Combining KN 046 and Regorafenib for Colorectal Cancer Treatment

A Phase II Multi-cohort Clinical Study Evaluating The Efficacy and Safety of KN046 in Combination With Regorafenib for Metastatic Microsatellite-Stable Colorectal Cancer: a Phase II Multi-cohort Study

This study is testing if a new combination of two drugs, KN 046 and regorafenib, can help people with a specific type of advanced colorectal cancer feel better and improve their treatment options.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 98 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Peking University Cancer Hospital & Institute (Academic / other)
• Drugs / interventions: chemotherapy, prednisone, immunotherapy
• Locations: 1 site (Beijing)
• Trial ID: NCT05985109 on ClinicalTrials.gov

What this trial studies

This Phase II clinical trial aims to enhance immunotherapy strategies for patients with microsatellite-stable metastatic colorectal cancer. It includes participants who either do not have liver metastasis, carry the BRAF V600E mutation, or cannot tolerate chemotherapy. Patients will receive a combination of regorafenib and KN046, a bispecific antibody targeting PD-L1 and CTLA-4, with the study evaluating both the efficacy and safety of this treatment approach.

Who should consider this trial

Good fit: Ideal candidates include adults with histologically confirmed colorectal adenocarcinoma who meet specific criteria regarding metastasis and treatment history.

Not a fit: Patients with colorectal cancer who have already undergone extensive treatment or have different genetic profiles may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with difficult-to-treat metastatic colorectal cancer.

How similar studies have performed: While there have been studies exploring immunotherapy in colorectal cancer, the specific combination of KN046 and regorafenib is novel and has not been extensively tested.

Eligibility criteria

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 ≥ 1.0\*10\^9/L PLT ≥ 75\*10\^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.

Where this trial is running

Beijing

• Beijing Cancer Hospital — Beijing, China (Recruiting)

Study contacts

• Principal investigator: Lin Shen — Peking University Cancer Hospital & Institute
• Study coordinator: Ting Xu, MD

Conditions Colorectal Cancer