Phase Ib/II Study of QL1706 + Fruquintinib + SCRT vs. Standard Third-Line Therapy in Unresectable Liver-Metastatic pMMR/MSS Colorectal Cancer: Safety, Tolerability, and Efficacy.

A Phase Ib/II Study Evaluating the Safety, Tolerability, and Efficacy of Epalolitovoreli Monoclonal Antibody (QL1706) and Fruquintinib Combined With Short-Course Radiotherapy (SCRT) Versus Standard Third-Line Therapy in Patients With Unresectable Liver-Metastatic pMMR/MSS Colorectal Cancer.

This study is designed to evaluate the safety, tolerability, and efficacy of Epalolitovoreli Monoclonal Antibody (QL1706) combined with Fruquintinib and Short-Course Radiotherapy (SCRT), compared with standard third-line therapy, in the treatment of patients with unresectable liver-metastatic pMMR/MSS colorectal cancer.

Study Overview

• Status: Not yet recruiting
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: QL1706 + Fruquintinib + Short-Course Ablative Radiotherapy (SCART); Drug: Standard Third-Line Therapy

• Study Type: Interventional
• Enrollment (Estimated): 76
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zhenyu Lin, MD; Phone Number: 027-83262683; Email: whxhlzy@hust.edu.cn

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China
      • Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
      • Contact: Zhenyu Lin, MD; Phone Number: 15827130393; Email: tojilin@gmail.com
      • Contact: Tao Zhang, MD,PHD; Phone Number: 862785871982; Email: 1277577866@qq.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Signed written informed consent, and ability to comply with the scheduled visits and related procedures as specified in the protocol.
2. Age ≥18 years and ≤75 years, male or female.
3. Histologically or cytologically confirmed metastatic colorectal cancer with unresectable liver metastasis(es) measuring ≥5 cm in the longest diameter.
4. Confirmed pMMR (proficient mismatch repair) or MSS (microsatellite stable) status by immunohistochemistry (IHC), next-generation sequencing (NGS), or PCR testing.
5. Disease progression after, intolerance to, lack of access to, or refusal of standard second-line therapy.

6. Baseline* hematologic tests (within 7 days prior to the first dose of study drug) meeting the following criteria:

   • Hemoglobin ≥90 g/L.
   • Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L.
   • Platelet count ≥100 × 10⁹/L.
   • Eosinophil count ≤1.5 × Upper Limit of Normal (ULN).

7. Baseline serum biochemical tests (within 7 days prior to the first dose) meeting the following criteria:

   • Total bilirubin ≤1.5 × ULN (if total bilirubin >1.5 × ULN but direct bilirubin ≤ ULN, enrollment is permitted).
   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤3 × ULN.
   • Serum creatinine ≤1.5 × ULN or creatinine clearance (CCr) ≥45 mL/min (calculated using the Cockcroft-Gault formula with actual body weight).
   • Albumin ≥30 g/L.

8. Baseline coagulation tests (within 7 days prior to the first dose) meeting the following criteria:

   • International normalized ratio (INR) ≤1.5 × ULN (or ≤3 × ULN if on stable-dose anticoagulation therapy).
   • Partial thromboplastin time (PTT) [or activated partial thromboplastin time (aPTT)] ≤1.5 × ULN (or ≤3 × ULN if on stable-dose anticoagulation therapy).
9. Baseline urinalysis (within 7 days prior to the first dose) meeting the following criterion: Urine protein (UPRO) <2+ or 24-hour urine protein quantification <1 g.
10. At least one measurable lesion as defined by RECIST v1.1 criteria.
11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
12. Life expectancy ≥3 months.
13. For female patients of childbearing potential or male patients with partners of childbearing potential, agreement to use effective contraception strictly throughout the treatment period and for 6 months thereafter.

Exclusion Criteria:

• 1. History of allergy to any study drug, including Epalolitovoreli Monoclonal Antibody and Fruquintinib.

  2. Pregnant or breastfeeding women, or women planning to become pregnant within 6 months before, during, or after the last dose of study drug.

  3. Known history of active seizures, active central nervous system metastases, spinal cord compression, carcinomatous meningitis, or leptomeningeal metastases; newly diagnosed brain or leptomeningeal metastases.

  4. Cardiovascular or cerebrovascular diseases with significant clinical implications, including:

  • Ventricular arrhythmias or other uncontrolled arrhythmias requiring medical intervention (e.g., antiarrhythmic medication).
  • Severe conduction disorders (e.g., third-degree atrioventricular block).
  • Heart rate-corrected QT interval (QTc, calculated using Fridericia's formula) ≥480 ms.
  • Uncontrolled hypertension (systolic blood pressure >160 mmHg and/or diastolic blood pressure >100 mmHg), history of hypertensive crisis or hypertensive encephalopathy.
  • History of myocarditis.
  • Current congestive heart failure requiring treatment.
  • New York Heart Association (NYHA) Class III or IV cardiovascular disease.
  • Acute coronary syndrome (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to the first dose.
  • Cerebrovascular accident or transient ischemic attack within 6 months prior to the first dose.

  • Interstitial lung disease, pulmonary fibrosis, pneumoconiosis, drug-related pneumonia, radiation pneumonitis requiring steroid or other treatment, severe pulmonary dysfunction, or history of other forms of restrictive lung disease.

    5. History of allergic constitution, asthma, or atopic dermatitis. 6. Patients with massive pleural effusion or massive ascites. 7. Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement for adrenal or pituitary insufficiency) is not considered systemic treatment.

    8. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.

    9. Known or suspected hypersensitivity to the study drugs or any of their excipients.

    10. History of significant toxicity related to immune checkpoint inhibitors or Fruquintinib-class drugs that led to permanent discontinuation of the treatment.

    11. Residual toxicity > Grade 1 from any prior anti-tumor therapy (except for persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, and hypomagnesemia).

    12. Active uncontrolled bleeding, known bleeding tendency, severely unhealed wounds, ulcers, or fractures; such as esophageal or gastric varices requiring immediate intervention (e.g., ligation or sclerotherapy); or evidence of portal hypertension deemed by the investigator to confer a high risk of bleeding.

    13. Patients with risk of bowel obstruction (except surgically cured or completely resolved obstruction) or gastrointestinal perforation within 28 days prior to the first dose in this study (including, but not limited to, acute diverticulitis, intra-abdominal abscess, abdominal cancer, history of gastrointestinal perforation and/or fistula within 6 months prior to screening).

    14. Patients with current or recent (within 6 months) significant gastrointestinal disease or conditions, including:

    a) History of clinically significant gastrointestinal bleeding. b) Active peptic ulcer. c) Diarrhea ≥ Grade 2 within 2 weeks prior to the first dose. 15. Patients with uncontrolled tumor-related pain or symptomatic hypercalcemia. 16. Known positive HIV test, active Hepatitis B, Hepatitis C (HCV), tuberculosis, or history of such infections. Exceptions are as follows:

  • Patients who are HBsAg positive or HBcAb positive must have HBV DNA ≤2.5 × 10³ copies/mL or ≤500 IU/mL or below the limit of detection to be eligible.
  • Patients with positive HCV serology are eligible if HCV RNA is negative or below the limit of detection.

  • Patients who have received HCV treatment and have undetectable viral loads are eligible.

    17. Severe/active/uncontrolled infection requiring systemic intravenous antibiotic therapy, or unexplained fever (>38°C) within 2 weeks prior to the first dose.

    18. Diagnosis of another malignancy within 5 years prior to the first dose, except for radically treated basal cell carcinoma, squamous cell carcinoma of the skin, radically resected carcinoma in situ, radically treated localized prostate cancer, papillary thyroid carcinoma, etc.

    19. Prohibited medications and other treatments (patients must not receive any of the following):

  • Any chemotherapy or small molecule targeted therapy within 2 weeks or 5 half-lives (whichever is shorter) prior to the first dose, without delayed toxicity.
  • Any monoclonal antibody therapy within 4 weeks prior to the first dose.
  • Participation in any interventional clinical trial involving medical devices or other therapies within 2 weeks prior to the first dose.
  • Palliative radiotherapy within 2 weeks prior to the first dose.
  • Live vaccines for infectious disease prevention within 4 weeks prior to the first dose.
  • Immunosuppressive or systemic corticosteroid therapy (>10 mg/day prednisone equivalent) within 2 weeks prior to the first dose.
  • For patients on anticoagulant therapy, coagulation parameters are not stably controlled within the target range, or there is unstable thrombosis, pulmonary embolism events, or clinically significant bleeding events within the past 6 months.

  • Any major surgery within 4 weeks prior to the first dose. 20. Any disease, treatment, laboratory abnormality, history of substance abuse, or current evidence that, in the investigator's judgment, may compromise the patient's safety, interfere with obtaining informed consent, affect patient compliance, or impact the safety evaluation of the study drug.

    21. Patients deemed unsuitable for participation in this study by the investigator.

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: QL1706 + Fruquintinib + Short-Course Ablative Radiotherapy (SCART); Patients will receive the PD-1/CTLA-4 bispecific antibody Epalolitovoreli Monoclonal Antibody (QL1706) at a dose of 5 mg/kg by intravenous infusion every 3 weeks (Q3W). Patients will concomitantly receive oral Fruquintinib once daily (QD). The dose will be determined in a Phase Ib dose-escalation phase exploring 3 mg and 4 mg QD levels, using a modified 3+3 design to establish the Recommended Phase II Dose (RP2D). Patients will undergo Short-Course Ablative Radiotherapy (SCART) to the liver metastasis/metastases. The prescribed dose is 15 Gy in 3 fractions to the Gross Tumor Volume (GTV) and 45-72 Gy in 3 fractions to the Subclinical Target Volume (STV). Treatment with QL1706 and Fruquintinib will continue until disease progression, unacceptable toxicity, or other protocol-specified discontinuation criteria.	Drug: QL1706 + Fruquintinib + Short-Course Ablative Radiotherapy (SCART); Patients will receive the PD-1/CTLA-4 bispecific antibody Epalolitovoreli Monoclonal Antibody (QL1706) at a dose of 5 mg/kg by intravenous infusion every 3 weeks (Q3W). Patients will concomitantly receive oral Fruquintinib once daily (QD). The dose will be determined in a Phase Ib dose-escalation phase exploring 3 mg and 4 mg QD levels, using a modified 3+3 design to establish the Recommended Phase II Dose (RP2D). Patients will undergo Short-Course Ablative Radiotherapy (SCART) to the liver metastasis/metastases. The prescribed dose is 15 Gy in 3 fractions to the Gross Tumor Volume (GTV) and 45-72 Gy in 3 fractions to the Subclinical Target Volume (STV). Treatment with QL1706 and Fruquintinib will continue until disease progression, unacceptable toxicity, or other protocol-specified discontinuation criteria.
Active Comparator: Standard Third-Line Therapy; Patients will receive one of the following standard-of-care third-line therapies for metastatic colorectal cancer, selected by the investigator based on the patient's prior treatment history and comprehensive condition: Cetuximab with or without Irinotecan (for patients not previously treated with cetuximab). Regorafenib. Fruquintinib. Trifluridine/Tipiracil (TAS-102) with or without Bevacizumab.	Drug: Standard Third-Line Therapy; Patients will receive one of the following standard-of-care third-line therapies for metastatic colorectal cancer, selected by the investigator based on the patient's prior treatment history and comprehensive condition: Cetuximab with or without Irinotecan (for patients not previously treated with cetuximab). Regorafenib. Fruquintinib. Trifluridine/Tipiracil (TAS-102) with or without Bevacizumab.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival（PFS）	Progression-free survival (PFS) is defined as the time from the initiation of study treatment to the first occurrence of disease progression or death from any cause, whichever comes first.	an expected average of 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	The time from the date of randomization to the death caused by any cause	an expected average of 5 years
dverse events (AEs) were graded according to the NCI CTCAE version 5·0	Adverse events and surgical safety	an expected average of 1.5 years

Collaborators and Investigators

• Sponsor: Tao Zhang
• Investigators: Principal Investigator: Tao Zhang, MD, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology

Study record dates

Study Major Dates

• Study Start (Estimated): January 21, 2026
• Primary Completion (Estimated): August 31, 2027
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: January 13, 2026
• First Submitted That Met QC Criteria: January 13, 2026
• First Posted (Actual): January 20, 2026

Study Record Updates

• Last Update Posted (Actual): January 20, 2026
• Last Update Submitted That Met QC Criteria: January 13, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• 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; HMPL-013
• Other Study ID Numbers: ZLK20250622

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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