Advanced or metastatic rectal cancer

This trial will investigate the safety, tolerability, and preliminary efficacy of a combination of cetuximab/bevacizumab, FOLFOX/FOLFIRI, and HCB101 in patients with advanced or metastatic colorectal cancer.

HCB101

HCB101

150mg/10mL

- Number/incidence and percentage of subjects experiencing adverse events (AEs), serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and dose-limiting toxicities (DLTs);

- MTD and RP2D for HCB101 concomitant medications:

1. Participants must understand and be willing to sign an informed consent form, including compliance with the Inform Consent Form (ICF) and the regulations and limitations listed in this program, including trial follow-up and trial-related procedures.

2. Gender not limited; age ≥ 18 years at the time of signing the participant consent form.

3. Patients with histologically or cytopathologically confirmed unresectable locally advanced or metastatic colorectal cancer, with wild-type RAS and BRAF, and who have failed prior immunotherapy and chemotherapy (i.e., second-line patients).

4. Must have at least one measurable lesion meeting the RECIST v1.1 definition.

5. At screening, the East Coast Cancer Clinical Research Consortium (ECOG) performance status score must be 0-2.

6. Able to provide preserved or fresh tumor tissue samples for CD47 expression, immune score, and whole exome sequencing (WES) testing. (If applicable)

7. Life expectancy ≥ 12 weeks, as assessed by the trial administrator.

8. Sufficient organ function according to the laboratory test parameters in the table below (no blood transfusions, blood separation transfusions, erythropoietin, leukotrophic hormone, or other related medical support received within 14 days prior to the first dose).

 Absolute neutrophil count ≥ 1.5 × 10⁹/L.

 Platelets ≥ 75 × 10⁹/L.

 Heme ≥ 9.5 g/dL.

 Total bilirubin ≤ 1.5 times the upper limit of normal (ULN), < 3.0 times ULN for patients with Gilbert’s disease.

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times the ULN, and ≤ 5 times the ULN for subjects with liver metastases.

• Creatinine clearance ≥ 30 mL/min (calculated according to the Cock-croft-Gault formula);

• Coagulation function: International Normalized Ratio (INR), prothrombin time (PT), and activated partial thromboplastin time (aPTT) ≤ 1.5 times the ULN (INR is only applicable to subjects not receiving anticoagulation therapy).

9. A) Female subjects should meet at least one of the following criteria before participating in the trial:

a. Infertility (i.e., physiological inability to conceive), including women who have undergone hysterectomy, bilateral oophorectomy, or bilateral salpingectomy.

b. Postmenopause (complete cessation of menstruation ≥ 1 year).

c. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during the screening period (7 days prior to the first dose), not be breastfeeding, and use a highly effective method of contraception throughout the entire trial period (i.e., from the start of enrollment to a maximum of 6 months after the last dose). A highly effective method of contraception is defined as one with an annual failure rate of less than 1% when used correctly and consistently.

B) Male participants are eligible to participate in the trial if they have undergone vasectomy or agree to use a highly effective method of contraception for a maximum of 6 months from the start of enrollment to the last dose and to avoid sperm donation.

Target disease, comorbidities, and past medical history:

1. Known history of allergy to any component of the investigational drug.

2. Subjects with other malignancies requiring treatment within 2 years prior to the first dose will be excluded, except for locally curable basal cell or squamous cell skin cancer that has received radical treatment and other malignancies that have not recurred within 2 years.

3. Primary tumors of the central nervous system (CNS), or active or untreated CNS metastases and/or carcinomatous meningitis. Subjects who have previously received treatment for brain metastases are eligible to participate in this trial provided they are clinically stable for at least 28 days, have no evidence of new or expanding brain metastases, and have not used high-dose corticosteroids in the 14 days prior to the investigational drug dose. Subjects using low-dose corticosteroids [prednisone ≤ 20 mg daily or equivalent] are eligible to participate.

4. Clinically serious cardiovascular disease, including: ① a history of congestive heart failure (New York Heart Association grade > 2); ② a history of unstable angina within 6 months prior to the first dose; ③ a new onset of angina or myocardial infarction within 6 months prior to the first dose; ④ a new onset of atrial fibrillation, supraventricular arrhythmia, or ventricular arrhythmia within 6 months prior to the first dose, and still in an unstable state requiring treatment or intervention. Subjects with a history of atrial fibrillation, supraventricular arrhythmia, or ventricular arrhythmia are permitted entry into the trial if their condition is stabilized.

5. Clinically significant past or present ECG abnormalities as determined by the trial administrator, including QT prolongation at screening (QT interval > 470 msec using Fridericia’s correction), pacemaker implantation, or a prior diagnosis of congenital QT prolongation syndrome.

6. Aside from hair loss and anemia, according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, prior treatment-related toxicities have not recovered to ≤ Grade 1 or the baseline (Note: For subjects with chronic Grade 2 toxicities who have stabilized after adequate treatment, this is determined by the trial administrator, e.g., chemotherapy-induced Grade 2 neuropathy).

7. Known congenital or acquired bleeding disorders or bleeding tendencies.

8. Requirement for red blood cell (RBC) transfusions within 3 months prior to screening, defined as receiving more than 2 units of RBC transfusions/4 weeks.

9. Diagnosis of hemolytic anemia or Evans syndrome within 3 months prior to screening.

Concomitant medication/treatment and prior medication/treatment guidelines:

10. Underwent major surgery or radical radiation therapy within 28 days prior to the first dose of the investigational drug.

11. Received palliative radiation therapy within 14 days prior to the first dose of the investigational drug.

12. Received radiopharmaceutical treatment (strontium, samarium, etc.) within 56 days prior to the first dose of the investigational drug.

13. Received any investigational or approved systemic cancer treatment (including chemotherapy, immunotherapy, hormone therapy, and herbal/alternative therapies or targeted therapy for cancer indications) within 14 days or 5 half-lives (whichever is longer) prior to the first dose of the investigational drug.

14. Used herbal remedies within 14 days prior to the first dose of the investigational drug.

15. Currently receiving anticoagulant therapy, such as vitamin K antagonists. Subjects using low molecular weight heparin or coagulation factor Xa inhibitors will be evaluated individually for inclusion in the trial. There are no restrictions on aspirin doses up to 100 mg daily.

16. Previously received any treatment targeting the CD47-SIRPα pathway.

17. Received or planned to receive a live virus or live bacterial vaccine within 28 days prior to or throughout the trial period. Subjects requiring COVID-19 vaccination during treatment with the investigational drug must receive a non-live virus vaccine [e.g., a vaccine made from messenger ribonucleic acid (mRNA) or a completely deactivated/non-replicating genetically modified virus].

18. Participated in another clinical trial within 14 days or 5 half-lives (whichever is longer) prior to the first dose of the investigational drug. Or used the investigational medical device within 28 days prior to the first dose of the investigational drug.

Infection-related provisions:

19. Poorly controlled acute infection, or active infection requiring systemic treatment, or received systemic antibiotics within 14 days prior to the first dose of the investigational drug (except for systemic antibiotics used for the prevention of upper respiratory tract infections without violating concomitant medications).

20. Subjects with a known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome, or a positive HIV test with a CD4+ T cell count < 350 cells/µL, or who do not wish to be tested for HIV.

21. Subjects with known active hepatitis B or C. Subjects testing positive for hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibody must undergo further testing for hepatitis B virus (HBV) DNA titer (excluding those with DNA titers higher than 2500 copies/mL or 500 IU/mL) and HCV RNA (HCV RNA exceeding the detection limit of the test method) to exclude those with active hepatitis B or C infection requiring treatment.

22. Active pulmonary tuberculosis.

23. Individuals with a history of alcoholism or drug abuse.

24. Any other medical condition (such as Child-Pugh Category B or C, pulmonary, metabolic, congenital, endocrine, or central nervous system disorders, etc.) that, in the opinion of the trial administrator, may impair the subject's right, safety, welfare, or ability to sign the subject consent form, cooperate with and participate in the trial, or that may impair the interpretation of the trial results due to mental illness or social condition.