A Study of SI-B001+SI-B003± Chemotherapy in the Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer

Study Overview
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Brief Summary
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Phase Ib: To observe the safety and tolerability of the combination of SI-B001 and SI-B003, and to determine the recommended dose of phase II clinical study (RP2D) in the indication of locally advanced or metastatic non-small cell lung cancer. Phase II: To evaluate the efficacy of SI-B001+SI-B003 combination with or without chemotherapy in patients with locally advanced or metastatic non-small cell lung cancer.

Official Title
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A Phase Ib/II Clinical Trial to Evaluate the Safety and Efficacy of SI-B001+SI-B003 With or Without Chemotherapy (SI-B001+SI-B003± Chemotherapy) in the Treatment of Locally Advanced or Metastatic Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: SI-B001
* Drug: SI-B003


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; Participants must consent to complete ctDNA testing during the screening period, including: EGFR, ALK, MET, ROS1, BRAF, NTRK, RET, HER2, KRAS and other genes detection and complete data; Histologically or cytologically confirmed locally advanced or metastatic non-small cell lung cancer; Stage Ib: locally advanced or metastatic non-small-cell lung cancer with negative driver genes (AGA-negative, including ALK fusion, MET exon 14 skipping mutation, ROS1 rearrangement, BRAF V600 mutation, NTRK fusion, and RET rearrangement) after failure of standard therapy; Phase II: Cohort_A: Previously untreated, locally advanced or metastatic non-small cell lung cancer patients with wild-type EGFR, wild-type ALK, and other driver genes negative (AGA negative, including MET exon 14 skipping mutation, ROS1 rearrangement, BRAF V600 mutation, NTRK fusion, and RET rearrangement negative); Cohort_B: Previously untreated patients with locally advanced or metastatic EGFRmut non-small cell lung cancer who had failed EGFR TKI therapy and had not received systemic chemotherapy. Note: a. Patients were eligible if they were treated directly with third-generation EGFR TKI, or if they were treated with first-generation or second-generation EGFR TKI before progression to third-generation TKI; b. If the patient has progressed after the first and second generation EGFR TKI treatment, but there is no indication for the third generation EGFR TKI treatment (no EGFR T790M mutation), the third generation EGFR TKI treatment is not required; Consent to provide archived tumor tissue samples or fresh tissue samples of primary or metastatic lesions; Phase Ib: participants could be enrolled if they could not provide tumor tissue samples if they met other inclusion and exclusion criteria. Stage II: PD-L1TPS test report (DAKO 22C3 antibody) of tumor tissue samples is required; If no relevant examination report is available, patients must provide a tumor tissue sample or fresh tissue sample (FFPE block or approximately 10-12 white slides with a size of 5μm) from the primary or metastatic tumor within 2 years for PD-L1 TPS, EGFR, or HER3 protein expression level detection. At least one measurable lesion meeting the RECIST v1.1 definition was required. Performance status score: ECOG ≤1; Toxicity from previous antineochemical therapy has returned to grade 1 or less as defined by NCI-CTCAE v5.0 (asymptomatic laboratory abnormalities such as elevated ALP, hyperuricemia, elevated serum amylase/lipase, and elevated blood glucose were considered by the investigator, and toxicity with no safety risk was judged by the investigator; Except for alopecia, grade 2 peripheral neurotoxicity, and hypothyroidism stable with hormone replacement therapy). No severe cardiac dysfunction, left ventricular ejection fraction ≥50%; The level of organ function must meet the following requirements and meet the following standards: Bone marrow function: absolute neutrophil count (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90 g/L; Liver function: total bilirubin ≤1.5×ULN (total bilirubin ≤3×ULN in subjects with Gilbert's syndrome and liver metastasis), AST and ALT ≤3×ULN in subjects without liver metastasis, AST and ALT ≤5.0×ULN in subjects 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 ≤1+ or ≤1000mg/24h; Female subjects of childbearing potential or male subjects with a fertile partner must use highly effective contraception from 7 days before the first dose until 24 weeks after the dose. Female subjects of childbearing potential had to have a negative serum pregnancy test within 7 days before the first dose. Exclusion Criteria: For stage Ib patients, patients with non-small-cell lung cancer with ALK fusion, MET exon 14 skipping mutation, ROS1 rearrangement, BRAF V600 mutation, NTRK fusion, or RET rearrangement on previous sequencing reports of tissue samples or ctDNA before informed consent were excluded; For phase II Cohort_A: Genetic sequencing reports from prior tissue samples or ctDNA before signing informed consent, or screening ctDNA suggesting the following genetic alterations: Patients with ALK fusion, MET exon 14 skipping mutation, ROS1 rearrangement, BRAF V600 mutation, NTRK fusion, or RET rearrangement were excluded. Phase II patients were excluded from the study if any of the following conditions occurred: patients suitable for local treatment and willing to receive local treatment; received systemic chemotherapy, but not chemotherapy for locally advanced disease as part of multimodal therapy (this treatment must have been completed more than 6 months after the first dose of trial medication; The above chemotherapy includes induction chemotherapy, concurrent chemoradiotherapy and adjuvant chemotherapy). Clinically symptomatic parenchymal or leptomeningeal metastases that were judged by the investigator to be ineligible for enrollment. Patients with central nervous system (CNS) metastases and/or carcinomatous meningitis (meningeal metastases) and/or spinal cord compression. Patients who had received treatment for brain metastases (radiotherapy or surgery; Patients who had stopped radiotherapy and surgery 28 days before the first dose) and stable brain metastases were eligible. Patients with cancerous meningitis (meningeal metastasis) were excluded even if they were treated and judged to be stable, and patients with brain edema and treated with mannitol were excluded even if they were judged to be asymptomatic. Stability is defined as meeting the following four criteria: seizure-free status for > 12 weeks with or without antiepileptic medication; no need for corticosteroids; screening MRI results, which showed a stable imaging state compared to the subjects' previous MRI results; stable and asymptomatic for more than one month after treatment; Participants who participated in any other clinical trial within 4 weeks before the study dose (whichever was the last dose); Chemotherapy, biotherapy, immunotherapy, definitive radiotherapy, major surgery, or large area radiotherapy (more than 30% bone marrow area or too large area irradiation) administered within 4 weeks or 5 half-lives prior to the first dose, whichever is shorter; Anti-tumor therapy such as palliative radiotherapy within 2 weeks (but palliative radiotherapy for bone lesions is allowed), small molecule targeted therapy (including small molecule tyrosine kinase inhibitors), and modern traditional Chinese medicine preparations approved by NMPA for anti-tumor therapy; Major surgery (investigator-defined) within 4 weeks before the first dose; Systemic corticosteroids (> 10mg/ day of prednisone, or other corticosteroids equivalent) or immunosuppressive agents are required within 2 weeks before the study administration; Exceptions include inhaled or topical administration of steroids or physiological replacement doses of steroids for adrenal insufficiency; Pulmonary disease grade ≥3 according to NCI-CTCAE v5.0; Patients with existing or a history of interstitial lung disease (ILD); Have active infection requiring intravenous anti-infective therapy; Prior immunotherapy with grade ≥3 irAE or grade ≥2 immune-related myocarditis; Administration of live attenuated vaccine within 4 weeks before the first dose of study drug; Use of immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferon, etc., within 14 days before the first use of the study drug; Patients at risk for active autoimmune disease, or with a history of autoimmune disease, Including but not limited to Crohn's disease, ulcerative colitis, systemic lupus erythematosus, sarcoidosis, Wegener syndrome, autoimmune hepatitis, systemic sclerosis, Hashimoto's thyroiditis, autoimmune vasculitis, autoimmune neuropathy (Guillain-Barre syndrome), etc. Exceptions were type I diabetes, hypothyroidism that was stable with hormone-replacement therapy (including that due to autoimmune thyroid disease), psoriasis or vitiligo that did not require systemic therapy, and hypothyroidism that was stable with hormone-replacement therapy. Patients with other malignant tumors within 5 years before the first drug administration, except those who have been cured skin squamous cell carcinoma, basal cell carcinoma, superficial bladder cancer, prostate/cervix/breast cancer in situ and other researchers think can be enrolled; Human immunodeficiency virus antibody (HIV Ab) positive, active tuberculosis, active hepatitis B virus infection (HBsAg positive or HBcAb positive and HBV-DNA copy number > 500IU/ml) or hepatitis C virus infection (HCV antibody positive and HCV-RNA > central detection limit); Hypertension poorly controlled by medication (systolic blood pressure &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg); Has a history of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias or Ⅲ degree atrioventricular block requiring clinical intervention; prolonged QT interval at rest (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 cardiovascular and cerebrovascular events occurred within 6 months before the first dose; patients with New York Heart Association (NYHA) functional class ≥II heart failure; Previous history of allogeneic stem cell, bone marrow or organ transplantation; Patients with a history of allergy to recombinant humanized antibodies or to any of the excipients of SI-B001 or SI-B003; A history of autologous or allogeneic stem cell transplantation; Pregnant or lactating women; 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: Study treatment<br>Participants will receive treatment during the first cycle. Participants with clinical benefits received more cycles of additional therapy. Administration will be discontinued due to disease progression or occurrence of intolerable toxicity or other reasons. | Drug: SI-B001<br>* Administration by intravenous infusion<br>Drug: SI-B003<br>* Administration by intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib/II: 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 of SI-B001+SI-B003. | Up to approximately 24 months | 
| Phase Ib/II: 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 | 
| Phase Ib: Dose Limited Toxicity (DLT) | The incidence and severity of adverse events (TEAE) during treatment were graded according to the National Cancer Institute Standard for Common Terminology for Adverse Events (NCI-CTCAE, v5.0). | Up to approximately 24 months | 
| Phase Ib: Maximum Tolerated dose (MTD) or maximum administered dose (MAD) | In the dose increment stage, the highest dose whose estimated DLT rate is closest to the target DLT rate but does not exceed the upper bound of the equivalent interval of DLT rate is selected as MTD. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib/II: 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+SI-B003. The type, frequency and severity of TEAE will be evaluated during the treatment of SI-B001+SI-B003. | Up to approximately 24 months | 
| Phase Ib/II: 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 | 
| Phase Ib/II: 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 | 
| Phase Ib/II: Progression-free survival (PFS) | The PFS is defined as the time from the participant's first dose of SI-B001+SI-B003 to the first date of either disease progression or death, whichever occurs first. | Up to approximately 24 months | 
| Phase Ib/II: Cmax | Maximum serum concentration (Cmax) of SI-B001+SI-B003 will be investigated. | Up to approximately 24 months | 
| Phase Ib/II: Tmax | Time to maximum serum concentration (Tmax) of SI-B001+SI-B003 will be investigated. | Up to approximately 24 months | 
| Phase Ib/II: Ctrough | Ctrough is defined as the lowest serum concentration of SI-B001+SI-B003 prior to the next dose will be administered. | Up to approximately 24 months | 
| Phase Ib: T1/2 | Half-life (T1/2) of SI-B001+SI-B003 will be investigated. | Up to approximately 24 months | 
| Phase Ib: AUC0-t | AUC0-t is defined as area under the serum concentration-time curve from time 0 to the time of the last measurable concentration. | Up to approximately 24 months | 
| Phase Ib: CL | The serum clearance rate of SI-B001+SI-B003 per unit time will be investigated. | Up to approximately 24 months | 
| Phase Ib/II: Anti-drug antibody (ADA) | Frequency and titer of anti-SI-B001, SI-B003 antibody (ADA) will be evaluated. | Up to approximately 24 months | 
| Phase Ib/II: Neutralizing antibody (Nab) | Incidence and titer of Nab of SI-B001 and SI-B003 will be evaluated. | Up to approximately 24 months |