrent chronic or acute illness such as pulmonary (COPD or asthma) or cardiac (NYHA class III or IV) or hepatic disease or other illness considered by the study coordinator to constitute an unwarranted high risk for participation in this study. Homozygous UGT1A1*28 genotype. Homozygous dihydropyrimidine dehydrogenase (DPYD) genotype (tested for *2A, *13, 2846A>T, and 1236G>A). Current use of strong CYP3A4-inhibitors or inducers. If patients use this CYP3A4-modulating medication, it is allowed to stop it within 14 days of start of treatment. Pregnant or lactating women. Concomitant participation in a competing clinical study. Absence of assurance of compliance with the protocol. An organic brain syndrome or other significant psychiatric abnormality which would comprise the ability to give informed consent, and preclude participation in the full protocol and follow-up.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A classic phase I '3+3' dose-escalation study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intraperitoneal irinotecan 50 mg + CAPOX<br>Intraperitoneal irinotecan, dose level 1 50 mg flat dose + oral capecitabine and systemic oxaliplatin (CAPOX) (dose via standard of care) | Drug: Irinotecan<br>* 3 weekly IP irinotecan (max 6 cycles), dose via dose-escalation design as specified per arm.<br>* Other names: Intraperitoneal irinotecan;Drug: CAPOX<br>* Capecitabine 1000 mg/m2 twice daily day 1-14 (per os), and Oxaliplatin 130 mg/m2 on day 1 IV infusion.<br>|
| Experimental: Intraperitoneal irinotecan 75 mg + CAPOX<br>Intraperitoneal irinotecan, dose level 2 75 mg flat dose + oral capecitabine and systemic oxaliplatin (CAPOX) (dose via standard of care) | Drug: Irinotecan<br>* 3 weekly IP irinotecan (max 6 cycles), dose via dose-escalation design as specified per arm.<br>* Other names: Intraperitoneal irinotecan;Drug: CAPOX<br>* Capecitabine 1000 mg/m2 twice daily day 1-14 (per os), and Oxaliplatin 130 mg/m2 on day 1 IV infusion.<br>|
| Experimental: Intraperitoneal irinotecan 100 mg + CAPOX<br>Intraperitoneal irinotecan, dose level 3 100 mg flat dose + oral capecitabine and systemic oxaliplatin (CAPOX) (dose via standard of care) | Drug: Irinotecan<br>* 3 weekly IP irinotecan (max 6 cycles), dose via dose-escalation design as specified per arm.<br>* Other names: Intraperitoneal irinotecan;Drug: CAPOX<br>* Capecitabine 1000 mg/m2 twice daily day 1-14 (per os), and Oxaliplatin 130 mg/m2 on day 1 IV infusion.<br>|
| Experimental: Intraperitoneal irinotecan 150 mg + CAPOX<br>Intraperitoneal irinotecan, dose level 4 150 mg flat dose + oral capecitabine and systemic oxaliplatin (CAPOX) (dose via standard of care) | Drug: Irinotecan<br>* 3 weekly IP irinotecan (max 6 cycles), dose via dose-escalation design as specified per arm.<br>* Other names: Intraperitoneal irinotecan;Drug: CAPOX<br>* Capecitabine 1000 mg/m2 twice daily day 1-14 (per os), and Oxaliplatin 130 mg/m2 on day 1 IV infusion.<br>|
| Experimental: Intraperitoneal irinotecan 200 mg + CAPOX<br>Intraperitoneal irinotecan, dose level 5 200 mg flat dose + oral capecitabine and systemic oxaliplatin (CAPOX) (dose via standard of care) | Drug: Irinotecan<br>* 3 weekly IP irinotecan (max 6 cycles), dose via dose-escalation design as specified per arm.<br>* Other names: Intraperitoneal irinotecan;Drug: CAPOX<br>* Capecitabine 1000 mg/m2 twice daily day 1-14 (per os), and Oxaliplatin 130 mg/m2 on day 1 IV infusion.<br>|
| Experimental: Intraperitoneal irinotecan 250 mg + CAPOX<br>Intraperitoneal irinotecan, dose level 6 250 mg flat dose + oral capecitabine and systemic oxaliplatin (CAPOX) (dose via standard of care) | Drug: Irinotecan<br>* 3 weekly IP irinotecan (max 6 cycles), dose via dose-escalation design as specified per arm.<br>* Other names: Intraperitoneal irinotecan;Drug: CAPOX<br>* Capecitabine 1000 mg/m2 twice daily day 1-14 (per os), and Oxaliplatin 130 mg/m2 on day 1 IV infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated dose | The maximum tolerable dose and recommended phase II dose of intraperitoneal irinotecan added to systemic chemotherapy (capecitabine/oxaliplatin) | 18 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 | Toxicity graded according to the CTCAE v.5.0 determined at every cycle by the medical oncologist. Toxicity will be summarized descriptively. | 18 weeks | 
| Area Under the Curve (AUC) ratio intraperitoneal/systemic irinotecan | During the first irinotecan intraperitoneal cycle, pharmacokinetic measurements wil be obtained. These will be withdrawn at specific time-points, namely prior to infusion, at the end of the intraperitoneal infusion, ass well as 30 minutes, 1, 1.5, 2, 3, 4, 6, and 24 hours post infusion. Blood samples from a peripheral venous catheter and peritoneal fluid will be drawn from the peritoneal access port. We assume that the AUC of irinotecan and SN-38 follow a log-normal distribution. Therefore, the analysis will be performed on log-transformed data. The antilog will be taken from the ratio and corresponding 95% confidence interval boundaries will be reported. | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peritoneal metastases, Gastric cancer, Intraperitoneal, Irinotecan