Cetuximab, Irinotecan, Toripalimab in RAS/BRAF Wild-type Ultraselected Right-sided Colorectal Cancer Study

Official title

Negative Ultraselection of Patients With RAS/BRAF Wild-type Refractory Right-Sided Metastatic Colorectal Cancer Receiving Cetuximab in Combination With Toripalimab and Irinotecan: A Phase II, Single-arm Study

Overview

The objective of this clinical trial is to evaluate the efficacy and safety of cetuximab combined with PD-1 inhibitor and irinotecan in negative ultraselection RAS/BRAF wild-type refractory right-sided metastatic colorectal cancer.

Detailed description

The present study focuses on exploring the effectiveness and safety of cetuximab combined with a PD-1 inhibitor and irinotecan in treating refractory, right-sided metastatic colorectal cancer (mCRC) patients who are negative ultraselected for RAS/BRAF mutations. Colorectal cancer ranks among the most prevalent digestive malignancies globally, with right-sided mCRC generally exhibiting poorer outcomes than left-sided cases. Current treatment guidelines vary based on genetic mutations and tumor location, recommending cetuximab for left-sided RAS/BRAF wild-type mCRC and alternative therapies for right-sided or mutated cases. Despite limited clinical data on EGFR inhibitors for right-sided mCRC, retrospective analyses suggest varying efficacy outcomes. The study aims to address these gaps by investigating cetuximab and PD-1 inhibitor combination therapy in this specific patient population, potentially enhancing treatment options for refractory mCRC.

Interventions

• Drug Cetuximab
  Cetuximab: 500 mg/m², intravenous infusion, once every 2 weeks
• Drug Toripalimab
  Toripalimab: 3 mg/kg, intravenous infusion, once every 2 weeks.
• Drug Irinotecan
  Irinotecan: 150 mg/m², intravenous infusion, once every 2 weeks.

Primary outcome measures

• Objective Response Rate [Time frame: Assessed after every 4 cycles (each cycle is 14 days) for up to 24 months]

Secondary outcome measures (5)

• Disease Control Rate [Time frame: Assessed after every 4 cycles (each cycle is 14 days) for up to 24 months]
• Duration of Response [Time frame: Assessed after every 4 cycles (each cycle is 14 days) for up to 24 months]
• Progression-Free Survival [Time frame: Assessed up to 24 months]
• Overall Survival [Time frame: Assessed throughout the study duration (5 years)]
• Adverse events (Treatment-related) [Time frame: Assessed throughout the study duration (5 years)]

Eligibility criteria

Inclusion criteria

• Histologically confirmed colorectal adenocarcinoma.
• Primary tumor located in the right colon.
• Metastatic disease with at least one measurable lesion according to RECIST v1.1 criteria.
• Histologically tested as RAS/BRAF V600E wild-type and negative ultraselected for mutations including: RAS/BRAF V600E/PIK3CA/PTEN/EGFR (ECD), HER2 and MET amplification, and ALK/RET/NTRK1 gene fusions.
• Patients who have progressed after previous treatments including bevacizumab, irinotecan, oxaliplatin, and 5-fluorouracil, with tumor progression occurring during or within 3 months after irinotecan treatment.
• No prior treatment with anti-EGFR or PD-1 antibodies.
• Normal hematological function (platelets >90×10\^9/L; white blood cells >3×10\^9/L; neutrophils >1.5×10\^9/L).
• Serum bilirubin ≤1.5 times the upper limit of normal (ULN), transaminases ≤5 times ULN.
• No ascites, normal coagulation function, albumin ≥35 g/L.
• Liver function classified as Child-Pugh grade A.
• Serum creatinine less than ULN, or calculated creatinine clearance >50 ml/min (using the Cockcroft-Gault formula).
• At least one measurable lesion according to RECIST v1.1 criteria.
• ECOG performance status of 0-2.
• Expected survival >3 months.
• Signed written informed consent.
• Willing and able to undergo follow-up until death or study completion or termination.

Exclusion criteria

• Severe arterial thrombosis or ascites.
• Bleeding tendencies or coagulation disorders.
• Hypertensive crisis or hypertensive encephalopathy.
• Severe uncontrolled systemic complications such as infections or diabetes.
• Clinically significant cardiovascular diseases such as cerebrovascular accident (within 6 months prior to enrollment), myocardial infarction (within 6 months prior to enrollment), uncontrolled hypertension despite appropriate medication, unstable angina, congestive heart failure (NYHA grade 2-4), or arrhythmias requiring medication.
• History of or physical examination showing central nervous system diseases (e.g., primary brain tumor, uncontrolled epilepsy, any history of brain metastasis or stroke).
• Other malignancies within the past 5 years (except for basal cell carcinoma of the skin after curative surgery and/or carcinoma in situ of the cervix).
• Use of immunosuppressive drugs within 1 week before treatment, excluding nasal, inhaled, or other topical steroids or physiological doses of systemic steroids (i.e., not exceeding 10 mg/day of prednisone or an equivalent dose of other steroids) or steroids used to prevent contrast agent allergies.
• Steroid-dependent interstitial lung disease.
• Known active autoimmune disease requiring symptomatic treatment or history of such disease within the past 2 years. Patients with vitiligo, psoriasis, alopecia, or -Graves' disease not requiring systemic treatment within the past 2 years, hypothyroidism requiring only thyroid hormone replacement, and type I diabetes requiring only insulin replacement can be enrolled.
• Known history of primary immunodeficiency.
• Known active tuberculosis.
• Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation.
• Receipt of any investigational drug treatment within the last 28 days before the study.
• Allergy to any drugs in the study.
• Pregnant or breastfeeding women.
• Women of childbearing potential (within 2 years of last menstruation) or men capable of fathering a child who are not using or refuse to use effective non-hormonal contraceptive methods (e.g., intrauterine device, barrier method combined with spermicide, or sterilization).
• Inability or unwillingness to comply with the study protocol.
• Presence of any other disease, functional impairment caused by metastatic lesions, or suspicious conditions found during a physical examination indicating a contraindication to the study drugs or high risk for treatment-related complications.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Sun Yat-sen University Cancer Center — Guangzhou

Identifiers

NCT: NCT06547203 · CITRUS

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗