Clinical Study of SI-B001+SI-B003± Chemotherapy in Patients With Locally Advanced or Metastatic Head and Neck Squamous Cell Carcinoma

Study Overview
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Brief Summary
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Phase Ib: To observe the safety and tolerability of SI-B001+SI-B003 in combination and to identify RP2D in locally advanced or metastatic head and neck squamous cell carcinoma indications. Initial efficacy, pharmacokinetic characteristics and immunogenicity were evaluated. Phase II: To evaluate the efficacy of SI-B001+SI-B003 two-drug combination chemotherapy. Safety and tolerance, PK/PD, immunogenicity were evaluated.

Detailed Description
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Phase Ib: To observe the safety and tolerability of SI-B001+SI-B003 combination and to determine the recommended dose (RP2D) for Phase II clinical studies in locally advanced or metastatic head and neck squamous cell carcinoma indications. To evaluate the initial efficacy, pharmacokinetic characteristics and immunogenicity of SI-B001+SI-B003 in patients with locally advanced or metastatic head and neck squamous cell carcinoma. Phase II: To evaluate the efficacy of SI-B001+SI-B003 dual-agent chemotherapy in patients with locally advanced or metastatic head and neck squamous cell carcinoma. The safety, tolerability, PK/PD and immunogenicity of SI-B001+SI-B003 combined chemotherapy in patients with locally advanced or metastatic head and neck squamous cell carcinoma were evaluated.

Official Title
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Phase Ib/II Clinical Study of SI-B001+SI-B003 Dual-drug No-combination or Combined Chemotherapy in Patients With Locally Advanced or Metastatic Head and Neck Squamous Cell Carcinoma

Conditions
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Squamous Cell Carcinoma of Head and Neck

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: Sign the informed consent voluntarily and follow the requirements of the scheme. No gender Limitation. Age ≥18 years and ≤75 years. Expected survival time ≥3 months. Histologically or cytologically confirmed head and neck squamous cell carcinoma (HNSCC) occurring only in the mouth, oropharynx, hypopharynx, and larynx; Stage Ib: patients with locally advanced or metastatic HNSCC who have failed standard therapy or are intolerant; Stage II: Patients with locally advanced or metastatic HNSCC without local radical therapy Pointers and without systemic therapy. Agrees to provide archived tumor tissue specimens or fresh tissue samples from primary or metastatic sites; Phase Ib: If a subject is unable to provide a tumor tissue sample, he/she may be enrolled after evaluation by the investigator if other admission criteria are met; Phase II: PD-L1 CPS test report of tumor tissue samples should be provided; If there is no relevant examination report, agree to submit archived tumor tissue samples or fresh tissue samples (FFPE blocks or about 6-12 5μm white sheets) from the primary or metastatic sites within 2 years for PD-L1 CPS testing. There must be at least one measurable lesion that meets the RECIST v1.1 definition. Score requirements for physical condition: ECOG≤1 score. The toxicity of previous antitumor therapy has returned to ≤1 as defined by NCI-CTCAE v5.0. (The investigators considered asymptomatic laboratory abnormalities such as elevated ALP, hyperuricemia, serum amylase/lipase, and elevated blood glucose, as well as toxicity that the investigators judged to be of no safety risk, Such as hair loss, grade 2 peripheral neurotoxicity, stable hypothyroidism with hormone replacement therapy, etc.). No serious cardiac abnormality, left ventricular ejection fraction ≥50%. The organ function level must meet the following requirements and meet the following criteria: a) bone marrow function: neutrophil absolute value (ANC) ≥1.5×109/L, platelet count ≥100×109/L, hemoglobin ≥90 g/L; b) Liver function: total bilirubin TBIL≤1.5×ULN (total bilirubin ≤3×ULN in subjects with Gilbert's syndrome, liver cancer or liver metastasis), AST and ALT ≤3×ULN in subjects without liver metastasis, AST and ALT ≤5.0×ULN in subjects with liver metastasis; c) Kidney 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 thrombin time (APTT) ≤1.5×ULN. Urine protein ≤1+ or ≤1000mg/24h. Fertile female subjects or fertile male subjects with partners must use highly effective birth control from 7 days before initial dosing until 24 weeks after dosing. Fertile female subjects must have a negative serum pregnancy test within 7 days prior to initial dosing. Exclusion Criteria: The primary site is nasopharynx, salivary glands, sinuses, skin, or squamous cell carcinoma with unknown primary site. Phase II patients could not be included in this study under any of the following conditions: c) Patients suitable for local treatment and willing for local treatment; d) Have received systematic chemotherapy, but not chemotherapy for locally advanced disease as part of multimodal therapy (this treatment must have ended more than 6 months after the initial trial; The above chemotherapy includes induction chemotherapy, concurrent chemoradiotherapy and adjuvant chemotherapy). Patients with clinical symptoms of brain parenchymal metastases or meningeal metastases were not considered suitable for inclusion. Participants who participated in any other clinical trial within 4 weeks prior to administration of this trial (based on the time of last administration). Received chemotherapy, radiotherapy (small area radiotherapy for bone pain patients with bone metastases is within 2 weeks before the first use of the study drug), biological therapy, endocrine therapy, immunotherapy and other antitumor treatments within 4 weeks before the first use of the study drug, except the following: a) Oral fluorouracil and small-molecule targeted drugs within 2 weeks prior to the first use of the study drug or within 5 half-lives of the drug, whichever is longer; b) Traditional Chinese medicines with anti-tumor indications should be used within 2 weeks before the first use of study drugs. Major surgery within 4 weeks prior to initial dosing (as defined by the investigator). Systemic corticosteroids (> 10mg/ day prednisone, or equivalent corticosteroids) or immunosuppressant therapy were required within 2 weeks prior to administration. The exception is inhaled or topical use of hormones, or physiological replacement dose of hormone therapy due to adrenal insufficiency. According to NCI-CTCAE v5.0, it was defined as ≥ grade 3 pulmonary disease. Patients with present or history of interstitial lung disease (ILD). Has an active infection that requires intravenous anti-infective therapy. Had received immunotherapy and developed grade 3 irAE or grade 2 immune-associated myocarditis. Live attenuated vaccine was administered within 4 weeks prior to the first administration of the study drug. Use of immunomodulatory drugs, including but not limited to thymosin, interleukin-2, interferon, etc. within 14 days prior to the first use of the study drug. Patients who are at risk for active autoimmune disease, or have 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 include type I diabetes, hypothyroidism with stable hormone replacement therapy (including hypothyroidism caused by autoimmune thyroid disease), and psoriasis or vitiligo that do not require systemic therapy. Patients with other malignancies within 5 years prior to the first administration of the drug, except for cured skin squamous cell carcinoma, basal cell carcinoma, superficial bladder carcinoma, and carcinoma in situ of the prostate/cervix/breast that the researchers considered acceptable for inclusion. Human immunodeficiency virus antibody (HIVAb) positive, active tuberculosis, active hepatitis B virus infection (HBsAg positive or HBcAb positive with HBV-DNA copy number > 500IU/ml) or hepatitis C virus infection (HCV antibody positive with HCV-RNA > lower limit of central detection). Poorly controlled hypertension (systolic blood pressure &gt; 150 mmHg or diastolic blood pressure &gt; 100 mmHg). a history of severe cardiovascular and cerebrovascular diseases, including but not limited to: a) severe cardiac rhythm or conduction abnormalities, such as ventricular arrhythmias requiring clinical intervention, degree III atrioventricular block, etc.; b) Prolonged QT interval at rest (QTc > 450 msec in men or 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 prior to initial administration; c) Heart failure with the New York Heart Association (NYHA) heart function Grade ≥II. History of allogeneic stem cell, bone marrow, or organ transplantation. Patients with a history of allergy to recombinant humanized antibodies or to any excipient component of SI-B001 or SI-B003. History of autologous or allogeneic stem cell transplantation. A pregnant or nursing woman. Other conditions included in this clinical trial were not considered appropriate.

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: 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: 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 | 
| Phase 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 | 

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: T1/2 | Half-life (T1/2) of SI-B001+SI-B003 will be investigated. | Up to approximately 24 months | 
| Phase Ib/II: AUC0-t | Blood concentration - Area under time line. | Up to approximately 24 months | 
| Phase Ib/II: CL | To study the serum clearance rate of SI-B001+SI-B003 per unit time. | 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/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 |