Gentulizumab in Relapsed/Refractory Acute Myelogenous Leukemia or Myelodysplastic Syndrome
brief 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.
detailed 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).
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