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Dual CD33-CLL1-CAR-T Cells in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05016063
Recruitment Status : Not yet recruiting
First Posted : August 23, 2021
Last Update Posted : August 23, 2021
Sponsor:
Collaborator:
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
Information provided by (Responsible Party):
Xi Zhang, MD, Xinqiao Hospital of Chongqing

Brief Summary:
Phase I, interventional, single-arm, open-label, treatment study to evaluate the safety and effectiveness of CD33-CLL1 CAR in patients with relapsed and/or refractory acute myeloid leukemia (AML).

Condition or disease Intervention/treatment Phase
Leukemia, Myeloid, Acute Drug: Fludarabine Drug: Cytoxan Biological: Dual CD33-CLL1 CAR-T cells Early Phase 1

Detailed Description:

AML bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CLL1 expression comprise a rare population that also plays an important role in disease progression and relapse for myeloid malignancies. CD33 is widely expressed in AML. Targeting both CD33 and CLL1 surface antigens together may offer two distinct benefits. First, targeting both bulk disease and leukemic stem cells together allows for a more comprehensive ablation of the disease. Second, dual targeting of myeloid malignancies by both CD33 and CLL1 directed therapy overcomes the pitfalls of single-antigen therapy by preventing relapse due to antigen loss. While loss of a single antigen under antigen-specific selection pressure is possible, loss of two antigens simultaneously is much less likely.

CD33-CLL1 CAR is a compound Chimeric Antigen Receptor immunotherapy with two distinct functional CAR molecules expressed on a T-cell, directed against the surface proteins CLL1 and CD33. CD33-CLL1 CAR intends to target the mechanisms of single-CAR relapse, specifically antigen escape and leukemic stem cells.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I Study to Evaluate the Safety and Effectiveness of Dual CD33-CLL1 CAR-T Therapy in Relapsed/Refractory Acute Myeloid Leukemia
Estimated Study Start Date : September 1, 2021
Estimated Primary Completion Date : September 1, 2022
Estimated Study Completion Date : September 1, 2023


Arm Intervention/treatment
Experimental: Dual CD33-CLL1 CAR-T cells
CD33-CLL1 CAR T cells
Drug: Fludarabine
recommendation: 30mg/m2 (D-5~D-3),determined by tumor burden at baseline.

Drug: Cytoxan
recommendation: 300-500mg/m2 (D-5~D-3),determined by tumor burden at baseline.

Biological: Dual CD33-CLL1 CAR-T cells
CD33-CLL1 CAR-T infusion (starting at dose level 1 [DL1]: 0.5 x 106 transduced CAR-T cells/kg) on Day 0.




Primary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 4 weeks after infusion ]
    Assessment of morphologic complete remission (CR), complete remission with incomplete recovery of counts (CRi), no residual disease as analyzed by flow cytometry analysis, and molecular remission by molecular studies

  2. the safety evaluation of Dual CD33-CLL1 CAR-T cells [ Time Frame: within 4 weeks after infusion ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0


Secondary Outcome Measures :
  1. Progression-free survival (PFS) [ Time Frame: up to 2 years after infusion ]
    Surviavl without disease progression

  2. Overall survival(OS) [ Time Frame: up to 2 years after infusion ]
    Surviavl



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ECOG performance status score ≤ 2.
  2. Life expectancy ≥ 12 weeks from the time of enrollment.
  3. Disease status at the time of enrollment: -Patients with AML (except M3) who have not achieved complete remission after standard chemotherapy regimens; -Not suitable or unconditional for allogeneic hematopoietic stem cell transplantation; -Patients with recurrent acute myeloid leukemia after autologous hematopoietic stem cell transplantation without active graft-versus-host disease (GVHD).
  4. CD33 expression must be detected on greater than 50% of the malignant cells by immunohistochemistry or greater than 80% by flow cytometry.
  5. Adequate main organ function as assessed by the following laboratory requirements: creatinine ≤ 2.5 × upper limit of normal, cardiac ejection fraction ≥ 40%, oxygen saturation ≥ 90%, total bilirubin ≤ 3 × upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal, Hgb≥80g/L.
  6. Without history of accepting anti-cancer therapy, including chemotherapy, radiotherapy, immunotherapy (immune suppressive drugs or corticosteroid treatment) within 4 weeks of screening.
  7. Women of child-bearing age must have evidence of negative pregnancy test.
  8. Subjects of reproductive potential must agree to use acceptable birth control methods within 1 year after treatment, as described in protocol.
  9. After discussion by the expert group, the patient's condition was analyzed and combined with the general physical condition of the patient, the benefit of participating in the clinical trial was greater than the risk.
  10. All participants must have the ability to understand and willingness to sign a written informed consent.

Exclusion Criteria:

  1. Diagnosis of acute promyelocytic leukemia (APL M3): t(15;17)(q22;q12); (promyelocytic leukemia [PML]/retinoic acid receptor [RAR] alpha [a]) and variants excluded.
  2. Active acute or chronic GVHD or requirement of immunosuppressant medications for GVHD within 4 weeks of enrollment.
  3. Have been diagnosed with or treated other malignant tumors other than AML within 5 years before screening, except for the following conditions: participants with adequately treated cervical carcinoma in situ, basal cell or squamous cell skin cancer; or received radical treatment Local prostate cancer, ductal carcinoma in situ.
  4. There are serious systemic diseases: New York Heart Association (NYHA) stage III or IV congestive heart failure; cerebrovascular accident or myocardial infarction or hemodynamic instability caused by arrhythmia within 6 months before signing the informed consent; impaired cardiac function (LVEF<50%) assessed by echocardiographic scan.
  5. Sever illness or medical condition, which would not permit the patient to be managed according to the protocol, including active uncontrolled infection.
  6. Pregnant or lactating women.
  7. Subjects with radiologically-detected CNS chloromas or CNS 3 disease (presence of ≥ 5/μL white blood cells (WBCs) in cerebral spinal fluid (CSF) and cytospin positive for blasts [in the absence of a traumatic lumbar puncture] and/or clinical signs of CNS leukemia such as a cranial nerve palsy from active disease). Subjects with adequately treated CNS leukemia are eligible.
  8. Human immunodeficiency virus (HIV) seropositivity; hepatitis B surface antigen is positive or HBV DNA is higher than the detection limit of the analysis method; hepatitis C antibody is positive or HCV RNA is higher than the detection limit of the analysis method; syphilis antibody and syphilis rapid plasma reagin are positive; CMV DNA is positive.
  9. Patients who suffer from allergies for any cytokines or antibodies.
  10. Contraindications for fludarabine or cyclophosphamide treatment.
  11. Receiving corticosteroids at >20 mg daily prednisone dose or equivalent.
  12. Drug abuse and addiction.
  13. History of mental disorders.
  14. Other patients that researchers considered unsuitable for inclusion.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05016063


Contacts
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Contact: xi zhang, PhD/MD 13808310064 ext +86 zhangxxi@sina.com
Contact: ruihao huang, MD 18984398751 ext +86 1169731117@qq.com

Locations
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China, Chongqing
Department of Hematology, Xinqiao Hospital
Chongqing, Chongqing, China, 400037
Sponsors and Collaborators
Xinqiao Hospital of Chongqing
Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd.
Investigators
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Principal Investigator: xi zhang, PhD/MD Department of Hematology, Xinqiao Hospital
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Responsible Party: Xi Zhang, MD, Chef of Hematology Department, Xinqiao Hospital of Chongqing
ClinicalTrials.gov Identifier: NCT05016063    
Other Study ID Numbers: Dual CD33-CLL1 CAR-T cells
First Posted: August 23, 2021    Key Record Dates
Last Update Posted: August 23, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Fludarabine
Cyclophosphamide
Antineoplastic Agents
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists