Colorectal Cancer Metastatic, Microsatellite Stable (MSS) Colorectal Cancer (CRC)
Conditions
Keywords
PD-1/CTLA-4, QL1706, Bevacizumab, FOLFIRI, Second-line
Brief summary
Thsi study is a randomised, parallel-controlled phase II/III trial evaluating FOLFIRI plus bevacizumab with or without QL1706 as second-line therapy for metastatic colorectal cancer. The primary endpoint is PFS. Secondary endpoint includes overall survival, objective response rate, safety profiles, immune-related adverse events, and patient quality of life. Exploratory analyses focus on dynamic shifts in tumour immune microenvironment and biomarkers, aiming to identify predictive signatures for therapeutic efficacy and immune toxicities.
Detailed description
This is a prospective, randomised, parallel-controlled phase II/III clinical trial designed to investigate the efficacy and safety of adding QL1706, a dual PD-1/CTLA-4 bispecific immune checkpoint inhibitor, to the standard second-line FOLFIRI plus bevacizumab regimen in patients with metastatic colorectal cancer. Eligible participants who have progressed after first-line oxaliplatin-based systemic therapy will be randomly assigned to either the experimental group receiving combination treatment with FOLFIRI, bevacizumab and QL1706 or the control group treating with FOLFIRI plus bevacizumab alone, to conduct head-to-head comparative analysis of clinical outcomes. The primary endpoint of the trial is progression-free survival. Secondary endpoints comprehensively evaluating overall survival, objective response rate, disease control rate, the incidence and severity of treatment-related adverse events and immune-related adverse events. Exploratory analyses are pre-specified in this trial. Serial detection and dynamic analysis of tumour immune microenvironment characteristics and multiple peripheral biomarkers will be performed to clarify the immunomodulatory effect of the triple combination regimen. Furthermore, correlative analyses will be conducted to screen and validate potential predictive signatures, including immune cell subsets, cytokine profiles and molecular biomarkers, for clinical treatment response and immune-related toxicities, aiming to provide precise evidence for individualised second-line immunotherapy combined with targeted chemotherapy for metastatic colorectal cancer.
Interventions
DRUGFOLFIRI + bevacizumab + QL1706
QL1706 (4mg/kg on day 1), Bevacizumab (5 mg/kg on day 1) plus mFOLFIRI ( irinotecan 180 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 8 cycles and followed by QL1706 plus bevacizumab and fluoropyrimidine based maintence treatment.
Bevacizumab (5 mg/kg on day 1) plus mFOLFIRI ( irinotecan 180 mg/m2, and folinic acid 400 mg/m2 followed by bolus 5-fluorouracil 400 mg/m2 and 5-fluorouracil 2400mg/m2 as a 46-hour continuous infusion on day 1) for 8 cycles and followed by bevacizumab and fluoropyrimidine based maintence treatment.
Sponsors
Sun Yat-sen University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
None (open label)
Intervention model description
Prospective, parallel control, Phase 3
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 1\. Willing and able to provide written informed consent. 2. Age ≥ 18 years old. 3.Histologically confirmed metastatic colorectal adenocarcinoma with pMMR/MSS status. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2. 5.Discontinued first-line oxaliplatin-based doublet chemotherapy for metastatic colorectal cancer due to intolerable toxicities or disease progression; OR developed recurrent metastatic disease within 6 months after the last dose of adjuvant chemotherapy. 6.Presence of evaluable lesions on imaging examinations. 7. Adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment. 8.Willing and able to comply with study procedures and scheduled visit schedules
Exclusion criteria
* 1.Patients complicated with digestive tract diseases including duodenal ulcer, ulcerative colitis, intestinal obstruction, or other conditions judged by the investigator to potentially cause gastrointestinal hemorrhage or perforation; or massive pleural effusion or ascites requiring intervention. 2.Previous or concurrent cancer that is distinct in primary site or histology from colon cancer within 5 years prior to randomization. 3. Radiological evidence of brain metastases. 4. Prior treatment with irinotecan hydrochloride, or prior receipt of PD-1 and/or CTLA-4 immunotherapy in the first-line setting. 5. Autoimmune diseases requiring continuous systemic steroid therapy. 6. History of laparotomy, thoracotomy or intestinal resection within 28 days prior to enrollment; or unhealed wounds (excluding suture wounds from central venous catheter implantation), gastrointestinal ulcers or traumatic fractures. 7. Any of the following events occurring within 12 months before study enrollment: myocardial infarction, severe/unstable angina pectoris, New York Heart Association (NYHA) class ≥ 2 cardiac insufficiency, clinically significant supraventricular or ventricular arrhythmias, and symptomatic congestive heart failure. 8.Confirmed human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related diseases. 9. Active inflammatory bowel disease or other colorectal diseases causing chronic diarrhea; interstitial lung disease, non-infectious pneumonia, or uncontrolled systemic diseases (e.g., diabetes mellitus, hypertension, pulmonary fibrosis, acute pneumonia, etc.). 10. Breastfeeding or pregnant women; lack of effective contraceptive. 11. Other severe physical or psychiatric illnesses, or laboratory abnormalities that may increase the risks of study participation or interfere with study outcomes; or patients deemed unsuitable for this study by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | 2 years | The PFS is defined as the time from the start of treatment to the date of first documented PD or death as a result of any cause, whichever occurred first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) | 2 years | The percentage of subjects with total number of Complete Response (CR) + total number of Partial Response (PR) |
| Overall Survival (OS) | 5 years | OS is defined as the time from date of randomization to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact. |
| Toxicity assessed using the NCI common toxicity criteria, version 5.0. | 2 years | The grade of toxicity will be assessed using the NCI common toxicity criteria, version 5.0. |
Countries
China
Contacts
CONTACTYanhong Deng, PhD
CONTACTJianwei Zhang, doctor
PRINCIPAL_INVESTIGATORYanhong Deng, PhD
Sixth Affiliated Hospital, Sun Yat-sen University
Outcome results
None listed