Lubiprostone Combined With Maintenance Therapy for Prevention of Postoperative Recurrence in Peritoneal Metastatic Colorectal Cancer, A Randomized Controlled Phase II Study

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).