Colorectal Neoplasms Malignant, Neoplasm, Metastatic
Conditions
Keywords
Bevacizumab, Immune checkpoint inhibitors, Cetuximab, Irinotecan
Brief summary
Primary endpoint: objective response rate Secondary endpoints: progression-free survival (PFS), overall survival (OS) and adverse events.
Detailed description
This randomized, multi-center, open-label phase II trial studies the efficacy and safety of irinotecan and cetuximab with or without bevacizumab plus sintilimab in the treatment for RAS wild-type metastatic colorectal cancer (mCR) in third- or later-line setting. Patients with refractory mCRC have limited treatment options after failure of standard chemotherapies and anti-angiogenic agents. The BOND-3 trial showed that adding bevacizumab to cetuximab and irinotecan may improve outcomes in this setting. Meanwhile, programmed death-1 (PD-1) inhibitors have demonstrated activity in MSI-high tumors but have limited efficacy in MSS mCRC. Preclinical and clinical evidence suggests that anti-VEGF therapy can modulate the tumor immune microenvironment and may synergize with PD-1 blockade. This study therefore tests whether the quadruple combination (bevacizumab + sintilimab + cetuximab + irinotecan) can improve objective response rate compared with cetuximab and irinotecan alone in this heavily pretreated population. The primary efficacy analysis will be conducted on the intention-to-treat population. Assuming an ORR of 11% in the control arm and 26% in the experimental arm, with a one-sided alpha of 0.05 and power of 80%, the required sample size is approximately 160 to account for 5% dropout.
Interventions
DRUGCetuximab
250mg/m\^2/week with a loading dose of 400mg/m\^2
DRUGIrinotecan
125mg/m\^2 on D1 and D8 every three weeks
DRUGBevacizumab
7.5mg/kg every three weeks
DRUGSintilimab
200mg every three weeks
Sponsors
Guangdong Provincial People's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Metastatic and unresectable colorectal adenocarcinom; * RAS wild-type and MSS tumor; * Measurable lesions; * Failed to at least two lines of standard treatment containing fluoropyrimidine, irinotecan and bevacizumab; * Eastern Cooperative Oncology Group performance status 2 or less; * White blood cell≥ 3\*10\^9/L, neutrophil≥ 1.5\*10\^9/Lplatelet count≥75\*10\^9/L, hemoglobin≥60g/L; * Total serum bilirubin≤upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5\*ULN or ≤5\*ULN for subjects with liver metastasis; * Creatinine ≤ ULN or creatinine clearance ≥ 80 mL/min; * Urinary protein negative or 24-hour urinary protein ≤ 2g; * Activated partial thromboplastin time≤ULN and international normalized ratio≤1.5; * Any major surgery ≥ 4 weeks and any minor surgery ≥ 1 week and fully recovered from the procedure; * Life expectancy \> 3 months; * Provide fully informed written consent;
Exclusion criteria
* Other aggressive malignancies within 3 years (Exceptions: non-melanoma skin cancer or carcinoma-in-situ of the cervix that has been treated); * Allergy or intolerance to any of the study drugs; * Human immunodeficiency virus positive; * Concurrent anti-cancer therapy including radiation therapy, chemotherapy, targeted agents or biological agents not otherwise specified within two weeks; * Malignant bowel obstruction; * Prior treatment with PD-1 antibody; * Autoimmune diseases; * Significant bleeding events or pre-existing bleeding diathesis within 6 months (unless the source of bleeding has been resected); * Gastrointestinal perforation within 12 months; * Serious or non-healing wound, ulcer, or bone fracture; * Blood pressure \>= 160/90 mmHg after active anti-hypertensive therapy; * Arterial or venous thrombotic or embolic events within 6 months (including but not limited to transient ischemic attack, cerebrovascular accident, unstable angina or myocardial infarction); * Uncontrolled illness including active infection, symptomatic congestive heart failure, cardiac arrhythmia, respiratory failure, symptomatic pulmonary fibrosis, interstitial pneumonitis or psychiatric illness that may interfere with the conduct of the study; * Known or suspected brain or central nervous system (CNS) metastases, or carcinomatous meningitis; * Any of the following: pregnant, nursing, childbearing potential but unwilling to employ contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 12 months | the proportion of participants who achieved a complete or partial response according to RECIST 1.1 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival | 12 months | the interval from randomization to first disease progression or death from any cause or last follow-up |
| Overall Survival | 18 months | the interval from randomization to death from any cause or last follow-up |
| Adverse Events | 18 months | reported according to NCI Common Terminology Criteria for Adverse Events 5.0 |
Countries
China
Contacts
CONTACTJian Xiao, MD
CONTACTXiaoru Lin
PRINCIPAL_INVESTIGATORJian Xiao, MD
Guangdong Provincial People's Hospital
Outcome results
None listed