Overview
The study is an interventional Phase II clinical trial aiming to optimize immunotherapy strategies for microsatellite-stable colorectal cancer. We will include three types of metastatic colorectal cancer patients: those without liver metastasis, or carrying BRAF V600E mutation, or unable to tolerate chemotherapy as their initial or second-line treatment. The participants will receive a combination treatment of regorafenib and KN046 which is a PD-L1/CTLA-4 bispecific antibody. Treatment efficacy and safety profile would be evaluated in this study.
Eligibility
Inclusion Criteria:
I01. Subjects are able to comprehend the informed consent form, voluntarily participate,
and sign the informed consent form.
I02. Subjects are ≥18 years old on the day of signing the informed consent form, with no
gender restrictions.
I03. Histologically confirmed colorectal adenocarcinoma, including signet ring cell
carcinoma and mucinous adenocarcinoma.
I04. According to RECIST 1.1 criteria, there should be at least one measurable or evaluable
lesion at baseline. If the subject has only one measurable or evaluable lesion at baseline,
the lesion must not have been exposed to radiotherapy previously, or there must be evidence
of significant progression after radiotherapy treatment completion.
I05. ECOG performance status of 0 or 1. I06. Expected survival ≥3 months. I07. Archived
tumor tissue samples or freshly obtained tumor tissue samples are available.
I08. Female subjects of childbearing potential or male subjects with partners of
childbearing potential agree to use highly effective contraception from 7 days before the
first dose until 120 days after the last dose. Female subjects of childbearing potential
must have a negative serum pregnancy test within 7 days before the first dose.
I09. Subjects have the ability and willingness to comply with the study protocol's visits,
treatment plan, laboratory tests, and other study-related procedures.
I10. Within the first 7 days of initial dosing, subjects should have good organ function:
HGB ≥ 80g/L NEU ≥ 1.010^9/L PLT ≥ 7510^9/L Cr≤1.5×ULN or CrCl≥50mL/min（ Cockcroft-Gault
method） TBiL ≤ 1.5×ULN ALT and AST ≤3 ×ULN； for patients with liver metastasis ALT and AST
≤5 ×ULN urine protein <2+；if urine protein ≥ 2+，24 hour urinary protein quantity <2g； INR，
APTT，PT ≤ 1.5 ×ULN
I11. For each cohort, the previous treatment history must meet the following conditions:
Cohort A: pMMR/MSS mCRC with no BRAF V600E mutation, who failed fluoropyrimidine,
oxaliplatin, and irinotecan treatments, and without definitive active liver metastases at
enrollment (judged by the investigator based on medical history and imaging).
Cohort B: pMMR/MSS mCRC with BRAF V600E mutation, who failed fluoropyrimidine, oxaliplatin,
and irinotecan treatments.
Cohort C: MSS mCRC that has not intolerant or unsuitable for or refuse to receive standard
first-line or second-line chemotherapy.
Exclusion Criteria:
E01. Subjects with untreated active brain metastases or meningeal metastases; if the
subject's brain metastases have been treated and the metastases are stable (brain imaging
at least 4 weeks before the first dose shows stable lesions, and there is no evidence of
new neurological symptoms or the neurological symptoms have returned to baseline), then
enrollment is allowed.
E02. Subjects with a history of gastrointestinal perforation or fistula within 6 months
before the first dose. If the perforation or fistula has been treated with resection or
repair, and the disease is judged to be recovered or improved by the investigator, then
enrollment is allowed.
E03. Subjects who have received any other interventional clinical trial or any other
antitumor treatment within 28 days or 5 half-lives before the first dose (whichever is
shorter). Palliative radiotherapy for bone metastases to relieve symptoms is permitted.
E04. Subjects who have undergone major surgery within 28 days before the first dose (e.g.,
major abdominal or thoracic surgery; excluding drainage, diagnostic puncture, or peripheral
vascular access replacement).
E05. Subjects who require systemic corticosteroids (≥10 mg/day prednisone or equivalent) or
immunosuppressive therapy for a continuous 7-day period within 14 days before the first
dose. Inhaled or locally applied steroids and physiological replacement doses of steroids
due to adrenal insufficiency are allowed. Short-term (≤7 days) corticosteroids for
prophylaxis (e.g., contrast dye allergy) or treatment of non-autoimmune diseases (e.g.,
delayed hypersensitivity reaction caused by exposure to allergens) are allowed.
E06. Subjects who have received live vaccines (including attenuated live vaccines) within
28 days before the first dose.
E07. Subjects with interstitial lung disease or a history of non-infectious pneumonia
requiring oral or intravenous corticosteroid treatment.
E08. Subjects with active autoimmune diseases requiring systemic treatment within 2 years
before the start of the study or those considered at risk of recurrence or planned
treatment for autoimmune diseases as judged by the investigator. Exclusions include a) skin
diseases that do not require systemic treatment (e.g., vitiligo, alopecia, psoriasis, or
eczema); b) hypothyroidism caused by autoimmune thyroiditis, requiring stable doses of
hormone replacement therapy; c) type 1 diabetes requiring stable doses of insulin
replacement therapy; d) childhood asthma fully resolved with no need for intervention in
adulthood; e) the investigator judges that the disease will not relapse without external
triggering factors.
E09. Subjects with a history of other malignant tumors within 5 years, excluding cured skin
squamous cell carcinoma, basal cell carcinoma, non-invasive bladder carcinoma, localized
low-risk prostate cancer (defined as stage ≤T2a, Gleason score ≤6, and prostate-specific
antigen (PSA) ≤10 ng/mL (if measured) in patients who have undergone curative treatment and
have no biochemical recurrence of prostate-specific antigen (PSA)), in situ cervical/breast
carcinoma, or Lynch syndrome.
E10. Subjects with uncontrolled comorbidities, including but not limited to: a) active HBV
or HCV infection; b) subjects who are HBsAg positive and/or HCV antibody positive during
screening must undergo HBV DNA and/or HCV RNA testing. Only subjects with HBV DNA ≤500
IU/mL (or ≤2000 copies/mL) and/or HCV RNA negative can be enrolled; HBV DNA monitoring will
be at the discretion of the investigator based on the subject's condition during the trial;
c) known HIV infection or AIDS history; d) active tuberculosis; e) active infection or
systemic use of anti-infective drugs for more than 1 week within 28 days before the first
dose; fever of unknown cause within 2 weeks before the first dose; f) uncontrolled
hypertension (resting blood pressure ≥160/100 mmHg), symptomatic congestive heart failure
(NYHA II-IV), unstable angina or myocardial infarction within 6 months, or the presence of
QTc prolongation or the risk of arrhythmia (baseline QTc >470 msec <Fridericia method
correction>, difficult-to-correct hypokalemia, long QT syndrome, atrial fibrillation with
resting heart rate >100 bpm, or severe valvular heart disease); g) active bleeding that
cannot be controlled after medical treatment.
E11. Toxicity from previous antitumor treatments has not recovered to Grade ≤2 (NCI-CTCAE
v5.0) or baseline, except for alopecia, skin pigmentation (allowed at any level), and
immune-related adverse reactions requiring physiological replacement (e.g., hypothyroidism,
hypopituitarism, type 1 diabetes).
E12. History of allogeneic bone marrow or organ transplantation. E13. Previous history of
allergic reactions, hypersensitivity reactions, or intolerance to antibody drugs (e.g.,
severe allergic reactions, immune-mediated hepatotoxicity, immune-mediated
thrombocytopenia, or anemia).
E14. Pregnant and/or lactating females. E15. Other conditions that, in the investigator's
opinion, may affect the safety or compliance of the study drug treatment, including but not
limited to moderate to large pleural/ascites/pericardial effusion, uncorrectable
pleural/ascites/pericardial effusion, intestinal obstruction or subacute intestinal
obstruction, psychiatric disorders, etc.
E16. Previous treatment with any immune checkpoint inhibitors or T-cell co-stimulatory
drugs, including but not limited to PD-1/PD-L1, CTLA-4, LAG3, and other immune checkpoint
inhibitors, therapeutic vaccines, etc.
E17. Previous treatment with regorafenib.