Lubiprostone Combined With Maintenance Therapy for Prevention of Postoperative Recurrence in Peritoneal Metastatic Colorectal Cancer

Peritoneal metastasis (PM) is a distinct and clinically challenging dissemination pattern of colorectal cancer (CRC), often associated with limited intraperitoneal drug penetration, fibrotic remodeling, and an immunosuppressive peritoneal microenvironment. Despite intensive multimodal treatment-including systemic therapy and cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC)-postoperative recurrence and progression remain common, and the role of postoperative maintenance strategies in PM-CRC is not well established.

Preclinical work conducted by the study team supports a role for purinergic signaling, particularly the P2Y receptor axis (e.g., P2RY2), in processes relevant to peritoneal implantation and stromal remodeling. In these models, lubiprostone demonstrated inhibitory effects on P2RY2-associated signaling and showed peritoneum-focused antitumor activity when combined with systemic chemotherapy, with a favorable tolerability profile at treatment-relevant exposures. Together, these observations provide the scientific rationale to evaluate lubiprostone as a low-toxicity, accessible candidate for long-term postoperative maintenance to delay recurrence or progression in patients with CRC and peritoneal metastases who have undergone adequate cytoreduction.

This study is a prospective, open-label, randomized, controlled phase II trial. Participants will be randomized 1:1 to receive either investigator-selected standard-of-care (SOC) maintenance therapy alone or SOC maintenance therapy plus lubiprostone. Randomization will use a block allocation sequence generated by an independent statistician. Because the study compares a pharmacologic add-on strategy to SOC maintenance, blinding is not applied.

SOC maintenance therapy is individualized by treating investigators according to contemporary guideline-based practice and patient-specific factors (e.g., prior systemic therapy exposure, performance status, age, molecular profile, and primary tumor location). The protocol specifies permitted maintenance approaches and rules for regimen selection and modification; however, the study does not mandate a single uniform maintenance regimen across all participants. Lubiprostone is administered orally during the maintenance period, and treatment may continue until protocol-defined discontinuation criteria are met (e.g., disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified reasons). The protocol includes guidance for temporary interruption or dose adjustment of lubiprostone to manage treatment-emergent adverse events.

Disease status is evaluated using standardized imaging procedures to ensure consistency across participants. Cross-sectional imaging is performed at protocol-defined intervals; when conventional imaging is indeterminate, \^68Ga-FAPI PET/CT may be used to clarify disease status per protocol guidance and local availability. Tumor burden and peritoneal disease distribution may be documented using a standardized regional approach, including peritoneal cancer index (PCI) assessment performed according to the protocol workflow (e.g., independent radiology review).

Safety surveillance includes routine clinical assessments and laboratory monitoring during study treatment and for a defined period after the last study-related treatment. Adverse events are collected systematically, graded using standard toxicity criteria specified in the protocol, and reported according to applicable regulatory and oversight requirements. The protocol highlights management considerations for anticipated lubiprostone-associated gastrointestinal symptoms (e.g., nausea, diarrhea, abdominal discomfort) and emphasizes prompt evaluation for suspected mechanical gastrointestinal obstruction.

The statistical analysis plan evaluates whether adding lubiprostone to SOC maintenance shows a superiority signal on time-to-event efficacy outcomes, with primary analyses conducted in the intention-to-treat population and supportive analyses in the per-protocol population. Safety analyses include participants who receive at least one dose of study-related treatment as defined in the protocol. No interim efficacy analysis is planned; ongoing safety data are reviewed through an independent safety monitoring process.

• 3-year Progression-Free Survival (PFS) rate [Срок оценки: From randomization to 36 months (3 years).]
• 3-year Overall Survival (OS) Rate [Срок оценки: From randomization to 36 months (3 years).]
• Extraperitoneal (Distant) Metastasis Rate [Срок оценки: Up to 36 months (3 years) after randomization.]
• Treatment Toxicity (Adverse Events) [Срок оценки: From start of study treatment through 30 days after the end of treatment.]
• Quality of Life Evaluated by EORTC QLQ-C30 v3.0 [Срок оценки: Baseline; every 3 months during treatment; and at end of follow-up (up to 36 months).]