IPa-Gastric Trial

Gastric cancer with peritoneal metastases is one of the most challenging clinical situations we face. Despite real advances in systemic therapy over the past decade, median overall survival for these patients remains stubbornly short, in the range of 8 to 14 months, and quality of life is very often impaired by progressive ascites, bowel obstruction, and pain.

The core problem is biological: the plasma-peritoneal barrier substantially limits the delivery of systemically administered chemotherapy to peritoneal deposits, meaning that high systemic doses are needed to achieve even modest peritoneal exposure, driving toxicity without necessarily driving response. Objective response rates to systemic chemotherapy in this setting hover around 30%.

Intraperitoneal (IP) paclitaxel offers a logical solution. Because paclitaxel is a large, lipophilic molecule, it can be delivered directly into the abdominal cavity via a simple subcutaneous port, achieving peritoneal drug concentrations orders of magnitude higher than systemic administration while limiting systemic absorption. Asian phase III trials, including the PHOENIX-GC trial and the recently reported DRAGON 01 trial, suggest meaningful improvements in overall survival and, in a striking subset of patients, the possibility of downstaging to conversion surgery with curative intent. Yet no randomised trial has evaluated this approach in a Western population. That is the gap the IPa-Gastric trial is designed to close.

IPa-Gastric is an open-label, multicentre, randomised phase III trial comparing intraperitoneal paclitaxel combined with standard systemic therapy versus standard systemic therapy alone as first-line treatment in Western patients with gastric or gastro-oesophageal junction adenocarcinoma and peritoneal metastases.

Population: Patients aged ≥18 years with histologically or cytologically confirmed gastric or GOJ (Siewert II/III) adenocarcinoma and peritoneal metastases confirmed by biopsy, cytology from ascites, or peritoneal wash. Staging laparoscopy with PCI assessment within four weeks of enrolment is required. Patients with positive cytology (CYT+) but no clinically manifest peritoneal deposits at laparoscopy are also eligible after at least four cycles of systemic therapy if they remain CYT+. No other distant metastases are permitted (ovarian metastases excepted). ECOG performance status 0–1.

Intervention: Standard investigator-choice systemic therapy (fluoropyrimidine/platinum backbone ± anti-HER2, anti-CLDN18.2, immunotherapy as clinically indicated) plus intraperitoneal paclitaxel 40 mg/m² administered on days 1 and 8 of a 21-day cycle (or 40–60 mg/m² on day 1 of a 14-day cycle) via a surgically placed subcutaneous intraperitoneal port catheter.

Control: Standard systemic therapy alone.

Primary endpoint: Overall survival (time from randomisation to death from any cause).

Key secondary endpoints: Progression-free survival, health-related quality of life (EORTC QLQ-C30 and OG-25), ascites-related outcomes, rate of conversion to curative-intent surgery, and toxicity.

Sample size: Adaptive design with a pre-planned target of 262 patients and a maximum of 340 after an interim analysis-based sample size update.

Trial period: Q4 2025 – Q4 2030. The sponsor is Karolinska University Hospital; the coordinating investigators are Prof Magnus Nilsson and Dr Lisa Liu Burström (Karolinska). The trial has a multinational steering committee spanning Sweden, Norway, the Netherlands, Italy, the UK, Germany, and Denmark.

EU CT Number: 2024-514879-17-00

The primary question is straightforward: does adding IP paclitaxel to standard systemic therapy improve overall survival for Western patients with peritoneally metastasised gastric cancer?

Beyond survival, we want to understand whether IP paclitaxel can meaningfully control ascites, one of the most debilitating aspects of this disease, and whether it can create opportunities for conversion surgery in patients who are initially unresectable. Asian data suggest that up to 30% of patients treated with IP paclitaxel may become eligible for curative-intent resection; if this holds in Western populations, the implications for long-term survival would be profound.

We are also collecting longitudinal quality-of-life data throughout treatment, which matters enormously in a disease where palliation is often the realistic goal. And a translational programme embedded in the trial will help us understand the pharmacology of IP paclitaxel in Western patients and identify potential biomarkers of response.

The IPa-Gastric trial needs participating centres across Europe. Involvement requires the ability to place subcutaneous intraperitoneal port catheters, perform staging laparoscopy, and deliver IP paclitaxel, skills well within the repertoire of any upper GI or peritoneal surgery unit. Training support is available.

Gastric cancer with peritoneal metastases deserves better than what systemic chemotherapy alone currently offers. The IPa-Gastric trial is the Western world's best opportunity to establish whether IP paclitaxel can change that. We hope you will join us.