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Gentulizumab administered IV once a week and a dosing cycle is 4 weeks

Gentulizumab will be administered by intravenous infusion once a week, with every 28 days as a dosing cycle .

Gentulizumab

Cheng Hou, Doctor

Huagang Li, bachelor

Junmin Li, Doctor

Gentulizumab Injection is an anti-CD47 monoclonal antibody. As a member of the immunoglobulin superfamily, CD47 is expressed at low levels on many cells of the body, including hematopoietic cells (red blood cells, lymphocytes, platelets, etc.) and non-hematopoietic cells (placenta, liver and brain cells). It is overexpressed on many types of tumors. There is abundant supportive evidence that the expression of CD47 on tumor cells, though binding to SIRP on professional phagocytes, acts to prevent tumor cell phagocytosis, inhibit antigen cross-presentation, and block the production of pro-inflammatory molecules, thus promoting the development of a "cold" tumor microenvironment. Blocking CD47 can not only stimulate phagocytosis to cancer cells, but also promote macrophage recruitment towards neoplasm. At the same time, blocking CD47 can stimulate macrophages to secrete cytokines. These cytokines and chemokines can further recruit other immune cells to neoplasms. These newly recruited immune cells can provide a positive feedback and enhance the therapeutic response of blocking CD47. Therefore, the CD47/SIRPα axis blocking appears to be a potential therapeutic target for neoplasm.

Currently, no anti-CD47 antibody product has been granted marketing authorization for progressive hematological malignancies. Whereas Hu5F9-G4, a CD47 monoclonal antibody, is being tested in a series of ongoing clinical trials for AML, MDS, lymphomas and multiple solid tumors. The clinical research was designed based on non-clinical data and relevant experience of other CD47 monoclonal antibody.

In this phase Ia study, "3 + 3" dose escalation method combined with rapid titration will be used to evaluate the dose limiting (DLT) toxicity of each dose group, evaluate the safety and tolerance of Gentulizumab in the treatment of patients with progressive hematological malignancies, and determine the maximum tolerated dose (MTD) and phase II recommended dose (RP2D); At the same time, the pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, preliminary efficacy and biomarkers of gentulizumab will be evaluated to provide sufficient basis for new drug application (NDA) guidance and further clinical use.

Gentulizumab, developed by GeneScience Pharmaceuticals Co., Ltd. has completed all non clinical related studies. The company applied for clinical trial in June 2020 (acceptance No.: CXSL2000164), and obtained the notice of approval of drug clinical trial (Notice No.: 2020LP00360) approved by National Medical Products Administration on September 3, 2020 to carry out clinical trial for hematological malignancies.

PD: Gentulizumab demonstrated the anticipated PD effects in corresponding tumor models in vitro and in vivo.

PK: The observed PK characteristics are consistent with other monoclonal antibodies.

Toxicology: In the toxicity test in cynomolgus monkeys after single-dosing and repeated dosing, reversible changes in erythroid indexes related to pharmacological action were observed. The MTD was 450 mg/kg and the NOAEL for repeat dosing was 300 mg/kg.

Safety Window: Based on results from the GLP-compliant 4-week repeat-dose toxicology study with 6-week recovery in cynomolgus monkeys (QW 5, i.v., 30, 100 or 300 mg/kg with a priming dose of 10 mg/kg), gentulizumab-related transient changes were noted in hematology, coagulation and clinical chemistry parameters and the NOAEL was determined to be 10+300 mg/kg. The human equivalent dose (HED) is 10+300 mg/kg converted based on body weight. The maximum recommended starting dose (MRSD) is considered to be 1.67+50 mg/kg (1/6 of HED of NOAEL) for advanced cancer treatment. The proposed human starting dose (0.1 mg/kg) provides a substantial safety margin, which is 16.7-500-fold lower than the MRSD and 100-3000-fold lower than the HED of NOAEL.

The trial is divided into 3 parts: priming dose exploration, therapeutic dose exploration and phase II recommended dose (RP2D) exploration.

The first part, priming dose exploration. In this part, 5 dose levels are planned. "3 + 3" dose escalation method combined with rapid titration will be adopted. Thirteen to Thirty subjects will be enrolled. The investigational drug is administered IV once a week and a dosing cycle is 4 weeks.

The study process of first three dose levels (0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg) of part one is shown below: screening period (4 weeks), observation period for dose limiting toxicity (4 weeks), continuous dosing period (once a week, until the discontinuation criteria are met), safety follow-up period after discontinuation (28 days after the last administration) and progression free survival follow-up period after discontinuation (once every 12 weeks until the survival follow-up endpoint). The study process of the last two dose levels (1 mg/kg, 3 mg/kg) is shown below: screening period (4 weeks), observation period for dose limiting toxicity (5 weeks including 1 week of single priming dose), continuous dosing period (once a week, until the discontinuation criteria are met), safety follow-up period after discontinuation (28 days after the last administration) and progression free survival follow-up period after discontinuation (once every 12 weeks until the survival follow-up endpoint).

Connection between part one and two.

Investigator and sponsor determine the optimal priming dose of part two together based on data from part one. The categories of data include:

1. The degree of abnormalities of the peripheral erythrocyte, white blood cell and platelet count.
2. Whether is there a compensatory increase in reticulocytes.
3. PD indicators (RO of red blood cells, white blood cells, platelets and tumor cells) If the conclusion of part one is "priming dose required", optimal priming dose will be determined and the dosing module of part two will be single optimal priming dose plus therapeutic dose escalation.

If the conclusion of part one is "priming dose not required", the dosing module of part two will be therapeutic dose escalation.

The second part, therapeutic dose exploration. The second part will be divided into 3 therapeutic dose levels (10 mg/kg, 30 mg/kg, 45 mg/kg). "3 + 3" dose escalation method will be adopted.

The number of subjects enrolled is 9-18. The investigational drug is administered IV once a week and a dosing cycle is 4 weeks.

The third part, exploration of RP2D As MTD is discovered during the second part, 6-10 subjects will be further enrolled at MTD level. More data of safety and tolerance will be acquired and used for the calculation of RP2D. The study process and administration method are the same as those in the second part.

Statistical analysis datasets Full analysis set (FAS): Based on the principle of intention-to-treat, all the subjects who are successfully enrolled and have at least one treatment record will be included in the full analysis set of this trial. The following situations may cause the enrolled subjects to be excluded from the FAS set: for example, they do not meet the primary inclusion criteria, they do not take the investigational drug once, they do not have any data after enrollment, etc. Demographic data, baseline data and efficacy indicator will be statistically analyzed based on FAS.

Safety analysis set (SS): include all the subjects who receive at least one treatment and have safety evaluation data after treatment. The safety population was primarily used for the analysis of safety data.

Pharmacokinetic data set (PKS): All subjects who were enrolled in the PKS and received at least one dose of the investigational drug and had PK evaluation data after administration constituted the PK analysis set of this study. In the PK analysis set, different PK parameters may include different numbers of subjects depending on the actual situation of trial completion.

Part one, priming dose exploration: 5 dose levels (0.03 mg/kg, 0.1 mg/kg, 0.3 mg/kg, 1 mg/kg, 3 mg/kg) Part two, therapeutic dose exploration: 3 dose levels (10 mg/kg,30 mg/kg,45 mg/kg)

Gentulizumab in Relapsed/Refractory Acute Myelogenous Leukemia or Myelodysplastic Syndrome

A Phase Ia, Open-label, Dose Escalation Study of Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of Gentulizumab in Patients With Relapsed/Refractory Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Adverse events (AEs) refer to all adverse medical events occurred in subjects after the informed consent was signed, which may represent symptoms, signs, diseases, or laboratory examination abnormalities, but do not necessarily have a causal relationship with the investigational drug.

1. An SAE refers to any adverse medical event that meets any of the following criteria:
2. Results in death
3. Life-threatening: "Life-threatening" refers to an immediate risk of death for a severely ill patient and does not refer to the assumption that death may occur if it were to become severe in the future.
4. Event resulting in hospitalization or prolongation of hospitalization.
5. Event that results in significant or permanent disability/dysfunction. Disability refers to substantial disruption of a person's ability to perform normal activities of daily living.
6. Results in a congenital anomaly or birth defect.
7. Other important medical events: Events that may not immediately result in death, be life-threatening, or result in hospitalization/prolongation of hospitalization. However, based on medical judgment, these events may cause injuries to the subject or may require medical intervention to prevent any of the said circumstances from occurrence.

Multiple dosing pharmacokinetic (PK) parameters

Receptor occupancy (RO) of gentulizumab of red blood cells, white blood cells, platelets and neoplastic cells in peripheral blood

Ruijin Hospital

Shanghai Tong Ren Hospital

First Affiliated Hospital of Zhejiang University

Changchun GeneScience Pharmaceutical Co., Ltd.

Immune System Diseases

Lymphoma

Lymphoma, Non-Hodgkin

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphosarcoma

All Drugs and Chemicals

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Gentulizumab monotherapy 0.1, 0.3, 1, 3, 10, 30, 45 mg/kg administered intravenously once every week.

Gentulizumab is administered IV once a week, with every 4 weeks as an administration cycle.

Jian Zhang, Doctor

The purpose of this study is to assess the safety and tolerability of gentulizumab, an anti-CD47 Monoclonal Antibody, in participants with solid tumors and non-Hodgkin lymphoma.

This is a first-in-human, escalating dose trial of an antibody that inhibits an anti-apoptotic signal in human macrophages. The major aims of the study are to define the safety profile of this new drug, and to determine a recommended dose and schedule for potential additional trials.

Gentulizumab in Patients With Advanced Solid Malignancies and Non-Hodgkin Lymphoma

A Phase Ia, Open-label, Dose Escalation Study of Safety, Tolerability, Pharmacokinetics of Gentulizumab, an Anti-CD47 Monoclonal Antibody, in Patients With Advanced Solid Malignancies and Non-Hodgkin Lymphoma (NHL)

ORR was defined as the percentage of participants who had complete response (CR) or partial response (PR) per RECIST v1.1 by investigator determination.

PFS was defined as the time ranging from the beginning of enrollment to the tumor progression for the first time or death.

The CTCAE criteria will be used to assess adverse events on this trial.

PD parameters include: receptor occupancy (RO) of gentulizumab of red blood cells, and white blood cells in peripheral blood.

Numbers of anti-drug antibody (ADA) and/or neutralizing antibody (NAb) positive participants will be used to assess the immunogenicity of gentulizumab.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Gentulizumab in Relapsed/Refractory Acute Myelogenous Leukemia or Myelodysplastic Syndrome	NCT05263271	Acute Myelogeno... Myelodysplastic...	Gentulizumab	18 Years - 75 Years	Changchun GeneScience Pharmaceutical Co., Ltd.
Gentulizumab in Patients With Advanced Solid Malignancies and Non-Hodgkin Lymphoma	NCT05221385	Solid Tumor Non-Hodgkin Lym...	Gentulizumab	18 Years - 70 Years	Changchun GeneScience Pharmaceutical Co., Ltd.

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