Phase III Multicenter Trial of PIPAC with Fluorouracil, Docetaxel, and Nivolumab in Oligometastatic Peritoneal Gastric Adenocarcinoma

The primary objective of this study is to evaluate whether the association of **pressurized intraperitoneal aerosol chemotherapy (PIPAC)** with chemotherapy, compared to chemotherapy alone, increases the percentage of patients with **gastric adenocarcinoma with peritoneal metastases** who undergo surgery with radical intent, specifically cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Additionally, the study aims to determine if this combination therapy enhances progression-free survival (PFS). These objectives are clinically relevant as they may offer insights into improving surgical outcomes and extending the time patients remain free from disease progression.

Secondary objectives include:

• Comparing overall survival (OS) in patients receiving chemotherapy and PIPAC versus those treated with first-line chemotherapy alone.
• Comparing disease-free survival (DFS) between the two treatment groups.
• Evaluating the degree of histological regression on peritoneal biopsies in the experimental arm.
• Assessing the degree of regression on the surgical specimen in patients undergoing surgery with radical intent.
• Evaluating changes in quality of life before and after treatment in both groups.
• Assessing safety in terms of incidence, nature, and severity of adverse events and laboratory abnormalities according to CTCAE v5 classification in the two arms.
• Conducting a cost-effectiveness evaluation.

The clinical trial involves participants diagnosed with **gastric adenocarcinoma with peritoneal metastases**. The study population includes both male and female subjects, aged between 18 and 75 years, who are in generally good health as indicated by an ECOG Performance Status scale of 0-1. The trial does not involve a vulnerable population. Participants were selected based on specific criteria, including a primary diagnosis of gastric adenocarcinoma not previously treated and confirmed peritoneal disease with a Peritoneal Cancer Index (PCI) of 6 or less. Lifestyle considerations such as the use of oral contraceptives are restricted due to the high thrombotic risk associated with the disease, although other contraceptive methods are permitted. The total number of participants is not provided, as the sponsor has not disclosed this information.

The clinical trial is designed to evaluate the efficacy of **pressurized intraperitoneal aerosol chemotherapy (PIPAC)** in combination with systemic chemotherapy for patients with **gastric adenocarcinoma with peritoneal metastases**. This is a randomized, multicenter, phase III trial comparing two treatment arms: one receiving PIPAC with chemotherapy and the other receiving chemotherapy alone. The primary objective is to assess whether the addition of PIPAC increases the percentage of patients eligible for surgery with radical intent and improves progression-free survival (PFS).

The trial employs a **randomized, double-blind, controlled** design to ensure unbiased results. Participants will be randomly assigned to one of the two treatment arms. The trial is expected to last until March 2029, with recruitment having started in December 2022. The expected duration of participant involvement is up to 12 cycles of chemotherapy, with each cycle lasting approximately one month. The maximum treatment period for most drugs is six months, except for **cisplatin** and **doxorubicin hydrochloride**, which have a maximum treatment period of four months.

Study visits are structured as follows: an initial inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and performance status. Follow-up visits will occur at regular intervals to monitor treatment response, adverse events, and overall health status. The end-of-study visit will evaluate the primary and secondary endpoints, including secondary resectability rate and overall survival. Participants may be withdrawn from the study early due to adverse events, disease progression, or withdrawal of consent.

Inclusion criteria include age between 18-75 years, a diagnosis of primary gastric adenocarcinoma with peritoneal metastases, and an ECOG performance status of 0-1. Exclusion criteria are not specified in the provided data. The trial will assess various endpoints, including the degree of histological regression, quality of life, and adverse events, using validated tools and criteria. The study aims to provide robust data on the potential benefits of integrating PIPAC into the treatment regimen for this patient population.

The clinical trial involves the administration of several **experimental medications**. **Fluorouracil** is provided as a solution for injection/infusion, with a maximum daily dose of 1652 mg/m². It is administered intravenously over a treatment period of up to 6 cycles. **Docetaxel** is supplied as a concentrate for solution for infusion, with a maximum daily dose of 75 mg/m², also administered intravenously for up to 6 cycles. **Nivolumab**, marketed as Opdivo, is a monoclonal antibody provided as a 10 mg/mL concentrate for solution for infusion, with a maximum daily dose of 240 mg, administered intravenously over a 6-cycle period.

**Oxaliplatin** is administered as a concentrate for solution for infusion, with a maximum daily dose of 85 mg/m², delivered intravenously for up to 6 cycles. **Calcium Levofolinate** is provided as a powder for solution for infusion, with a maximum daily dose of 200 mg/m², administered intravenously over a 6-cycle period. **Cisplatin** is supplied as a concentrate for solution for infusion, with a maximum daily dose of 10500 µg/m², administered intraperitoneally for up to 4 cycles. **Doxorubicin Hydrochloride** is provided as a concentrate for solution for injection/infusion, with a maximum daily dose of 2100 µg/m², administered intraperitoneally over a 4-cycle period.

All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The administration of these medications is conducted under strict clinical supervision to ensure adherence to the protocol and to monitor for any adverse effects.

Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include the **Secondary Resectability Rate** and **Progression-Free Survival (PFS)**. The Secondary Resectability Rate will be evaluated as the percentage of patients in the two arms who undergo cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) compared to the total number of participants at the end of 6 or 12 cycles of chemotherapy in Arm A and at the end of 6 cycles of chemotherapy and 3 PIPACs in Arm B. PFS will be measured at 1 and 3 years as the time from randomization to the first evidence of progression or death from any cause.

Secondary endpoints include overall survival at 1 and 3 years, disease-related survival (DRS) at 1 and 3 years, and the quality of life (QoL) assessed using the validated EORTC QLQ C30 questionnaire. Additionally, the degree of histological regression on the surgical specimen will be assessed using the Tumor Regression Grade (TRG) according to Mandard. Adverse events will be evaluated using CTCAE v.5 after each treatment cycle and PIPAC. The trial will also calculate incremental cost-effectiveness ratios (ICER) per additional resectable case and per year of life gained.

For patients in Arm B, starting from the second cycle of PIPAC, a Peritoneal Regression Grading Score (PRGS) will be assigned for each of the four biopsies performed, with an average PRGS score calculated as the arithmetic mean of the individual scores. In Arm A, this evaluation will be conducted during restaging after 3 months of treatment or at the end of 6 months for patients with stable disease who continue chemotherapy. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to determine the effectiveness of the treatment regimens.