Trial Title:
ctDNA-guided Treatment of TKI Plus PD-1 Inhibitor for Advanced pMMR/MSS Colorectal Cancer
NCT ID:
NCT06543836
Condition:
Metastatic Colorectal Cancer
Conditions: Official terms:
Colorectal Neoplasms
Immune Checkpoint Inhibitors
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Sintilimab
Description:
Sintilimab 200mg, d1, with a treatment cycle of 21 days, and efficacy assessment every 2
cycles.
Arm group label:
PD-1 inhibitor+Tyrosine kinase inhibitor(TKI)
Other name:
PD-1 inhibitor
Intervention type:
Drug
Intervention name:
Fruquintinib or Regorafenib
Description:
The treatment regimen consists of the following options:
Option 1: Fruquintinib 5mg Qd, d1-21, Q4w, and efficacy assessment every 1.5 months.
Option 2: Regorafenib 160mg Qd, d1-21, Q4w, and efficacy assessment every 1.5 months.
Arm group label:
Tyrosine kinase inhibitor(TKI)
Other name:
TKI
Intervention type:
Drug
Intervention name:
Fruquintinib
Description:
Fruquintinib 5mg Qd, d1-14, with a treatment cycle of 21 days, and efficacy assessment
every 2 cycles.
Arm group label:
PD-1 inhibitor+Tyrosine kinase inhibitor(TKI)
Other name:
TKI
Summary:
The efficacy of combining TKI with PD-1 inhibitor in the treatment of advanced MSS/pMMR
colorectal cancer with low levels of maxVAF in peripheral blood ctDNA failed with
standard treatment was assessed, compared to standard treatment as chosen by researchers.
Detailed description:
This study is a prospective, randomized phase II controlled trial. It will include
patients with histologically confirmed advanced metastatic pMMR/MSS colorectal
adenocarcinoma, who have failed with treatment with fluoropyrimidine (5-fluorouracil or
capecitabine), oxaliplatin, irinotecan plus bevacizumab/cetuximab (left-side RAS/BRAF
wild-type) and whose peripheral blood ctDNA test shows a maxVAF level lower than 6.5%.
Patients will be randomly assigned to receive a TKI + a PD-1 inhibitor (primarily
fruquintinib combined with sintilimab) or standard later-line treatment options
(regorafenib or fruquintinib monotherapy, at the discretion of the investigator) until
disease progression, death, intolerable adverse events, or withdrawal of informed
consent.
Criteria for 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).
Gender:
All
Minimum age:
18 Years
Maximum age:
80 Years
Healthy volunteers:
No
Locations:
Facility:
Name:
National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College
Address:
City:
Beijing
Zip:
100021
Country:
China
Status:
Recruiting
Contact:
Last name:
Aiping Zhou, M.D.
Phone:
8610-13691161998
Email:
zhouap1825@126.com
Investigator:
Last name:
Aiping Zhou, M.D.
Email:
Principal Investigator
Start date:
December 1, 2023
Completion date:
November 30, 2025
Lead sponsor:
Agency:
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Agency class:
Other
Source:
Cancer Institute and Hospital, Chinese Academy of Medical Sciences
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06543836
