A Study of SI-B003 and BL-B01D1+SI-B003 in Patients With Locally Advanced or Metastatic Esophageal Cancer, Gastric Cancer, Colorectal Cancer and Other Gastrointestinal Tumors

Study Overview
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Brief Summary
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Objective: To investigate the efficacy, safety and tolerability of SI-B003 monotherapy and BL-B01D1+SI-B003 dual agents in patients with locally advanced or metastatic esophageal cancer, gastric cancer, colorectal cancer and other gastrointestinal tumors, and to further explore the optimal dose and mode of combination.

Detailed Description
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Objective: To investigate the efficacy of SI-B003 alone or BL-B01D1+SI-B003 in the treatment of patients with locally advanced or metastatic esophageal cancer, gastric cancer, colorectal cancer and other gastrointestinal tumors. To explore the safety and tolerability of SI-B003 alone and BL-B01D1+SI-B003 in patients with locally advanced or metastatic esophageal cancer, gastric cancer, colorectal cancer and other gastrointestinal tumors, and to further explore the optimal dose and mode of combination. Secondary objective: To explore the pharmacokinetics of investigational drugs BL-B01D1 and SI-B003. To explore the immunogenicity of BL-B01D1 and SI-B003. To explore drug-drug interactions (DDI).

Official Title
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A Phase II Clinical Study to Evaluate the Efficacy and Safety of SI-B003 Monotherapy and BL-B01D1+SI-B003 Combination Therapy (BL-B01D1+SI-B003) in Patients With Locally Advanced or Metastatic Esophageal Cancer, Gastric Cancer, Colorectal Cancer and Other Gastrointestinal Tumors

Conditions
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Esophageal Cancer, Gastric Cancer, Colorectal Cancer

Intervention / Treatment
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* Drug: SI-B003
* Drug: BL-B01D1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily sign the informed consent and follow the requirements of the protocol; No gender limit; Age: ≥18 years old and ≤75 years old; expected survival time ≥3 months; Patients with locally advanced or metastatic esophageal cancer, gastric cancer, colorectal cancer and other gastrointestinal tumors confirmed by histopathology and/or cytology; Note: Gastric cancer requires definitive HER2 positivity (IHC 3+ or IHC 2+ /ISH +) or HER2 negativity (IHC 2+ /ISH- or IHC 1+). RAS genotype should be determined in colorectal cancer. Consent to provide archival tumor tissue samples or fresh tissue samples from primary or metastatic lesions within 2 years; Participants who were unable to provide tumor tissue samples could be enrolled if they met other inclusion and exclusion criteria after evaluation by investigators; Must have at least one measurable lesion according to RECIST v1.1 definition; ECOG 0 or 1; Toxicity of previous antineoplastic therapy has returned to grade 1 or less as defined by NCI-CTCAE v5.0 (except for asymptomatic laboratory abnormalities considered by investigators, such as elevated alkaline phosphatase, hyperuricemia, and elevated blood glucose; Toxicities that were judged by the investigators to be no safety risk, such as alopecia and grade 2 peripheral neurotoxicity, were excluded. Or decreased hemoglobin (≥90 g/L); No severe cardiac dysfunction, left ventricular ejection fraction ≥50%; Organ function levels must meet the following criteria if blood transfusions, cell growth factors, and/or platelet-raising agents are not allowed within 14 days prior to screening: Bone marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥90×109/L, hemoglobin ≥90 g/L; Liver function: total bilirubin (TBIL≤1.5 ULN), AST and ALT ≤2.5 ULN in patients without liver metastasis, AST and ALT ≤5.0 ULN in patients with liver metastasis; Renal function: creatinine (Cr) ≤1.5 ULN, or creatinine clearance (Ccr) ≥50 mL/min (according to Cockcroft and Gault formula). Coagulation function: international normalized ratio (INR) ≤1.5, and activated partial thromboplastin time (APTT) ≤1.5 ULN; Urine protein ≤2+ or ≤1000mg/24h; For premenopausal women with childbearing potential, a pregnancy test must be performed within 7 days before the start of treatment, serum or urine must be negative for pregnancy, and must be non-lactating; All enrolled patients (male or female) were advised to use adequate barrier contraception throughout the treatment cycle and for 6 months after the end of treatment. Exclusion Criteria: Anti-tumor therapy such as chemotherapy, biological therapy, immunotherapy, radical radiotherapy, major surgery, and targeted therapy (including small-molecule tyrosine kinase inhibitors) have been used within 4 weeks or 5 half-life periods (whichever is shorter) before the first dose in this study; Mitomycin and nitrosoureas were administered within 6 weeks before the first dose; Oral fluorouracil drugs such as S-1, capecitabine, or palliative radiotherapy within 2 weeks before the first dose; The use of immunomodulatory drugs within 2 weeks before the first dose of this study, including but not limited to thymosin, interleukin-2, interferon, etc., must be excluded; Systemic corticosteroid therapy (> 10mg/ day prednisone, or other corticosteroid equivalent) within 2 weeks before the first dose of the study; Exceptions were inhaled or topical corticosteroids or physiological replacement doses of corticosteroids for adrenal insufficiency; Patients with prior immunotherapy and grade ≥3 irAE or grade ≥2 immune-related myocarditis defined according to the CSCO guidelines must be excluded; History of severe heart disease, such as symptomatic congestive heart failure (CHF) ≥ grade 2 (CTCAE 5.0), New York Heart Association (NYHA) ≥ grade 2 heart failure, transmural myocardial infarction, unstable angina, etc; Prolonged QT interval (QTc > 450 msec in men or QTc > 470 msec in women), complete left bundle branch block, and III degree atrioventricular block; Active autoimmune and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel disease, and Hashimoto's thyroiditis; Type I diabetes mellitus, hypothyroidism that can be controlled only by replacement therapy, and skin diseases (such as vitiligo and psoriasis) that do not require systemic treatment were excluded; Other malignant tumors diagnosed within 5 years before the first drug administration in this study, except for radical skin basal cell carcinoma, skin squamous cell carcinoma, superficial bladder cancer, radical resection of carcinoma in situ, such as breast carcinoma in situ; Prior to the initiation of study treatment, present: Poorly controlled diabetes (fasting blood glucose ≥ 13.3 mmol/L) Poorly controlled hypertension (systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg) History of hypertensive crisis or hypertensive encephalopathy. Pulmonary disease defined as grade ≥3 according to CTCAE v5.0; The patient was diagnosed with grade ≥1 radiation pneumonitis according to the RTOG/EORTC definition. Patients with existing or a history of interstitial lung disease (ILD); Unstable deep vein thrombosis, arterial thrombosis, and pulmonary embolism requiring medical intervention within 6 months before screening; Infusion-related thrombosis was excluded; Unstable (poorly controlled clinical symptoms or requiring drainage) patients with serous effusion such as pericardial effusion, pleural effusion, and peritoneal effusion; Patients with central nervous system (CNS) metastases and/or carcinomatous meningitis (meningeal metastases). Patients who had received treatment for brain metastases (radiotherapy or surgery; Patients with stable brain metastases who had stopped radiotherapy or surgery 28 days before the first dose were eligible. Patients with cancerous meningitis (meningeal metastasis) were excluded even if they were treated and judged to be stable. Stability is defined as meeting the following four criteria: seizure-free status for > 12 weeks with or without antiepileptic medication; no need for corticosteroids; stable on two consecutive MRI scans (at least 4 weeks apart); stable and asymptomatic for more than one month after treatment. Patients with a history of allergy to recombinant humanized antibody or human-mouse chimeric antibody or any of the ingredients of BL-B01D1 or SI-B003; Prior organ transplantation or allogeneic hematopoietic stem cell transplantation (Allo-HSCT); Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBV-DNA copy number > 103 IU/ml) or hepatitis C virus infection (HCV antibody positive and HCV-RNA > detection limit); Active infection requiring systemic treatment, such as severe pneumonia, bacteremia, sepsis, etc; Enrollment in another clinical trial within 4 weeks before the first dose of this study (calculated from the time of the last dose); Patients who received live vaccine within 4 weeks before the first dose in the study; Patients with a history of mental illness or drug abuse who are unable to comply with clinical trial requirements; Other conditions for participation in the trial were not considered appropriate by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SI-B003 or BL-B01D1 + SI-B003<br>Participants received SI-B003 or BL-B01D1 + SI-B003 therapy in the first cycle (3 weeks). Participants who had a clinical benefit could receive additional cycles of additional treatment. Administration will be discontinued because of disease progression or intolerable toxicity or for other reasons. | Drug: SI-B003<br>* SI-B003 was administered intravenously every 3 weeks (Q3W).<br>Drug: BL-B01D1<br>* BL-B01D1 was administered by intravenous infusion on D1 and D8 in a 3-week cycle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (ORR) | ORR is defined as the percentage of participants, who has a CR (disappearance of all target lesions) or PR (at least a 30% decrease in the sum of diameters of target lesions). The percentage of participants who experiences a confirmed CR or PR is according to RECIST 1.1. | Up to approximately 24 months | 
| Recommended Phase II Dose (RP2D) | The RP2D is defined as the dose level chosen by the sponsor (in consultation with the investigators) for phase II study, based on safety, tolerability, efficacy, PK, and PD data collected during the dose escalation study . | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | The PFS is defined as the time from the first dose of medication to disease progression or death, whichever occurred first. | Up to approximately 24 months | 
| Disease control rate (DCR) | The DCR is defined as the percentage of participants who has a CR, PR, or Stable Disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease [PD: at least a 20% increase in the sum of diameters of target lesions and an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered PD]). | Up to approximately 24 months | 
| Duration of response (DOR) | The DOR for a responder is defined as the time from the participant's initial objective response to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Treatment-Emergent Adverse Event (TEAE) | TEAE is defined as any adverse and unexpected change in body structure, function, or chemistry or any exacerbation of an existing condition (i.e., any clinically significant adverse change in frequency and/or intensity) during treatment. The type, frequency, and severity of TEAE will be assessed during treatment. | Up to approximately 24 months |