Gentulizumab in Relapsed/Refractory Acute Myelogenous Leukemia or Myelodysplastic Syndrome

NCT05263271 | Unknown Phase 1

• 1 other identifier: Gensci059-Ia-B
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Myelogenous Leukemia; Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (2)

• adverse events (AEs)

  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.

  ICF signing to 90 days after last administration or initiation of new anti-tumor treatment

• serious adverse events (SAEs)

  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.

  ICF signing to 90 days after last administration or initiation of new anti-tumor treatment

Secondary Outcomes (3)

• The plasma drug peak concentration (Cmax)

  First administration to 90 days after the last administration or initiation of new anti-tumor treatment

• The area under the drug time curve (AUC)

  First aAdministration to 90 days after the last administration or initiation of new anti-tumor treatment

• Pharmacodynamic (PD) parameters

  First administration to 90 days after the last administration or initiation of new anti-tumor treatment

Other Outcomes (3)

• Anti-drug Antibody (ADA) and Neutralizing Antibody (NAb)

  First administration to 28 days after the last administration or initiation of new anti-tumor treatment

• Progression-free survival response)

  From date that informed consent forms were signed until the date of disease progression

• Duration of response response)

  The duration from the first evaluation of the disease as complete response or partial response to the first evaluation as progressive disease or death from any cause

Study Arms (1)

Experimental cohort

EXPERIMENTAL

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

Drug: Gentulizumab

Interventions

Gentulizumab DRUG

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

Experimental cohort

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• The patient has the willingness to communicate with the Investigator, be able to understand and follow the trial requirements, volunteer to participate in the trial, understands and signs the written ICF, and is willing and able to comply with the visit schedule, administration plan, laboratory examination, and other clinical trial procedures.
• Gender: Male or female.
• Age ≥18
• Life expectancy ≥ 3 months.
• Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
• Patients with relapsed/refractory AML or MDS for whom there exists no standard treatment options available.
• AML diagnosed according to the 2016 WHO classification. Patients with acute promyelocytic leukemia (APL) are excluded. See Appendix 1.
• For the patients MDS diagnosed according to the World Health Organization (WHO) classification system and evaluated as moderate-risk, high-risk, and very high-risk according to the Revised International Prognostic Scoring System (IPSS-R) for Myelodysplastic Syndrome.
• The white blood cell (WBC) count in the patient's peripheral blood must be ≤ 20 × 109/L within 7 days of the first dose of the study drug. The patients with WBC count \> 20 × 109/L may be treated with hydroxyurea (maximum dose 4 g/d) during the Screening period to achieve entry criteria. Hydroxyurea may be continued for the first 4 weeks of treatment (Cycle 1) to control blast counts at the discretion of the Investigator; hydroxyurea must be stopped after the first 4 weeks of treatment.
• Hb levels must be above 5 g/dL on the day of the first dose of the study drug, and may be maintained by transfusion. Transfusion is permitted in the duration of trial.
• Platelet count ≥ 10,000 cells/uL with no evidence of medically significant bleeding or medical predisposition to bleeding. Platelets may be maintained by transfusion at the discretion of the Investigator.
• Adequate liver and kidney function as evidenced by meeting the following requirements:
• Serum creatinine (Cr) ≤ 1.5 × the upper limit of normal (ULN) or creatinine clearance (CrCl) ≥ 60 mL/min (based on Cockcroft-Gault formula)
• Aspartate aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5.0 times ULN for patients with liver metastasis/infiltration)
• Serum total bilirubin (TBIL) ≤ 1.5 × ULN except for patients with Gilbert's syndrome, who are included if total bilirubin is \< 3 × ULN or if direct bilirubin is \< 1.5 × ULN.

You may not qualify if:

• Female patients who are pregnant or lactating or have a positive pregnancy test at baseline.
• Patients with previous severe allergic reactions to the investigational drug or its components.
• Patients who have received any of the following treatments:
• Prior treatment with the CD47/SIRPα pathway as the therapeutic target.
• Systemic antitumor therapy or any experimental therapy including within 7 days or 5 half-lives, whichever is longer, before the first dose. If a patient is receiving cytarabine, oral fluorouracils and endocrine therapy, the patient must be off the drug for at least 2 weeks or until the patient has recovered from toxic effects. If a patient is receiving nitrosourea, mitomycin or monoclonal antibody, the patient must be off the drug for at least 6 weeks or until the patient has recovered from toxic effects. If the elution time is insufficient due to schedule or PK characteristics, discussion with sponsor will be needed.
• Expected to require treatment with other systemic anti-tumor therapies such as chemotherapy, immunotherapy, biotherapy or hormone therapy (except for palliative radiotherapy) during the study.
• Prior vaccination with anti-tumor vaccines or live attenuated vaccines within 4 weeks before the first dosing.
• Prior treatment with immunomodulatory drugs within 4 weeks before the first dose of study drug, except for topical, nasal and inhaled corticosteroids, or physiologic doses of systemic steroids (i.e., ≤ 10 mg/day prednisone or its equivalents).
• Not Receiving any investigational drug within 4 weeks before the first administration, or participated in another clinical study at the same time except that the patient participated in an observational, non-intervention clinical study, or was in the follow-up period of an intervention clinical study.
• No allogeneic transplantation within 6 months, no active graft-versus-host disease (GVHD), not receiving immunosuppressive treatment for GVHD within 4 weeks.
• Symptomatic central nervous system metastases or primary leukemia including leptomeningeal disease or spinal cord compression. Patients with asymptomatic CNS disease who are radiologically and neurologically stable ≥ 4 weeks following CNS-directed therapy and are on a stable or decreasing dose of corticosteroids are eligible for study entry.
• Patients with history of any active autoimmune disease, history of autoimmune disease, or disease or syndrome requiring treatment with systemic steroids or immunosuppressive medications (dermatological conditions that do not require systemic treatment or patients with resolved childhood asthma/allergies that do not require any intervention in adulthood; patients with a history of autoimmune-mediated hypothyroidism on a stable dose of thyroxine replacement therapy may be enrolled in the study).
• History of immunodeficiency, including a positive HIV test, and other acquired, or congenital immunodeficiency disease.
• History of ≥ Grade 3 thromboembolic event within the past 12 months, or current thrombolytic or anticoagulant therapy due to high risk of thrombus.
• History of genetic or acquired causes of bleeding or anemia.

Sponsors & Collaborators

• Changchun GeneScience Pharmaceutical Co., Ltd.: lead
• Ruijin Hospital: collaborator
• Shanghai Tong Ren Hospital: collaborator
• First Affiliated Hospital of Zhejiang University: collaborator

Study Sites (1)

Ruijin Hospital, Shanghai Jiao Tong University School of Medicine

Shanghai, Shanghai Municipality, 200025, China

RECRUITING

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Study Officials

• Junmin Li, Doctor

  Ruijin Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cheng Hou, Doctor

CONTACT

+86-13552524785; houcheng@gensci-china.com

Huagang Li, bachelor

CONTACT

86-18521091678; lihuagang@gensci-china.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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)

Study Record Dates

• First Submitted: December 24, 2021
• First Posted: March 2, 2022
• Study Start: April 1, 2021
• Primary Completion: July 30, 2024
• Study Completion: July 30, 2024
• Last Updated: March 2, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)