A Clinical Study of SI-B001 Combined With Docetaxel in the Treatment of Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma

Study Overview
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Brief Summary
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Main objectives: To evaluate the benefit of SI-B001+ docetaxel on overall survival (OS) of bidotaxel. To evaluate the benefit of SI-B001+ Docetaxel over Docetaxel's progression-free survival (PFS) based assessment. Secondary objectives: To evaluate the investigator-evaluated progression-free survival (PFS) benefit of SI-B001+ Docetaxel against docetaxel; To evaluate the difference of objective response rate (ORR), disease control rate (DCR) and duration of response (DOR) between SI-B001+ docetaxel and bidocetaxel. To evaluate the type, frequency and severity of adverse events (TEAE) and drug-related adverse events (TRAE) during treatment with SI-B001+ docetaxel in comparison with docetaxel. The pharmacokinetic (PK) characteristics of SI-B001 will be evaluated. The immunogenicity of SI-B001 will be evaluated. Subject quality of life.

Official Title
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Phase III Clinical Study of SI-B001 Combined With Docetaxel Second-line Therapy in Patients With Non-small Cell Lung Adenocarcinoma and Lung Squamous Cell Carcinoma Without Actionable Genomic Alterations Who Failed Only First-line Treatment With PD-1/PD-L1 Monoclonal Antibody Plus Platinum-Based Chemotherapy

Conditions
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Non-small Cell Lung Adenocarcinoma, Squamous Cell Carcinoma of Lung

Intervention / Treatment
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* Drug: SI-B001
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sign the informed consent voluntarily and follow the program requirements; No gender limitation; Age ≥18 years and ≤80 years; Expected survival time ≥3 months; Histologically or cytologically confirmed, locally advanced or metastatic EGFR wild-type, ALK wild-type, and other driver negative (AGA negative, including MET 14 exon jump mutation, ROS1 rearrangement, BRAF V600 mutation, NTRK fusion, RET rearrangement, HER2 mutation, Patients with HER2 amplification (> 3.2 copies), KRAS G12 mutation (e.g., G12C, G12D, G12V, etc.) negative), non-small cell lung cancer (squamous cell carcinoma, adenocarcinoma), who only received anti-PD-1 /PD-L1 monoclonal antibody + platino-containing dimorphization and disease progression or intolerance at the first line; Note: a. Platinum-containing chemotherapy (induction chemotherapy, chemoradiotherapy and adjuvant chemotherapy) in multi-mode therapy for locally advanced patients with disease progression during treatment or within 6 months after the last administration can be counted as first-line therapy. If no treatment with anti-PD-1 /PD-L1 monoclonal antibody is received, the inclusion criteria cannot be met. Inclusion criteria were met if maintenance therapy with anti-PD-1 /PD-L1 monoclonal antibody and disease recurrence/progression occurred within 6 months after the last administration of platinum-containing chemotherapy drugs; b. For patients who need genetic testing or IHC testing and receive platinum-containing diplination first, they should only receive platinum-containing diplination at most in the first 2 cycles, and then add anti-PD-1 /PD-L1 monoclonal antibody for combination therapy, which meets the inclusion criteria; Patients receiving anti-PD-1 /PD-L1 monoclonal antibody and then sequential chemotherapy drugs did not meet the inclusion criteria; c. Any change of medication during front-line treatment shall be counted as an increase in the number of treatment lines; Subject shall agree to complete ctDNA test during the screening period, including: EGFR, ALK, MET, ROS1, BRAF, NTRK, RET, HER2, KRAS and other genes detection and complete data; There must be at least one measurable lesion consistent with the RECIST v1.1 definition; If there is only one measurable lesion, baseline imaging of the lesion should not be performed until at least 14 days after biopsy if biopsy has been performed; If the target lesion at the site of previous radiotherapy is the only measurable lesion, the investigator must provide imaging data before and after showing significant progression of the lesion to confirm clear progression of the lesion and at least 3 months after the end of radiotherapy; Physical status score ECOG 0 or 1; The toxicity of previous antitumor therapy has returned to class 1 as defined by NCI-CTCAE v5.0 (alopecia, fatigue, hyperpigmentation, hypothyroidism stabilized by hormone replacement therapy, grade 2 peripheral neurotoxicity after chemotherapy, and other inclusion criteria excluded); No serious cardiac dysfunction, left ventricular ejection fraction ≥50%; If blood transfusion, albumin, colony-stimulating factors, any cell growth factors, and/or thrombocytophors are not permitted within 14 days prior to the initial use of the study drug, organ function levels must meet the following requirements and meet the following criteria: Bone marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90 g/L; Liver function: total bilirubin TBIL≤1.5×ULN (total bilirubin ≤3×ULN in subjects with Gilbert's syndrome or liver metastasis), AST and ALT ≤2.5×ULN in subjects without liver metastasis, AST and ALT ≤5.0×ULN in patients with liver metastasis, albumin ≥30 g/L; Renal function: creatinine (Cr) ≤1.5×ULN, or creatinine clearance (Ccr) ≥50 mL/min (according to Cockcroft and Gault formula); Coagulation function: International standardized ratio (INR) ≤1.5, and activated partial thromboplastin time (APTT) ≤1.5×ULN; Urinary protein ≤2+ or < 1000mg/24h; A pregnancy test must be performed within 7 days before the start of treatment for premenopausal women who are likely to have children, and the serum-pregnancy must be negative and must be non-lactation; All enrolled patients (male or female) should take adequate barrier contraception throughout the treatment cycle and for 6 months after completion of treatment. Exclusion Criteria: Patients with previous use of docetaxel; Patients with non-small cell lung cancer except lung squamous cell carcinoma and lung adenocarcinoma confirmed by histological or cytological examination (excluding patients with squamous cell carcinoma or adenocarcinoma combined with other types of non-small cell lung cancer); The gene sequencing report of previous tissue samples or ctDNA before signing the informed consent, or the gene sequencing report of ctDNA during the screening period indicated that there were positive MET 14 exon jump, positive ROS1 rearrangement, positive BRAF V600 mutation, positive NTRK fusion, positive RET rearrangement, and positive HER2 mutation. Patients with HER2 amplification (> 3.2 copies) and KRAS G12 mutation positive (e.g., G12C, G12D, G12V, etc.) should be excluded. Used chemotherapy, biotherapy, immunotherapy, radical radiotherapy, major surgery, extensive radiotherapy (more than 30% bone marrow radiotherapy or extensive radiotherapy) within 4 weeks before the first dose or within 5 half-lives (whichever is shorter), Anti-tumor therapy has been used within 2 weeks, such as palliative radiotherapy (but it is allowed for bone lesions), small-molecule targeted therapy (including small-molecule tyrosine kinase inhibitors), and modern Chinese medicine preparations approved and marketed for anti-tumor therapy with NMPA; The medical history of severe cardiac and cerebrovascular diseases in the previous six months was screened, such as: symptomatic congestive heart failure (CHF) ≥2 (CTCAE v5.0) medical history, New York Heart Society (NYHA) ≥3 heart failure, unstable angina pectoris, acute coronary syndrome, myocardial infarction, cerebrovascular accident, transient ischemic attack, cerebral infarction, etc.; Prolonged QT interval (male QTc > 450 msec or female QTc > 470 msec, QTc interval calculated by Fridericia formula), complete left bundle branch block, degree III atrioventricular block, frequent and uncontrolled arrhythmias: Such as atrial fibrillation, atrial flutter, ventricular fibrillation, ventricular flutter (transient atrial fibrillation, except for atrial flutter); Active autoimmune diseases and inflammatory diseases, such as systemic lupus erythematosus, psoriasis requiring systemic treatment, rheumatoid arthritis, inflammatory bowel diseases, Hashimoto's thyroiditis, etc., except type I diabetes mellitus, hypothyroidism that can be controlled by alternative therapy alone, and skin diseases that do not require systemic treatment (e.g. Vitiligo, psoriasis); Diagnosis of other malignancies within 5 years prior to initial administration, with the exception of radically treated basal cell carcinoma of the skin, squamous cell carcinoma of the skin, and/or radically resected carcinoma in situ, which the investigators considered acceptable for inclusion; Hypertension poorly controlled by two antihypertensive drugs (systolic blood pressure &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg); Patients with past and present clinical manifestations or high risk factors of interstitial lung disease (ILD), drug-related pneumonia, radiation pneumonia, severe impairment of lung function or suspected interstitial lung disease; Patients with central nervous system (CNS) metastasis and/or cancerous meningitis (meningeal metastasis) and/or spinal cord compression. But have received brain metastases (radiation or surgery; Patients with stable BMS who had stopped radiotherapy or surgery 28 days before the first dose were enrolled. Patients with cancerous meningitis (meningeal metastasis) were excluded even after treatment and judged to be stable, and patients with cerebral edema and mannitol prophylaxis/treatment were excluded even if asymptomatic. The definition of stability should meet the following four requirements: The seizure-free state persists for > 12 weeks with or without the use of antiepileptic drugs; glucocorticoids are not required; MRI results during the screening period showed stable imaging status compared with previous MRI results of the subjects; asymptomatic and stable for more than 1 month after treatment; Patients who have a history of allergy to recombinant humanized antibody or human and mouse chimeric antibody or to SI-B001 and any excipient components of the chemotherapy drugs used in this study; History of autologous or allogeneic stem cell transplantation or organ transplantation; Positive human immunodeficiency virus antibodies (HIVAb), active hepatitis B virus infection (HBV-DNA > 103 copies/ml) or hepatitis C virus infection (HCV-RNA > lower limit of centre detection); Severe infections (CTCAE > Grade 2), such as severe pneumonia, bacteremia, sepsis, tuberculosis, etc., occurred within 4 weeks prior to the first use of the study drug; There was active pulmonary inflammation during screening; Patients with a large amount of serous effusion, or with symptoms of serous effusion, or poorly controlled serous effusion (poorly controlled is defined as two or more times of puncture and drainage in a month); Contraindicated fluid replenishment with superior vena cava syndrome; Received other investigational drugs or treatments within 4 weeks prior to initial dosing; A history of severe neurological or mental illness, including but not limited to: dementia, depression, seizures, bipolar disorder, etc.; Imaging examination indicated that the tumor had invaded or wrapped the great vessels of the chest (such as the pulmonary trunk, aorta trunk, pulmonary veins, etc.); Severe and unhealed wounds, sores or fractures within 4 weeks prior to signing the notice; Coughed up or coughed up (defined as coughing up or coughed up ≥1 teaspoon of blood or small blood clots or coughed up blood without sputum) within 4 weeks before signing the notification, but did not exclude blood in the sputum; Severe infusion reaction to antibody therapy in the past (CTCAE grade ≥3); Subjects with clinically significant bleeding or significant bleeding tendency within 4 weeks prior to signing the information, such as gastrointestinal bleeding, hemorrhagic gastric ulcer, vasculitis, etc.; History of intestinal obstruction, inflammatory bowel disease or extensive bowel resection, or presence of Crohn's disease, ulcerative colitis, or chronic diarrhea; Subjects who plan to receive live vaccine or receive live vaccine within 30 days prior to initial administration; Other conditions associated with participation in this clinical trial were not considered appropriate by the investigators.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Participants receive SI-B001 as intravenous infusion for the first cycle (3 weeks). Participants with clinical benefit could receive additional treatment for more cycles. The administration will be terminated because of disease progression or intolerable toxicity occurring or other reasons. | Drug: SI-B001<br>* Administration by intravenous infusion<br>|
| Experimental: Control group<br>Participants receive Docetaxel as intravenous infusion for the first cycle (3 weeks). Participants with clinical benefit could receive additional treatment for more cycles. The administration will be terminated because of disease progression or intolerable toxicity occurring or other reasons. | Drug: Docetaxel<br>* Administration by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | Overall survival (OS) is defined as the time between the subject's randomization date and subject's death. | Up to approximately 24 months | 
| Progression-free survival (PFS) | Progression-free survival (PFS) as assessed by BIRC was defined as the time between the date subjects were randomized and the first observation of disease progression (based on BICR's image-based assessment) or death. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | Objective response rate (ORR) is defined as the number of CR and PR in the treatment and control groups divided by the number of that group in the full analysis set (FAS). | Up to approximately 24 months | 
| Disease Control Rate (DCR) | Disease Control Rate (DCR) : Percentage of all randomized subjects who rated the best overall response (BOR) as complete response (CR), partial response (PR), and disease stabilization (SD) according to RECIST 1.1 criteria. | Up to approximately 24 months | 
| Duration of Response (DOR) | Duration of Response (DOR) : defined as the period from the date when tumor response is first recorded to the date when objective tumor progression is first recorded or the date of death. | Up to approximately 24 months | 
| Treatment Emergent Adverse Event (TEAE) | TEAE is defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally emerging, or any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition during the treatment of SI-B001. The type, frequency and severity of TEAE will be evaluated during the treatment of SI-B001. | Up to approximately 24 months | 
| Anti-drug antibody (ADA) | Characteristics of ADA will be evaluated. | Up to approximately 24 months |