Combining TKI and PD-1 inhibitor for advanced colorectal cancer treatment

ctDNA-guided Treatment of an Anti-angiogenic TKI Combined With a PD-1 Inhibitor for Advanced pMMR/MSS Colorectal Cancer Failed With Standard Therapy: a Randomized Controlled Phase 2 Clinical Trial

This study is testing a new treatment combining two types of cancer drugs to see if it can help people with advanced colorectal cancer that hasn't improved with standard treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 68 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: Cancer Institute and Hospital, Chinese Academy of Medical Sciences (Academic / other)
• Drugs / interventions: bevacizumab, cetuximab, fruquintinib, chemotherapy, immunotherapy, radiation, prednisone, sintilimab
• Locations: 1 site (Beijing, Beijing Municipality)
• Trial ID: NCT06543836 on ClinicalTrials.gov

What this trial studies

This phase II interventional trial evaluates the effectiveness of a combination treatment using a tyrosine kinase inhibitor (TKI) and a PD-1 inhibitor in patients with advanced metastatic colorectal cancer that has not responded to standard therapies. Participants will be randomly assigned to receive either the combination treatment or standard later-line therapies based on their ctDNA levels and previous treatment history. The study aims to assess the efficacy of this novel approach in patients with low levels of circulating tumor DNA (ctDNA).

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 to 80 with advanced pMMR/MSS colorectal cancer that has failed standard treatments and has low ctDNA levels.

Not a fit: Patients with colorectal cancer that is not pMMR/MSS or those who have not failed previous treatments may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with advanced colorectal cancer who have limited treatment alternatives.

How similar studies have performed: Other studies have shown promising results with similar combinations of targeted therapies and immunotherapy in various cancers, suggesting potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

1. Age range between 18 and 80 years old.
2. ECOG performance status of 0 or 1.
3. Histologically confirmed advanced or recurrent colorectal adenocarcinoma.
4. Confirmed normal expression of mismatch repair proteins (pMMR) by immunohistochemistry or microsatellite stable (MSS) by PCR/next-generation sequencing.
5. Blood ctDNA maxVAF \<6.5% as detected by NGS. blood samples of 8-10ml are to be collected from a qualified testing company for analysis.
6. Metastatic colorectal cancer that has failed with previous treatment with fluoropyrimidine (5-fluorouracil or capecitabine), oxaliplatin, irinotecan plus bevacizumab/cetuximab (left-side RAS/BRAF wildtype).
7. At least 28 days since the last systemic therapy (oral fluoropyrimidine ≥ 14 days), with the option of receiving palliative radiation therapy to limited areas if completed more than 3 weeks prior.
8. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST V1.1).
9. Expected survival of at least 3 months.
10. Adequate organ and bone marrow function, with laboratory values within the following limits within 7 days before enrollment:

    1. Complete blood count: Absolute neutrophil count (ANC) ≥1.5×10\^9/L, Platelet count (PLT) ≥100×10\^9/L, Hemoglobin (HGB) ≥9.0 g/dL.
    2. Liver function: Total bilirubin (TBIL) ≤1.5× upper limit of normal (ULN), Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5× ULN, or ≤5× ULN in the presence of liver metastasis.
    3. Kidney function: Serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance ≥50ml/min, Urinalysis showing urine protein \<2+, for patients with baseline urine protein ≥2+, 24-hour urine protein collection should show \<1g.
    4. Coagulation function: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤1.5 times ULN.
11. Normal electrocardiogram, left ventricular ejection fraction (LVEF) ≥50%.
12. No history of other malignancies, except for cured cervical carcinoma in situ, non-melanoma skin cancer, non-invasive bladder tumors, non-invasive lung cancer, or malignant tumors with continuous disease-free survival of ≥5 years following surgical resection.
13. Negative pregnancy test for women of childbearing potential, and willingness to use effective contraception during the clinical trial period.
14. Voluntary participation in the clinical trial with informed consent provided.

Exclusion Criteria:

1. Patients with a history of prior treatment with fruquintinib or similar small molecule oral targeted drugs primarily aimed at anti-angiogenesis (including marketed or investigational drugs).
2. Patients with a history of prior treatment with other PD-1/PD-L1/CTLA-4 antibody therapies or other immunotherapies targeting PD-1/PD-L1/CTLA-4.
3. Patients who experienced severe hypersensitivity reactions after monoclonal antibody administration in the past.
4. Patients with any active autoimmune disease or a history of autoimmune diseases (such as, but not limited to: autoimmune hepatitis, interstitial pneumonia, enteritis, vasculitis, nephritis, and patients requiring bronchodilators for medical intervention for asthma cannot be included). however, the following patients are allowed to be included: patients with vitiligo, psoriasis, alopecia that do not require systemic treatment, well-controlled type I diabetes, and hypothyroidism with normal thyroid function under replacement therapy.
5. Patients who require immunosuppressive agents, systemic corticosteroids, or absorbable local steroid therapy for achieving immunosuppression (dose \>10mg/day prednisone or equivalent) and are still on continued therapy within 2 weeks of initial dosing.
6. Patients with various factors affecting oral drug intake (such as dysphagia, post-gastrointestinal surgery, chronic diarrhea, and intestinal obstruction).
7. Patients with uncontrollable pleural effusion, pericardial effusion, or ascites requiring repeated drainage.
8. Patients with any signs or history of bleeding diathesis regardless of severity, patients who experienced any bleeding event ≥CTCAE Grade 3 within 4 weeks before initial dosing, or patients with unhealed wounds, fractures, active peptic ulcers, ulcerative colitis, or other gastrointestinal diseases with active bleeding or other conditions deemed by the investigator to potentially cause severe gastrointestinal bleeding or perforation.
9. Patients with known brain metastases with a history of organ transplantation.
10. Patients who received approved or investigational anti-tumor treatments within 4 weeks before the start of the study, including but not limited to chemotherapy, surgery, radiotherapy (within 3 weeks), biologically targeted therapy, interventional therapy, immunotherapy, and traditional Chinese medicine treatment for cancer (as per the indications in the traditional Chinese medicine instructions, participants can be included after a 2-week washout period) (Note: oral fluoropyrimidine drugs for less than 14 days, patients with adverse events from previous treatments, excluding alopecia, not recovered to ≤CTCAE Grade 1).
11. Patients vaccinated with preventive or attenuated vaccines within 4 weeks before the first dose.
12. Patients with any severe and/or uncontrolled diseases, including:

    1. patients with suboptimal blood pressure control (systolic blood pressure ≥150 mmHg, diastolic blood pressure ≥90 mmHg).
    2. patients who had thrombotic events, cerebrovascular accidents, myocardial infarctions, ≥Grade 2 congestive heart failure, or requiring treatment for arrhythmias (including QTc ≥480ms) within 6 months before the first dose.
    3. patients with active or uncontrolled severe infections (≥CTCAE Grade 2 infections), tuberculosis patients.
    4. patients with a clinically significant history of liver disease, including viral hepatitis, known carriers of hepatitis B virus (HBV) must exclude active HBV infection, i.e., HBV DNA positive (\>1 × 10\^4 copies/mL or \>2000 IU/mL), known hepatitis C virus infection (HCV) and HCV RNA positive (\>1 × 10\^3 copies/mL), or other decompensated liver diseases, chronic hepatitis requiring antiviral treatment.
    5. HIV positive.
    6. poorly controlled diabetes (fasting blood sugar ≥CTCAE Grade 2).

Where this trial is running

Beijing, Beijing Municipality

• National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College — Beijing, Beijing Municipality, China (Recruiting)

Study contacts

• Principal investigator: Aiping Zhou, M.D. — Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
• Study coordinator: Aiping Zhou, M.D.

Conditions Metastatic Colorectal Cancer