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

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

The goal of this phase II randomized controlled clinical trial is to evaluate whether adding lubiprostone to standard postoperative maintenance therapy can delay disease progression and recurrence in adult patients with colorectal cancer and peritoneal metastases (PM-CRC) who have undergone cytoreductive surgery with or without HIPEC after systemic treatment. The main questions it aims to answer are:

Does lubiprostone plus maintenance therapy improve the 1-year progression-free survival (PFS) rate compared with maintenance therapy alone?

Is lubiprostone safe and feasible for long-term use during the maintenance period in this PM-CRC population?

Researchers will compare lubiprostone + maintenance therapy versus maintenance therapy alone to see if the addition of lubiprostone prolongs PFS, reduces the risk of distant metastasis, improves overall survival, and maintains or improves quality of life.

Participants will:

Be randomly assigned to receive maintenance therapy with lubiprostone or maintenance therapy alone after surgery (CRS ± HIPEC) and prior systemic therapy, according to the study protocol.

Undergo scheduled follow-up assessments for disease status (progression/recurrence), survival outcomes, treatment-related toxicity, and quality of life using the EORTC QLQ-C30 (v3.0) questionnaire.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer Metastatic; Peritoneal Metastasis; Colorectal Cancer (CRC); MSS Metastatic Colorectal Cancer; Peritoneal (Metastatic) Cancer
• Intervention / Treatment: Drug: maintenance therapy plus lubiprostone; Drug: maintenance therapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 124
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Guangzhao Lv, MD, PhD; Phone Number: +86 020 87343920; Email: lvgz@sysucc.org.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Voluntarily participates and provides written informed consent.
• Histologically confirmed colon/rectal adenocarcinoma with molecular status confirmed as pMMR or MSS.
• Cytoreductive surgery (CRS) achieves CC0/CC1 cytoreduction.
• No extraperitoneal metastasis prior to treatment.
• ECOG performance status 0-1 with adequate organ function per protocol requirements.

Exclusion Criteria:

• Extensive multisystem metastases on baseline imaging assessment.
• Tumor carrying BRAF V600E mutation.
• dMMR/MSI-H, or confirmed pathogenic POLE/POLD1 mutation(s).
• Cachexia or decompensated organ dysfunction.
• History of another malignancy within the past 5 years.
• Known or suspected hypersensitivity/allergy to the study drug or related formulations.
• Multiple primary cancers.
• Any serious disease or other medical, psychological, or social condition that, in the investigator's judgment, may compromise participant safety or affect study results.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Investigator-Selected Maintenance Therapy + Lubiprostone; Participants receive investigator-selected standard-of-care maintenance therapy plus lubiprostone (24 μg orally twice daily) during the maintenance period, until disease progression, unacceptable toxicity, withdrawal, or other protocol-defined discontinuation criteria.	Drug: maintenance therapy plus lubiprostone; In experiment arm, participants receive investigator-selected standard-of-care maintenance therapy plus lubiprostone (24 μg orally twice daily) during the maintenance period, until disease progression, unacceptable toxicity, withdrawal, or other protocol-defined discontinuation criteria.
Active Comparator: Investigator-Selected Maintenance Therapy; Participants receive investigator-selected standard-of-care maintenance therapy during the maintenance period, until disease progression, unacceptable toxicity, withdrawal, or other protocol-defined discontinuation criteria.	Drug: maintenance therapy; In active comparator arm, participants receive investigator-selected standard-of-care maintenance therapy during the maintenance period, until disease progression, unacceptable toxicity, withdrawal, or other protocol-defined discontinuation criteria.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
1-year Progression-Free Survival (PFS) Rate	Progression-free survival is defined as the time from randomization to the first documented recurrence/progression event. Recurrence/progression is confirmed by at least one of the following: imaging assessment judged as recurrence by two radiologists; or physical examination + progressively rising tumor markers and/or MRD and other objective evidence supporting progression; or positive cytology/histology from biopsy. The date of recurrence is the date the above diagnostic confirmation is established; isolated CEA rise alone is not sufficient evidence of recurrence.	From randomization to 12 months (1 year).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
3-year Progression-Free Survival (PFS) rate	PFS is defined as the time from randomization to the first documented recurrence/progression event, using the same event confirmation rules as above (radiology/clinical objective evidence/positive pathology). Tumor assessments are performed at scheduled intervals (every 3 months or 6 months) and/or whenever clinical signs suggest progression.	From randomization to 36 months (3 years).
3-year Overall Survival (OS) Rate	Overall survival is defined as the time from randomization to death from any cause. Participants alive at the last follow-up are censored on that date.	From randomization to 36 months (3 years).
Extraperitoneal (Distant) Metastasis Rate	Proportion of participants who develop metastasis outside the peritoneum (extraperitoneal organs/tissues) during follow-up, confirmed by imaging and/or pathology.	Up to 36 months (3 years) after randomization.
Treatment Toxicity (Adverse Events)	Treatment-emergent adverse events graded and recorded according to NCI CTCAE v5.0, with emphasis on the incidence of Grade ≥3 adverse events.	From start of study treatment through 30 days after the end of treatment.
Quality of Life Evaluated by EORTC QLQ-C30 v3.0	Quality of life assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), version 3.0. Scores are linearly transformed to 0-100 scales. For the Global Health Status/QoL scale, higher scores indicate better quality of life. For Functional Scales (physical, role, emotional, cognitive, social), higher scores indicate better functioning. For Symptom Scales/Items (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties), higher scores indicate worse symptom burden/problems. The questionnaire is administered at baseline, every 3 months during treatment, and at the end of follow-up to compare longitudinal QoL differences between treatment groups.	Baseline; every 3 months during treatment; and at end of follow-up (up to 36 months).

Collaborators and Investigators

• Sponsor: Sun Yat-sen University

Study record dates

Study Major Dates

• Study Start (Estimated): February 24, 2026
• Primary Completion (Estimated): June 1, 2027
• Study Completion (Estimated): June 1, 2028

Study Registration Dates

• First Submitted: February 4, 2026
• First Submitted That Met QC Criteria: February 10, 2026
• First Posted (Actual): February 12, 2026

Study Record Updates

• Last Update Posted (Actual): February 12, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Colorectal cancer; Peritoneal metastasis; Lubiprostone; Maintenance therapy; Cytoreductive Surgery; Progression-free survival
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms; Colorectal Neoplasms; Neoplasm Metastasis; Fatty Acids; Lipids; Health Care Facilities Workforce and Services; Fatty Acids, Unsaturated; Fatty Acids, Monounsaturated; Alprostadil; Lubiprostone; Maintenance
• Other Study ID Numbers: 2025-FXY-439

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No