A Multicenter, Phase Ib/II Clinical Trial to Evaluate the Efficacy and Safety of Concurrent Combination Therapy of S-531011 Plus Fruquintinib or S-531011 Plus Fruquintinib Plus Pembrolizumab in Patients With MSS/pMMR Colorectal Cancer (IGNITE-CRC)

This study aims to evaluate the efficacy and safety of the concurrent combination therapy of S 531011 + fruquintinib or S 531011 + fruquintinib + pembrolizumab in patients with MSS/pMMR colorectal cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Metastatic Colorectal Neoplasms; Microsatellite Stable / Proficient Mismatch Repair Colorectal Cancer
• Intervention / Treatment: Biological: S-531011; Drug: Fruquintinib; Biological: Pembrolizumab

Detailed Description

This study aims to evaluate the efficacy and safety of the concurrent combination therapy of S-531011 plus fruquintinib, or S-531011 plus fruquintinib plus pembrolizumab, in patients with MSS/pMMR colorectal cancer. Eligible participants include patients with metastatic colon or rectal cancer who are 18 years of age or older, have an ECOG Performance Status of 0-1, and have MSS or pMMR tumor status. After written explanation and the provision of written informed consent, participants will be enrolled.

The study consists of a Phase Ib part and a Phase II part. In the Phase Ib part (N = 6-12/Arm), participants will be assigned to Arm A or Arm B. Enrollment into Arm B will begin only after enrollment into Arm A has been completed in both phases.

Arm A consists of S-531011 (intravenous, once every 3 weeks) plus fruquintinib (5 mg orally once daily on Days 1-21 of a 28-day cycle).

Arm B consists of S-531011 (intravenous, once every 3 weeks), fruquintinib (5 mg orally once daily on Days 1-21 of a 28-day cycle), and pembrolizumab (200 mg, intravenous, once every 3 weeks).

In the Phase II part (N = 22/Arm), the recommended dose determined in the Phase Ib part will be used.

• Study Type: Interventional
• Enrollment (Estimated): 68
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Akihito Kawazoe, MD; Phone Number: +81-4-7133-1111; Email: ignite-crc_core@east.ncc.go.jp
• Study Contact Backup: Name: Kazumasa Yamamoto, MD; Phone Number: +81-4-7133-1111; Email: ignite-crc_core@east.ncc.go.jp

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients with histologically confirmed unresectable adenocarcinoma of the colon or rectum.
2. Confirmed microsatellite stable (MSS) or proficient mismatch repair (pMMR) status.

3. Prior treatment with standard systemic chemotherapy and refractory or intolerant* to such therapies. Standard chemotherapy must include all of the following:

   - Fluoropyrimidine, irinotecan, and oxaliplatin (with or without anti-VEGF antibody therapy)

   - For patients with RAS and BRAF wild-type tumors: prior treatment with anti-EGFR monoclonal antibody (cetuximab or panitumumab)

   - For patients with BRAF V600E mutation: prior treatment with a BRAF inhibitor (encorafenib)

   *For patients who relapse during adjuvant chemotherapy or within 6 months after the last dose of postoperative adjuvant chemotherapy, that adjuvant therapy counts as prior systemic therapy.

4. Presence of measurable disease according to RECIST version 1.1.
5. Age ≥ 18 years at the time of informed consent.
6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
7. Laboratory values within 14 days prior to enrollment meeting all of the following (tests performed on the same weekday 2 weeks before the enrollment date are acceptable):

1. Absolute neutrophil count ≥ 1,500/mm³
2. Hemoglobin ≥ 9.0 g/dL
3. Platelet count ≥ 75,000/mm³
4. Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
5. AST (GOT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present
6. ALT (GPT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present
7. Creatinine ≤ 1.5 mg/dL
8. Proteinuria ≤ 1+ or < 1.0 g/24 h (urine protein-to-creatinine ratio < 1 may be used; if 24-hour urine is collected, the measured value takes precedence) 8. No blood transfusion within 7 days prior to enrollment (a transfusion given on the same weekday 1 week earlier is considered ineligible).

9. Women of childbearing potential must have a negative pregnancy test within 14 days prior to enrollment. Both male and female participants must agree to use appropriate contraception during the study and for 4 months after the last dose of study treatment. Female participants must also agree not to breastfeed during the study and for 4 months after the last dose. (Tests performed on the same weekday 2 weeks before the enrollment date are acceptable.) 10. Able to take oral medication. 11. Written informed consent obtained from the participant.

Exclusion Criteria:

1. Prior treatment with fruquintinib for metastatic colorectal cancer.
2. Prior treatment with any anti-CCR8 antibody, regardless of indication.
3. Receipt of chemotherapy, radiotherapy, immunotherapy, or any antitumor therapy, or investigational agents within 14 days prior to enrollment, or persistence of CTCAE Grade ≥ 2 toxicities from prior therapies (excluding alopecia, hyperpigmentation, and peripheral sensory neuropathy).
4. History of acute coronary syndrome (including myocardial infarction or unstable angina), coronary angioplasty, or stent placement within 6 months prior to enrollment.
5. History or current findings of congestive heart failure of NYHA Class III or higher.
6. Uncontrolled hypertension.
7. Known central nervous system metastases. (If CNS metastasis is clinically suspected, brain CT or MRI must be performed during screening.)
8. Active double primary malignancy (simultaneous or metachronous with disease-free interval < 2 years), except for carcinoma in situ or intramucosal carcinoma lesions considered curable by local therapy.
9. Serious comorbidities requiring inpatient treatment (e.g., paralytic ileus, bowel obstruction, pulmonary fibrosis, uncontrolled diabetes, heart failure, myocardial infarction, angina, renal failure, hepatic failure, psychiatric disorders, cerebrovascular disorders, or transfusion-requiring ulcers).

10. Active infections, including:

    - HBs antigen positive

    • Patients may be eligible if receiving nucleoside analog antiviral therapy and HBV-DNA < 20 IU/mL (1.3 log IU/mL).

      - HBs antibody positive or HBc antibody positive AND HBV-DNA positive

    • If HBV-DNA < 20 IU/mL, the patient may be eligible. - HCV antibody positive
    • Patients may be eligible if HCV-RNA is below the detection limit. - HIV positive

    • Patients may be eligible if HIV infection is ruled out by confirmatory testing.

      • Other active infections requiring treatment.
11. History of autoimmune disease or chronic/recurrent autoimmune disease (patients with type 1 diabetes, hypothyroidism manageable with hormone replacement, or localized skin diseases such as vitiligo, psoriasis, or alopecia not requiring systemic therapy are eligible).
12. Requirement for systemic corticosteroids or immunosuppressive agents, or receipt of such therapy within 2 weeks prior to enrollment (treatment given on the same weekday 2 weeks earlier renders the patient ineligible), except for temporary administration for testing, allergic reactions, or edema associated with radiotherapy.
13. Lack of willingness or inability to comply with study procedures.
14. Considered unsuitable for the study by the principal investigator or sub-investigator.

Pregnancy and Contraception:

A woman of childbearing potential includes any female who has experienced menarche, has not undergone permanent sterilization (e.g., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and is not postmenopausal. Postmenopause is defined as at least 12 consecutive months of amenorrhea without another medical cause. Women using oral contraceptives, intrauterine devices, or mechanical barrier methods are considered capable of becoming pregnant. If a female participant is determined to be not capable of becoming pregnant, this must be documented in source records.

Women must use effective contraception for at least 1 month prior to first study treatment, from the time of consent, and for at least 4 months after the last dose. Men must use effective contraception during study treatment and for at least 4 months after the last dose.

Acceptable contraception includes vasectomy or condom use for male participants or male partners, and tubal ligation, contraceptive pessary, intrauterine devices, or oral contraceptives for female participants or female partners.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A S-531011 + Fruquintinib; Participants receive S-531011 and fruquintinib. In the Phase Ib part, dose levels may vary according to the dose finding scheme. In Phase II, the recommended dose determined in Phase Ib will be used.	Biological: S-531011; S-531011 will be administered intravenously once every 3 weeks (q3w). In the Phase Ib part, A reduced dose of S-531011 may be used in Dose Level -1 according to the predefined dose-finding scheme by evaluating DLT profile. In the Phase II part, S-531011 will be administered at the recommended dose determined in the Phase Ib part.; Drug: Fruquintinib; Fruquintinib will be administered orally once daily on Days 1-21 of each 28-day cycle. In the Phase Ib part, fruquintinib will be started at 5 mg (Dose Level 0). A reduced dose of 4 mg may be used in Dose Level -1 according to the predefined dose-finding scheme by evaluating DLT profile. In the Phase II part, fruquintinib will be administered at the recommended dose determined in the Phase Ib part.; Other Names: FRUZAQLA
Experimental: Arm B S-531011 + Fruquintinib + Pembrolizumab; Participants receive S-531011, fruquintinib, and pembrolizumab. In the Phase Ib part, dose levels of S-531011 and fruquintinib may vary according to the dose finding scheme. In Phase II, the recommended dose determined in Phase Ib will be used. Pembrolizumab is administered at a fixed dose throughout both the Phase Ib and Phase II parts.	Biological: S-531011; S-531011 will be administered intravenously once every 3 weeks (q3w). In the Phase Ib part, A reduced dose of S-531011 may be used in Dose Level -1 according to the predefined dose-finding scheme by evaluating DLT profile. In the Phase II part, S-531011 will be administered at the recommended dose determined in the Phase Ib part.; Drug: Fruquintinib; Fruquintinib will be administered orally once daily on Days 1-21 of each 28-day cycle. In the Phase Ib part, fruquintinib will be started at 5 mg (Dose Level 0). A reduced dose of 4 mg may be used in Dose Level -1 according to the predefined dose-finding scheme by evaluating DLT profile. In the Phase II part, fruquintinib will be administered at the recommended dose determined in the Phase Ib part.; Other Names: FRUZAQLA; Biological: Pembrolizumab; Pembrolizumab will be administered intravenously at a dose of 200 mg once every 3 weeks (q3w).; Other Names: KEYTRUDA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Limiting Toxicity (DLT) Rate [Phase Ib Part]	Percentage of participants experiencing dose-limiting toxicities (DLTs).	Up to 29 days after first dose
Objective Response Rate (ORR) [Phase II Part]	Objective response rate assessed by the principal investigator or sub-investigator.Participants treated at the recommended dose in Phase Ib are included.	From baseline to objective disease progression or death, assessed up to 24 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Observed Serum Concentration of S-531011 (Cmax)	Maximum observed concentration of S-531011 in serum.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Time to Maximum Observed Serum Concentration of S-531011 (Tmax)	Time to reach the maximum observed serum concentration of S-531011.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Area Under the Serum Concentration-Time Curve of S-531011 (AUC)	Area under the serum concentration-time curve of S-531011.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Terminal Elimination Half-Life of S-531011 (t1/2)	Terminal elimination half-life of S-531011 estimated from serum concentration-time data.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Anti-S-531011 Antibody (ADA) Titer	Titer of anti-S-531011 antibodies measured to assess immunogenicity.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Incidence of Anti-S-531011 Antibody (ADA) Positivity	Proportion of participants with detectable anti-S-531011 antibodies.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Neutralizing Anti-S-531011 Antibody (NAb) Titer	Titer of neutralizing anti-S-531011 antibodies in participants who test positive for anti-S-531011 antibodies.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Incidence of Neutralizing Anti-S-531011 Antibody (NAb) Positivity	Proportion of participants with detectable neutralizing anti-S-531011 antibodies.	From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration
Duration of Response (DoR) [Phase Ib/II Part]	Duration of confirmed objective response.	From first documented response until disease progression or death from any cause, whichever occurs first, assessed up to 12 months after the last subject is enrolled
Disease Control Rate (DCR) [Phase Ib/II Part]	Percentage of participants achieving CR, PR, or SD.	Up to 12 months after the last subject is enrolled
Progression-Free Survival (PFS) [Phase Ib/II Part]	Time from enrollment to radiological progression or death.	From enrollment until disease progression or death from any cause, whichever occurs first, assessed up to 12 months after the last subject is enrolled
Overall Survival (OS) [Phase Ib/II Part]	Time from enrollment to death.	From enrollment until death from any cause, assessed up to 12 months after the last subject is enrolled
Incidence of Adverse Events [Phase Ib/II Part]	Percentage of participants experiencing adverse events.	From first dose until 30 days after last dose for all adverse events, and thereafter for related adverse events up to 12 months after the last subject is enrolled

Collaborators and Investigators

• Sponsor: National Cancer Center Hospital East
• Collaborators: Shionogi

Study record dates

Study Major Dates

• Study Start (Estimated): May 1, 2026
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): May 1, 2029

Study Registration Dates

• First Submitted: April 13, 2026
• First Submitted That Met QC Criteria: May 11, 2026
• First Posted (Actual): May 18, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 11, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Pembrolizumab; Immune Checkpoint Inhibitors; Antibodies, Monoclonal; Colorectal Neoplasms; Metastatic Colorectal Cancer; Combination Drug Therapy; Fruquintinib; DNA Mismatch Repair; Phase II Clinical Trial; Microsatellite Stability; Receptors, CCR8; CCR8 Antagonists; VEGFR Inhibitors; Phase Ib Clinical Trial
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; pembrolizumab; HMPL-013
• Other Study ID Numbers: EPOC2501; jRCT2031260047 (Other Identifier: Japan Registry of Clinical Trials)

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