Study on the Tolerability and Pharmacokinetics of HX009 in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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This is an open, multi-dose administration dose exploratory clinical phase I study to evaluate the safety, tolerability, and PK characteristics of HX009 injection in patients with advanced solid tumors and to initially measure its antitumor efficacy.

Detailed Description
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The study will follow a 3+3 dose-escalation scheme enrolling cohorts of at least 3 subjects sequentially at escalating doses. During study treatment, subjects will receive HX009 treatment via intravenous infusion once every 2 weeks. Dose escalation will continue until identification of an MTD or the maximum dose is reached. Dose-limiting toxicities (DLTs) will be assessed from the first dose of study treatment until 28 days . The study is divided into a screening period (28 days before first dose), treatment period , and survival follow-up period. Safety will be evaluated throughout the study up until at least 28 days after the last dose of study treatment. Blood samples will be collected at regular intervals for pharmacokinetics (PK) and immunogenicity evaluation. Tumor evaluation (assessed by the Investigator in accordance with Response Evaluation Criteria in Solid Tumors Version 1.1 [RECIST 1.1] and immune RECIST [iRECIST]) to assess efficacy will start from the first dose and occur every 8 weeks in the first 24 weeks and every 12 weeks thereafter.

Official Title
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Phase I Clinical Trial of Tolerability and Pharmacokinetics of HX009 in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: HX009


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects are eligible to be included in the study only if all of following criteria apply: Voluntarily agree to sign informed consent, understand the study and is willing and able to comply with all the trial procedures. Male or female subject aged 18-70 years (including the boundary value). Eastern Cooperative Oncology Group performance status of 0 to 1. Patients with cytologically or histopathological confirmed advanced malignant solid tumors that is refractory/relapsed to standard therapy (with disease progression or intolerance) or lack of effective treatment, or the subject refuses standard therapy. At least one extracranial lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) for response assessment, including measurable and non-measurable lesions. The number of subjects with all non-measurable lesions should be no more than 1/3 of the total enrolled subjects. Life expectancy ≥ 12 weeks, per investigator's discretion. For subjects who have received prior anti-tumor therapy, as follows: Systemic radiotherapy ≥ 3 weeks before the first dose, local radiotherapy to bone metastasis ≥ 2 weeks prior to the first administration of study treatment. Previous chemotherapy, immunotherapy (PD-1 antibody, PD-L1 antibody or CTLA-4 antibody, etc.), biological anti-tumor therapy (tumor vaccine, cytokines or growth factors), and targeted therapy ≥ 4 weeks before the first dose (small molecule targeted therapy ≥ 2 weeks prior to the first dose). Received previous immunotherapy, such as PD-1 antibody, PD-L1 antibody or CTLA-4 antibody, etc. Subjects never experienced a toxicity leading to permanent discontinuation of prior immunotherapy. Previously received anti-tumor herbal medicine or medications which content herbal ingredient approved for anticancer, with an interval of ≥ 2 weeks prior to the first dose. Patients with asymptomatic central nervous system (CNS) metastasis or asymptomatic brain metastasis after treatment, free of disease progression by computed tomography (CT) or magnetic resonance imaging (MRI) scan and be stable for at least 4 weeks without steroid therapy. Adequate organ and bone marrow hematopoietic function, as evidenced by: Absolute neutrophil count (ANC) ≥ 1.5 × 109/L. Absolute white blood cell count (WBC) ≥ 3.0 × 109/L. Platelet count ≥ 100 × 109/L. Hemoglobin ≥ 100 g/L (no blood transfusion within 2 weeks prior to signing informed consent). Serum creatinine ≤ 1.5 x upper limit of normal (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN (ALT and AST ≤5 × ULN for subjects with liver metastases). Serum total bilirubin (TBIL) ≤ 1.5 x ULN. International normalized ratio (INR) ≤ 2 x ULN or activated partial thromboplastin time (APTT) ≤ 1.5 x ULN (except for patients receiving anticoagulant therapy). Men with reproductive capacity or women with the possibility of pregnancy must use highly effective contraceptive methods (such as oral contraceptives, intrauterine contraceptive devices, abstinence or barrier contraception combined with spermicide) during the trial, and continue contraception for 12 months after the end of treatment. Voluntarily agrees to participate by signing written informed consent and is willing and able to comply with protocol and scheduled visits. Exclusion Criteria: Subjects are excluded from the study if any of the following criteria apply: Patients with other malignant tumors within 5 years before enrollment, except cured cervical carcinoma in situ and cured cutaneous basal cell carcinoma. Failure to recover from previously treated adverse reactions to CTCAE 5.0 grade ≤ 1, except for residual alopecia effects. Active, or history of, autoimmune diseases that may recur (eg, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulonephritis, etc.), or are at high risk (eg, receiving an immunosuppressive treatment for an organ transplant). however, subjects with the following are allowed to enroll: Type I diabetes that is stable after a fixed dose of insulin. Only requiring hormone replacement therapy for autoimmune hypothyroidism. Skin diseases not requiring systemic treatment (such as eczema, rash accounting for less than 10% of body surface, psoriasis without ophthalmic symptoms, etc.). Planning major surgery during the study, the 28-day screening period included. Requiring systemic corticosteroids (dose equivalent to >10 mg prednisone/day) or other immunosuppressive drugs within 14 days before the first dose of study treatment or during the study. The following are allowed: Use of topical or inhaled glucocorticoids A brief course of corticosteroids (≤7 days) for prophylaxis or for treatment of non-autoimmune conditions. Currently suffering from acute lung disorders, interstitial lung disease, interstitial pneumonia, pulmonary fibrosis, radiation pneumonitis, etc. Uncontrolled systematic diseases and stable after treatment, such as cardiovascular disorders (unstable angina pectoris or myocardial infarction 6 months prior to the first dose, etc.) diabetes, hypertension, etc. Arterial or venous thrombotic or embolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis or pulmonary embolism within 6 months prior to first dose. History of infection with human immunodeficiency virus, or other acquired, congenital immunodeficiency diseases, or history of organ transplantation, or history of stem cell transplantation. Patients with a history of pulmonary tuberculosis or pulmonary tuberculosis at screening. Patients with active chronic hepatitis B or active hepatitis C. Hepatitis B virus carriers, patients with stable hepatitis B after drug treatment (DNA titer should not be higher than 500 IU/mL or copy number < 1000 copies/ml) and cured hepatitis C patients (HCV RNA test negative) can be enrolled. Severe infections within 4 weeks before the first dose of study treatment, or active infections within 2 weeks before the first dose that require oral or intravenous antibiotics. Subjects with known previously serious allergic reactions to macromolecular protein preparations/monoclonal antibodies, or to any component of the investigational product (CTCAE 5.0 ≥ grade). Participation in other drug clinical trials within 4 weeks prior to the first dose. Alcohol dependence or history of drug abuse or drug abuse within the past 1 year. Patients with a clear history of neurological or psychiatric disorders, such as epilepsy, dementia, and poor compliance. Female subject who is pregnant or lactating. Patients with uncontrolled pleural effusion, abdominal effusion, or pericardial effusion. Received hematopoietic stimulating factors, such as colony stimulating factor and erythropoietin within 2 weeks before the first dose of study treatment. Subjects who, per the opinion of the investigator, are not suitable for participation in this trial for other reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: HX009<br>Study treatment: HX009 administered every 2 weeks (14 [±3] days) via intravenous infusion. | Drug: HX009<br>* The subjects will receive HX009 treatment via IV infusion once every 2 weeks at different dose escalation cohorts<br>* Other names: Recombinant humanized anti-CD47/PD-1 bifunctional antibody;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AE) of HX009 in patients with advanced solid tumors | Adverse events (AEs) determined by the investigator are recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0). | Collected adverse events from signing of informed consent through at least 28 days after the end of treatment, or until other cancer treatment regimens have been started (whichever occurs earlier). | 
| Incidence of Dose Limiting Toxicities (DLT) in HX009 in patients with advanced solid tumors | Incidence of Dose Limiting Toxicities (DLT) that would result in stopping dosing | At the end of Cycle 2 (each cycle is 14 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum plasma concentration of drug (Cmax) | Highest concentration of drug measured in the PK samples | At Cycle 1 ,Cycle 6 and Cycles 2 -5 (each cycle is 14 days) | 
| Pharmacokinetics (PK): Time to reach Cmax (Tmax) | Time from dosing until collection of the PK samples with the highest drug concentration. | At Cycle 1 ,Cycle 6 and Cycles 2 -5(each cycle is 14 days) | 
| Terminal Half-life （t½）of HX009 | Terminal phase elimination half-life | At Cycle 1 ,Cycle 6 and Cycles 2 -5 (each cycle is 14 days) | 
| Area Under the Serum Concentration-time Curve (AUC) | The area under the serum concentration-time curve . | At Cycle 1 ,Cycle 6 and Cycles 2 -5 (each cycle is 14 days) | 
| Number of Participants With Positive Anti-Drug Antibody (ADA) of HX009 | ADA blood samples were assayed for anti-HX009 antibodies. | At Cycles 1-6, 9, 13, 17, and then every 8 cycles up to approximately 1 years: within 1 hour before infusion (each cycle is 14 days). | 
| Objective response rate (ORR) of HX009 in patients with solid tumors | The ORR is defined as the percentage of participants in the analysis population who had a confirmed Complete Response or Partial Response. | Approximately 1 years | 
| Duration of response (DoR) of HX009 in patients with solid tumors | The DoR is defined as the time from the first recorded response (CR or PR) to the first recorded tumor progression or death due to any cause. | Approximately 1 years | 
| Progression-free survival (PFS) of patients with solid tumors treated with HX009 | The PFS is defined as the time from the start of the first dose to the first documented disease progression or death of any cause. | Approximately 1 years |