Gentulizumab in Relapsed/Refractory Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Myelodysplastic Syndromes Clinical Trial

Official title: 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

Status Recruiting

Clinical Trial Summary

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.

Clinical Trial Description

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. ;

Related Conditions & MeSH terms

• Acute Myelogenous Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

• NCT number: NCT05263271
• Study type: Interventional
• Source: GeneScience Pharmaceuticals Co., Ltd.
• Contact: Cheng Hou, Doctor
• Phone: +86-13552524785
• Email: houcheng@gensci-china.com
• Status: Recruiting
• Phase: Phase 1
• Start date: April 1, 2021
• Completion date: July 30, 2024