SI-B001 as a Single Agent or in Combination With Chemotherapy in the Treatment of Digestive System Malignancies

A Phase II Clinical Study to Evaluate the Efficacy and Safety of SI-B001 as a Single Agent or in Combination With Chemotherapy in the Treatment of Unresectable or Metastatic Digestive System Malignancies (Colorectal and Gastric Cancer)

This multi-center, open label Phase II clinical study is performed in patients with unresectable or metastatic malignant tumors of the digestive system (colorectal cancer, gastric cancer). This study is investigating the safety and efficacy of SI-B001 at monotherapy or optimal combination dose with chemotherapy in patients.

Inclusion Criteria:

1. Male or female, age ≥18;

2. Expected survival time ≥3 months;

3. Patients with unresectable or metastatic colorectal cancer or gastric cancer confirmed by histology or pathology:

   Cohort_A: Patients with unresectable or metastatic gastric cancer, HER2-negative, without standard treatment.

   Cohort_B: Patients with MSS KRASwt BRAFwt unresectable or metastatic colorectal cancer, failure of conventional chemotherapy combined with EGFR mab, and withdrawal of EGFR mab for less than 3 months.

   Cohort_C: MSS KRASwt BRAFwt patients with unresectable or metastatic colorectal cancer who have failed multiline conventional chemotherapy (without EGFR monoclonal antibody therapy).

   Cohort_D: MSI-H KRASwt BRAFwt patients with unresectable or metastatic colorectal cancer and previous first - or second-line treatment failure with anti-PD-1 (L1) mab (excluding EGFR mab).

   Cohort_E: MSI-H KRASwt BRAFwt patients with unresectable or metastatic colorectal cancer who have previously failed first-line anti-PD-1 (L1) mab therapy.

   Cohort_F: MSS KRASwt BRAFwt patients with unresectable or metastatic colorectal cancer who have failed standard therapy with first-line oxaliplatin or irinotecan plus fluorouracil plus or minus bevacizumab.

4. No previous anti-EGFR antibody therapy (excluding Cohort_B);

5. Agree to provide 4 specimens (thickness 5μm) of tumor tissue specimens (non-stained sections (anti-removal)) archiving from primary or metastatic tumors;agree to provide 6 unstained sections surgical specimens (anti-removal, thickness 10μm) or fresh tissue samples;

6. There must be at least one measurable lesion conforming to the RECIST V1.1 definition;

7. Cohort_A, B, C fitness scores ≤2, Cohort_D, E, F fitness scores ≤1;

8. Toxicity of previous antitumor therapy has been restored to ≤1 as defined by NCI-CTCAE V5.0 (except for toxicity that the researchers judge to be of no safety risk, such as hair loss, grade 2 peripheral neurotoxicity, and stabilized hypothyroidism after hormone replacement therapy);

9. Organ function levels must meet the following requirements and meet the following standards:

   A) Bone marrow function: absolute value of neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L (platelet count ≥75×109/L in Patients with Cohort_A, B and C), hemoglobin ≥90 g/L (hemoglobin ≥85 g/L in patients with Cohort_A, B and C); B) Liver function: Total bilirubin TBIL≤1.5×ULN (total bilirubin TBIL≤ 3×ULN in Gilbert's syndrome, liver cancer or liver metastases); AST and ALT ≤2.5×ULN in patients without liver metastasis; AST and ALT ≤5.0×ULN in patients with liver metastasis; C) Renal function: Creatinine (Cr) ≤1.5×ULN, or creatinine clearance (Ccr) ≥50 mL/min (according to Cockcroft and Gault formula); D) Urine routine / 24-hour protein quantification: qualitative urine protein ≤1+ (if qualitative urine protein ≥2+, 24 hours < 1g can be included); E) Cardiac function: left ventricular ejection fraction ≥50%; F) Coagulation function: International standardized ratio (INR) ≤1.5×ULN, and activated partial thrombin time (APTT) ≤1.5×ULN;

10. Eligible patients (male and female) who are fertile must agree to use a reliable contraceptive method (hormonal or barrier method or abstinence, etc.) with their partner during the trial and for at least 6 months after the last medication;Women of childbearing age must have a negative blood or urine pregnancy test within 7 days prior to the first use of the study drug.

Exclusion Criteria:

1. Colorectal cancer patients with HER2 positive (immunohistochemical +++, or immunohistochemical ++ with FISH amplification);

2. Have received chemotherapy, radiotherapy, biotherapy, endocrine therapy, immunotherapy and other anti-tumor therapy within 4 weeks prior to the first use of the study drug, except the following:

   Oral fluorouracil and small molecule targeted drugs are 2 weeks before the first administration of the study drug or within the 5 half-lives of the drug (whichever is longer); The traditional Chinese medicines with anti-tumor indications were within 2 weeks before the first use of the study drug;

3. Received an unmarketed clinical investigational drug or treatment within 4 weeks prior to the first use of the investigational drug;

4. Has undergone major organ surgery (excluding needle biopsy, tracheotomy, gastrostomy, etc.) or has significant trauma within 4 weeks before the first use of study drugs, or needs to undergo elective surgery during the trial;

5. Previous recipients of allogeneic hematopoietic stem cell transplantation or organ transplantation;

6. A history of serious cardiovascular and cerebrovascular diseases, including but not limited to:

   Severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, grade iii atrioventricular block, etc.

   In the resting state, QT interval was prolonged (QTc > 450 msec in men or QTc > 470 msec in women); Acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other grade 3 or higher cardio-cerebrovascular events within 6 months prior to the first administration; New York Heart Association (NYHA) heart function grade ≥II heart failure;

7. Active autoimmune and inflammatory diseases, such as systemic lupus erythematosus, inflammatory bowel disease, etc., except type I diabetes, hypothyroidism that can be controlled only with replacement therapy, and skin diseases that do not require systemic treatment (e.g., vitiligo, psoriasis);

8. A history of other malignant tumors within 3 years prior to the first administration, with no signs of recurrence and metastasis;

9. Poorly controlled hypertension (systolic blood pressure & GT;150 mmHg or diastolic pressure &gt;100 mmHg);

10. Pulmonary disease defined as grade 3 or higher according to CTCAE V5.0;Patients with past or present interstitial lung disease (ILD);

11. Cerebral parenchymal or meningeal metastases with clinical symptoms are not suitable for inclusion by the investigator;

12. Had ≥ grade 3 infusion-related reactions during prior anti-EGFR antibody therapy (Cohort_B only);

13. There are known allergic contraindications to any excipients of SI-B001 and chemotherapeutic agents selected in this study;

14. Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number > 104) or hepatitis C virus infection (HCV-RNA > center detection lower limit);

15. Active infections requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc.;

16. Pregnant or lactating women;

17. Persons with mental disorders or poor compliance;

18. The investigator considers that the subject has a history of other serious systemic diseases or other reasons and is not suitable to participate in this clinical study.