Fruquintinib and Pirfenidone in Combination With Anti-PD-1 Antibody in Advanced or Metastatic pMMR/MSS Colorectal Carcinoma

A Randomized Phase 1b/2 Clinical Trial Evaluating Fruquintinib and Pirfenidone in Combination With Anti-PD-1 Antibody in Patients With Standard Treatment Failure of Advanced or Metastatic pMMR/MSS Colorectal Carcinoma

The purpose of this study is to evaluate the efficacy and safety of fruquintinib and pirfenidone in combination with anti-PD-1 antibody in patients with standard treatment failure of advanced or metastatic pMMR/MSS colorectal adenocarcinoma.

Study Overview

• Status: Not yet recruiting
• Conditions: To Evaluate the Efficacy of Fruquintinib and Pirfenidone in Combination With Anti-PD-1 Antibody in Colorectal Carcinoma; To Evaluate Whether Pirfenidone Can Reshape the Tumor Microenvironment in Colorectal Cancer; Combination of Fruquintinib and Anti-PD-1 Antibody Was Reported to Improve Patient Prognosis in Colorectal Cancer
• Intervention / Treatment: Drug: Pirfenidone; Drug: Fruquintinib; Drug: Pembrolizumab

Detailed Description

In this study, we explored the potential effectiveness of fruquintinib and pirfenidone in combination with anti-PD-1 antibody, in MSS/pMMR unresectable locally advanced or metastatic colorectal cancer patients who failed standard chemotherapy and testified this new combination in preclinical models. 25 patients were included.

• Study Type: Interventional
• Enrollment (Estimated): 25
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Tao Zhang, MD; Phone Number: 86+02785871982; Email: whxhlzy@hust.edu.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Histologically confirmed diagnosis of unresectable locally advanced, recurrent or metastatic colorectal adenocarcinoma.
2. Tumor tissues were identified as mismatch repair-proficient (pMMR) by immunohistochemistry (IHC) method or microsatellite stability (MSS) by polymerase chain reaction (PCR).
3. Subjects must have failed at least two lines of prior treatment.
4. Subjects must have one measurable lesion according to RECIST v1.1 at least.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. 6. 18-75 years old.

7. Life expectancy of at least 12 weeks. 8. Adequate bone marrow, liver, renal and coagulation function as assessed by the laboratory required by protocol

Exclusion Criteria:

1. Previously received anti-programmed death-1 (PD-1) or its ligand (PD-L1) antibody or Pirfenidone.
2. Received last dose of anti-tumor therapy (chemotherapy, targeted therapy, tumor immunotherapy or arterial embolization) within 3 weeks of the first dose of study medication.
3. Received radiotherapy with 4 weeks of the first dose of study medication.
4. Underwent major operation within 4 weeks of the first dose of study medication or open wound, ulcer or fracture.
5. Known symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis. Subjects received prior treatment and have stable disease more than 4 weeks from first dose of study medication are permitted to enroll.
6. Active, known or suspected autoimmune disease or has a history of the disease within the last 2 years.
7. Interstitial lung disease requiring corticosteroids.
8. Active or poorly controlled serious infections.
9. Significant malnutrition.
10. Symptomatic congestive heart failure (NYHA Class II-IV) or symptomatic or poorly controlled arrhythmia.
11. Uncontrolled hypertension (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg) despite standard treatment.
12. Within 6 months prior to the enrollment, history of gastrointestinal perforation and/or fistula, gastrointestinal ulcer, bowel obstruction, extensive bowel resection, Crohn's disease, or ulcerative colitis, intra-abdominal abscesses, or long-term chronic diarrhea.
13. History or evidence of inherited bleeding diathesis or coagulopathy or thrombus
14. Any life-threatening bleeding within 3 months prior to the enrollment.
15. High risk of bleeding.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment; Pembrolizumab intravenous (IV) 200mg flat dose day 1 then every 3 weeks. Fruquintinib orally (PO) 3mg po qd. Pirfenidone (Esbriet) orally (PO) with food according to this schedule: two dose groups: 200mg, TID, po;500mg, TID ,po. Using "3-3" design, the observation period of DLT was 28 days.	Drug: Pirfenidone; Two doses of pirfenidone (200 mg,tid,po;500 mg,tid,po) were set up. Using the 3+3 design, the DLT observation period is 28 days.; Drug: Fruquintinib; 3mg, orally, qd; Drug: Pembrolizumab; 200mg iv every 3 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Grade 4 toxicity	CTCAE v5.0	Cycle 1 day 1 to Cycle 3 day 1 (Each cycle is 21 days)
Progression Free Survival (PFS)	The time from enrollment until tumor progression or death from any cause, whichever occurred first	2 year
Occurrence of Grade 3 toxicity	CTCAE v5.0	Cycle 1 day 1 to Cycle 3 day 1 (Each cycle is 21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	The proportion of patients with a PR or CR	2 year
Disease control rate (DCR)	The proportion of patients with a PR, CR, or SD	2 year
Duration of response (DoR)	For patients who achieved a complete response (CR) or partial response (PR), the time from the first tumor assessment demonstrating response until disease progression or death, whichever occurred first	2 year
Overall Survival (OS)	The time calculated from enrollment until death from any cause, with living patients censored at the last known survival date	2 year

Collaborators and Investigators

• Sponsor: Wuhan Union Hospital, China

Study record dates

Study Major Dates

• Study Start (Estimated): July 22, 2024
• Primary Completion (Estimated): July 22, 2026
• Study Completion (Estimated): December 30, 2026

Study Registration Dates

• First Submitted: May 24, 2024
• First Submitted That Met QC Criteria: July 1, 2024
• First Posted (Actual): July 3, 2024

Study Record Updates

• Last Update Posted (Actual): July 3, 2024
• Last Update Submitted That Met QC Criteria: July 1, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Pirfenidone,tumor microenvironment, PD-1 antibody
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Carcinoma; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Pembrolizumab; Pirfenidone
• Other Study ID Numbers: union-P

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: First use of pirfenidone to unlock the immunosuppressive microenvironment and thereby enhance immunotherapy efficacy in pMMR/MSS colorectal cancer
• IPD Sharing Time Frame: 5 years
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

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