Recombinant Humanized Anti-CD47/PD-1 Bifunctional Antibody HX009 in Patients With Relapsed/Refractory Lymphoma

Study Overview
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Brief Summary
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This study is a multi-center, open, single-arm phase I/II clinical study to evaluate the recombinant humanized anti-CD47/PD-1 bifunctional antibody HX009 injection in Chinese patients with relapsed/refractory lymphoma .

Detailed Description
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The study is comprised of two parts: phase I is the dose escalation part, and phase II is the efficacy exploratory part and the efficacy confirmation part. Phase I dose escalation part: it is planned to recruit patients with relapsed/refractory lymphoma.Four dose groups : 7.5 mg/kg, 15 mg/kg, 22.5 mg/kg and 30 mg/kg ,will be explored according to the 3+3 principle. First, 3 subjects were enrolled. If no DLT occur during the DLT observation period, the next dose group test was conducted;if DLT occurs in 2 or more of the 3 patients in this group, the climbing will be terminated or a lower dose group shall be recommended by the Safety Review Committee ; if DLT occurs in only 1 of the 3 patients, add 3 patient, if 3 patients did not develop DLT, the dose is escalated to the next group; if DLT occurs in 1 or more of the three additional patients, the dose escalation will be terminated or the Safety Review Committee recommends a new lower dose group. Safety Review Committee will be based on the safety and tolerability of every dose group and PK(pharmacokinetics) and PD (pharmacodynamics) data, for the next dose increasing amplitude and dosing cycle are discussed, at the same time also will recommend whether to increase the dose of unplanned group or dosing method and dosing cycle of exploration group. phase II is the efficacy exploratory part and the efficacy confirmation part. : 5 cohorts will be carried out in parallel to initially evaluate the effectiveness of recombinant humanized anti-CD47/PD-1 bifunctional antibody HX009 injection. The 5 cohorts in the efficacy exploration part are: Cohort 1: Relapsed/refractory diffuse large B-cell lymphoma; Cohort 2: Relapsed/refractory peripheral T-cell lymphoma; Cohort 3: Relapsed/refractory classic Hodgkin's lymphoma; Cohort 4: Relapsed/refractory mantle cell lymphoma; Cohort 5: Relapsed/refractory follicular lymphoma and marginal zone lymphoma; In the efficacy exploration part, each cohort will enroll 15 subjects, a total of 5 cohorts, and 75 patients are expected to be enrolled. According to the analysis of the Safety Review Committee , the cohort with the efficacy enters the efficacy confirmation part, and the number of subjects in the efficacy confirmation part is re-estimated according to statistics; the cohort without the efficacy trend is enrolled up to 15 patients (according to the analysis of the Safety Review Committee , the group can be stopped midway). In the second phase of efficacy confirmation , one or two indications with better safety and efficacy among the 5 cohorts in the efficacy exploration part will be selected to further confirm the efficacy of recombinant humanized anti-CD47/PD-1 bifunctional antibody HX009 injection And safety.

Official Title
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To Evaluate the Multi-center, Open, Single-arm Phase I/II Clinical Study of Recombinant Humanized Anti-CD47/PD-1 Bifunctional Antibody HX009 Injection in Chinese Patients With Relapsed/Refractory Lymphoma

Conditions
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Relapsed/Refractory Lymphoma

Intervention / Treatment
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* Drug: Recombinant humanized anti-CD47/PD-1 bifunctional antibody HX009 injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Volunteer to participate in clinical research, fully understand and know the research and sign the informed consent (ICF), willing to follow and have the ability to complete all research procedures. Male or female,age at dose-escalation part is 18 to 65 years old; age at efficacy exploration and confirmation is 18 to70 years old . Lymphoma diagnosed according to the 2017 WHO classification criteria and meets the following recurrence and refractory definition. Subjects enrolled in the group must meet the following criteria (subjects in the dose escalation part are included in the following tumor types, but not limited to the following categories; the efficacy exploration and confirmation part will be based on the following tumor types) (1)Patients with relapsed/refractory diffuse large B-cell lymphoma: need to have received at least two standard regimens of systemic treatment; (2)Relapsed/refractory peripheral T-cell lymphoma (except for angioimmunoblastic T-cell lymphoma): need to have received at least two standard regimens of systemic treatment; among them, subjects with NK/T-cell lymphoma need to be treated in the past Have been treated with pegaspase or L-asparaginase; (3)Relapsed/refractory classic Hodgkin's lymphoma: need to have received at least two standard regimens of systemic treatment, one of which includes PD-1 monoclonal antibody, and progresses in the treatment with PD-1 regimen or PD-1 persists Complete remission has not been achieved after treatment for more than 12 months; (4)Relapsed/refractory mantle cell lymphoma: requires at least two standard regimens of systemic treatment, one of which includes a BTK inhibitor; (5)Relapsed/refractory follicular lymphoma and marginal zone lymphoma; systemic treatment of at least two standard regimens is required; The Eastern Cooperative Oncology Group (ECOG) stamina score of 0-2 points within 14 days before the first medication; Life expectancy ≥3months The main organs function well and meet the following standards : Blood system (1)The absolute value of neutrophils (ANC) ≥1.5×10^9 /L; patients with bone marrow invasion, ANC ≥1.0×10^9 /L; (2)The subject has not received platelet transfusion within 1 week, and platelets 75×10^9/L (without bone marrow invasion), platelets ≥50.0×10^9/L (with bone marrow or spleen invasion); (3)The subject has not received red blood cell transfusion within 4 weeks, (4)hemoglobin (HB) ≥90g/L; with bone marrow invaded, HB≥80 g/L; liver function Aspartate aminotransferase ≤2.0×ULN; Alanine aminotransferase ≤2.0×ULN; Total bilirubin≤1.5×ULN (except Gilbert syndrome); Kidney function Serum creatinine≤1.5×ULN; Coagulation function International normalized ratio (INR) ≤ 2 times ULN, or activated partial thromboplastin time (APTT) ≤ 1.5 times ULN; 7. If you have ever received anti-tumor therapy, you need to meet the following conditions: The interval between systemic radiotherapy and the first administration is ≥3 weeks, and the interval between local radiotherapy or radiotherapy for bone metastasis is ≥2 weeks; Past chemotherapy, immunotherapy (CAR-T therapy, etc.), biological therapy (tumor vaccine, cytokines or growth factors that control cancer), targeted therapy, antibody-conjugated drugs, and the interval between the first administration ≥ 4 weeks or 5 half-life (whichever is longer) (the interval between the first administration of mitomycin or nitrosourea chemotherapeutics is ≥6 weeks); The interval between the first administration of traditional Chinese medicine and Chinese patent medicine with obvious anti-tumor treatment was ≥1 week; 8.Within 4 weeks before the first medication, the investigator found at least one measurable or evaluable tumor lesion according to Lugano criteria; measurable lesions: the longest diameter of the lymph node is ≥15 mm, and the lesions in other parts are ≥10 mm; a lesion that has previously received local treatment such as radiotherapy is considered a measurable lesion if it has been proven that the disease has progressed and meets the definition of a measurable lesion; 9.The female subjects' serum/urine pregnancy test within 2 weeks before the first administration of the drug must be negative; female subjects or male subjects whose spouse is of childbearing age need to agree from the signing of the informed consent form to after the last administration of the study drug Use contraceptive measures (such as oral contraceptives, intrauterine contraceptives, sexual desire control or barrier contraception combined with spermicide) for at least 12 months, and do not breastfeed . Exclusion Criteria: Those suffering from other malignant tumors within 5 years before enrollment, except for cured cervical carcinoma in situ, cured basal cell carcinoma of the skin, and squamous cell carcinoma of the skin; The adverse reactions of previous treatments failed to recover to CTCAE 5.0 grade score ≤1, except for residual hair loss effects; Active peptic ulcer, incomplete intestinal obstruction, active gastrointestinal bleeding and perforation; Known history of hereditary or acquired hemolytic or bleeding disorders; Subjects with primary or secondary central nervous system (CNS) lymphoma, or symptomatic CNS injury, or spinal cord compression, or cancerous meningitis; Pleural effusion, abdominal effusion or pericardial effusion with clinical symptoms; Those who have received blood transfusion therapy within 4 weeks before treatment or hematopoietic stimulating factor therapy, such as colony stimulating factor, erythropoietin, thrombopoietin, etc.; Active, or history of, autoimmune disease (within the past 2 years) that may recur (eg, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, autoimmune thyroid disease, multiple sclerosis, vasculitis, glomerulitis, 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 disease that does not require treatment such as eczema, rash that accounts for <10% of the body surface, psoriasis without ophthalmological symptoms (mainly manifested as dry eye, blepharitis, conjunctivitis, eyeball adhesion, keratitis and uveitis); 9.It is expected that there will be major surgeries during the 28 days screening period during the study period (except for diagnostic surgeries) 10.Subjects who need to receive systemic corticosteroids (dose equivalent to >10 mg prednisone/day) or other immunosuppressive drugs within 14 days before the first dose or during the study period; the following conditions are allowed to be included: Subjects use topical or inhaled glucocorticoids; Short-term (≤7 days) use of glucocorticoids to prevent or treat non-autoimmune allergic diseases; 11.Currently suffering from acute lung disease, interstitial lung disease, interstitial pneumonia, pulmonary fibrosis, radiation pneumonia that requires hormone therapy, etc.; 12.Uncontrolled systemic diseases after treatment, such as cardiovascular disease (unstable angina or myocardial infarction within 6 months, etc.), diabetes, hypertension, etc.; 13.Arterial or venous thrombosis or embolic events occurred within 3 months before the first administration, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis or pulmonary embolism; 14.Human immunodeficiency virus antibody positive or suffering from other acquired or congenital immunodeficiency diseases, history of organ transplantation or allogeneic stem cell transplantation; 15.Subject with a history of tuberculosis (without complete anti-tuberculosis treatment), or active tuberculosis at the time of screening; 16.Subjects with active chronic hepatitis B or active hepatitis C. Except for hepatitis B virus carriers, stable hepatitis B after drug treatment (DNA titer not higher than 500 IU/mL or copy number <1000 copies/mL) and cured hepatitis C subjects (HCV RNA test negative); 17.Those who have had a serious infection within 4 weeks before the first administration, or have an active infection within 2 weeks before the first administration of the drug and require oral or intravenous antibiotic treatment; 18.People who are known to have had severe allergic reactions to macromolecular protein preparations/monoclonal antibodies, or to any test drug component (CTCAE 5.0 grade >3); 19.Participated in other drug clinical trials within 4 weeks before the first administration; 20.Alcohol dependent or have a history of drug abuse or drug abuse within the past year; 21.Have a clear history of neurological or mental disorders, such as epilepsy, dementia, or poor compliance; 22.Women who are pregnant or breastfeeding; 23.Those who have received the new crown vaccine within one month before the first administration; 24.The researcher believes that the subjects who are not suitable for participating in this trial due to other reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: phase I dose escalation part,Phase II efficacy exploratory part and the efficacy confirmation part<br>In the phase I dose escalation part,with a standard 3+3 dose escalation design, the enrollment will proceed until the MTD has been defined or the highest dose level has been reached. 5 cohorts will be carried out in parallel in the phase II efficacy exploration part: Cohort 1: Relapsed/refractory diffuse large B-cell lymphoma; Cohort 2: Relapsed/refractory peripheral T-cell lymphoma; Cohort 3: Relapsed/refractory classic Hodgkin's lymphoma; Cohort 4: Relapsed/refractory mantle cell lymphoma; Cohort 5: Relapsed/refractory follicular lymphoma and marginal zone lymphoma; In the efficacy exploration part, each cohort will enroll 15 subjects, a total of 5 cohorts, and 75 cases are expected to be enrolled. In the phase II efficacy confirmation part, one or two indications with better safety and efficacy among the 5 cohorts in the efficacy exploration phase will be selected. | Drug: Recombinant humanized anti-CD47/PD-1 bifunctional antibody HX009 injection<br>* In the phase I dose escalation part:it is planned to recruit patients with relapsed/refractory advanced lymphoma, and 4 doses will be explored: 7.5mg/kg, 15mg/kg, 22.5mg/kg and 30mg/kg dose groups. once every two weeks (Q2W), every 14 days is a dosing cycle. Recommend Phase II dose based on the results of Phase I dose escalation part.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events in HX009 treatment of patients with relapsed/refractory lymphoma | Adverse events (AEs) determined by the investigator are recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0). | All AEs up to 28 days after the last dose of study drug,Or other tumor treatment programs have been started (the earlier date shall prevail); irAE should be followed up to 90 days after the last dose, or other tumor treatment programs have been started | 
| Objective response rate(ORR) of patients with solid tumors treated with HX009 per Investigator Assessment | Objective response rate (ORR) assessed according to the evaluation criteria of each tumor type | Tumor assessment every 6 weeks (±7 days)，up to 1 year | 
| Severity of adverse events in HX009 treatment of patients with relapsed/refractory lymphoma | Adverse events (AEs) determined by the investigator are recorded and graded according to the Common Terminology Criteria for Adverse Events (CTCAE - Version 5.0). | All AEs up to 28 days after the last dose of study drug,Or other tumor treatment programs have been started (the earlier date shall prevail); irAE should be followed up to 90 days after the last dose, or other tumor treatment programs have been started | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 6 months and 12 months progression-free survival (PFS ) | PFS is defined as the time from the start of the first dose and the first documented disease progression using RECIST 1.1 criteria or death of any cause. | Approximately 1 year | 
| Duration of Remission (DOR) | 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. | Tumor assessment every 6 weeks (±7 days),up to 1year | 
| Disease Control Rate (DCR) | The DCR is defined as the percentage of participants in the analysis population who had a confirmed Complete Response, or Partial Response, or Stable Disease using RECIST 1.1 criteria. | Tumor assessment every 6 weeks (±7 days),up to 1 year | 
| Time to peak plasma concentration (Tmax) of HX009 in patients with relapsed/refractory lymphoma | Key pharmacokinetic parameter | Approximately 1 year | 
| Peak plasma concentration (Cmax) of HX009 in patients with relapsed/refractory lymphoma | Key pharmacokinetic parameter | Approximately 1 year | 
| Elimination half-life (t1/2β) of HX009 in patients with relapsed/refractory lymphoma | Key pharmacokinetic parameter | Approximately 1 year | 
| Area under the concentration-time curve (AUC0-t) of HX009 in patients with relapsed/refractory lymphoma | Key pharmacokinetic parameter | Approximately 1 year | 
| Number of patients having detectable anti-drug antibody (ADA) of HX009 | Detection of ADA is a measure of immunogenicity of HX009 | Approximately 1 year | 
| Number of patients having detectable neutralizing antibody (Nab) of HX009 | Detection of Nab is a measure of immunogenicity of HX009 | Approximately 1 year |