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CD4CAR for CD4+ Leukemia and Lymphoma

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. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT03829540
Recruitment Status : Active, not recruiting
First Posted : February 4, 2019
Last Update Posted : September 21, 2022
iCell Gene Therapeutics
Information provided by (Responsible Party):
Huda Salman, Indiana University

Brief Summary:
This study is designed as a single arm open label Phase I, 3x3, multicenter study of CD4-directed chimeric antigen receptor engineered T-cells (CD4CAR) in patients with relapsed or refractory T-cell leukemia and lymphoma. Specifically, the study will evaluate the safety and tolerability of CD4CAR T-cells. Funding Source - FDA OOPD

Condition or disease Intervention/treatment Phase
T-cell Lymphoma T-cell Leukemia Biological: CD4CAR Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I, Multicenter Study of CD4- Directed Chimeric Antigen Receptor Engineered T-cells (CD4CAR) in Patients With Relapsed or Refractory CD4+ Hematological Malignancies
Actual Study Start Date : June 18, 2019
Estimated Primary Completion Date : December 2025
Estimated Study Completion Date : December 2037

Arm Intervention/treatment
Experimental: Treatment
Redirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells)
Biological: CD4CAR
CD4CAR cells transduced with a lentiviral vector to express the single-chain variable fragment (scFv) nucleotide sequence of the anti-CD4 molecule derived from humanized monoclonal ibalizumab and the intracellular domains of CD28 and 4-1BB co-activators fused to the CD3ζ T-cell activation signaling domain administered by IV infusions as a single dose (total dose of up to ~4x106 T Cells/KG)

Primary Outcome Measures :
  1. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: 18-24 months ]
    To assess the safety and feasibility of the chimeric antigen receptor T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells) according to CTCAE grading. The feasibility of treating those adverse events and their duration till resolution will also be described.

Secondary Outcome Measures :
  1. Duration of in vivo survival of the CD4CAR. [ Time Frame: 18-24 months ]
    Persistence of CD4CAR will be monitored by measuring the CD4CAR transgene copy number at variable time points.

  2. Rate of manufacturing failure [ Time Frame: 18-24 months ]
    The number of failed manufacturing attempts of CD4 CAR, per subject and overall, in this patient population. Manufacturing failure is defined as failure to manufacture the adequate CD4CAR cell dose for the particular cohort the patient is enrolled on. Three manufacturing attempts per patient are allowed.

  3. Clinical Response [ Time Frame: 18-24 months ]

    Clinical response to T-cell infusion will be evaluated by comparing disease before and after infusion identified by:

    • standard imaging (PET CT or PET MRI) for lymphoma patients
    • bone marrow biopsy for leukemia patients
    • peripheral blood cells morphology, flow cytometry panel, immunohistochemistry, and other blood molecular markers for both lymphoma and leukemia.

  4. trafficking of CD4CAR at tumor sites and at sites with significant toxicity [ Time Frame: 18-24 months ]
    Quantification of both of CD4CAR by flowcytometry and transgene copy number by polymerase chain reaction (PCR) will be measured at tumor sites in bone marrow and lymph nodes at variable time points if applicable. Same tests will be done on biopsies of organs that shows significant toxicity if need be.

  5. Number of participants with immune reactions against CD4CAR [ Time Frame: 18-24 months ]
    The absolute and relative number of subjects who develop immune reactions against the treatment over a period of 2 years. Human anti-mouse antibody (HAMA) ELISA tests will be carried out in the blood of participants at multiple times after initial treatment.

  6. Serum cytokines levels [ Time Frame: 18-24 months ]
    Serum cytokine levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 in addition to planned monitoring during CRS every 8 hours and until resolution. These cytokines include interleukin-6 (IL-6), interferon-γ, tumor necrosis factor, IL-2, IL-2-receptor-a, IL-8, and IL-10

  7. determine CD4CAR cell subsets during proliferation [ Time Frame: 18-24 months ]
    Participants' blood will be tested by flow cytometry to determine the relative abundance of cellular subsets that may result from CD4CAR T cells upon their proliferation. These subsets include Tcm, Tem, and Tregs.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria

In order to be eligible to participate in this study, an individual will be enrolled if they meet the following criteria:

  1. Patients must voluntarily sign and date informed consent forms that state his or her willingness to comply with all study procedures and availability for the duration of the study.
  2. Subjects with documented CD4+ hematologic malignancies. Male and female subjects with CD4+ T-cell malignancies with either relapsed or refractory disease (including those patients who have undergone a prior transplant and patients with an inadequate response after 4-6 cycles of standard chemotherapy)
  3. Patients who present with CD4+ Leukemia. Either relapsed disease or minimal residual disease (MRD); any of the following are eligible:

    3.1 Peripheral T-cell leukemia, NOS 3.2 T-cell prolymphocytic leukemia 3.3 Adult T-cell leukemia 3.4 T-cell large granular lymphocytic leukemia 3.5 T cell acute lymphoblastic leukemia (T-ALL)

  4. For patients with CD4+ Lymphoma. Either relapsed or refractory disease; any of the following are eligible:

    4.1 Peripheral T-cell lymphoma, not otherwise specified (NOS) 4.2 Sezary syndrome/cutaneous T-cell lymphoma 4.3 Angioimmunoblastic T-cell lymphoma 4.4 Adult T-cell lymphoma

  5. Age 18 years old or older
  6. Creatinine clearance of > 60 ml/min
  7. Liver enzymes < 3 x upper limit of normal
  8. Bilirubin < 2.0 mg/dL
  9. Serum albumin of ≥ 3gms/dl
  10. Pulmonary Function Test (PFT) with diffusing capacity of lung for carbon monoxide (DLCO) of ≥ 60%.
  11. Adequate echocardiogram with ejection fraction (EF) of ≥50%
  12. Adequate venous access for apheresis and no other contraindications for leukapheresis Eligibility for CD4CAR infusion

    1. No evidence of an active or uncontrolled infection for at least 72 hours
    2. Afebrile and not receiving antipyretics
    3. If previous history of corticosteroid chemotherapy, subject must off all but adrenal replacement doses
    4. Repeat baseline indicates presence of disease but not rapidly progressing disease.
    5. Specific organ functional criteria for cardiac, renal, and liver function similar to initial inclusion are met. Tests such as echocardiogram and PFTs need not be repeated if within 6 weeks of initial assessment
    6. Negative pregnancy testing (if applicable)

Screen Failure

First point screen failure: Inadequate T- lymphocytes for apheresis defined as T cell count at screening that does not meet the requirement of ≥ 107-135/µ/L

Second point screen failure: Failure of cytoreduction with conditioning chemotherapy and persistence of clinical high disease burden defined as extensive lymph node enlargement that is not reduced at least by 50% of original size, presence of central nervous system (CNS) disease or bone marrow replacement with ≥50% malignant cells.

Exclusion Criteria

  1. Pregnant or lactating women. The safety of this therapy on unborn children is not known. Female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion.
  2. Uncontrolled active infection.
  3. Active hepatitis B or hepatitis C infection.
  4. Concurrent use of systemic glucocorticoids in greater than replacement doses. Recent or current use of inhaled glucocorticoids is not exclusionary
  5. Previously treatment with any gene therapy products.
  6. Feasibility assessment during screening demonstrates < 30% transduction of target lymphocytes, or insufficient expansion (< 5-fold) in response to cluster of differentiation 3 (CD3)/CD28 costimulation. A total of three attempts will be carried out before deemed inadequate manufacturing
  7. Any uncontrolled active medical disorder that would preclude participation as outlined.
  8. HIV infection.
  9. Steroid dependency for any reason as well as the potential need to treat concomitant illnesses with steroids during the trial period, examples are patients with chronic obstructive pulmonary disease (COPD) and asthma known to require steroids to abort acute exacerbation.
  10. Patients declining to consent for treatment

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): NCT03829540

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United States, Indiana
Indiana University Melvin and Bren Simon Comprehensive Cancer Center
Indianapolis, Indiana, United States, 46202
Sponsors and Collaborators
Huda Salman
iCell Gene Therapeutics
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Study Chair: Huda Salman, MD Indiana University
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Responsible Party: Huda Salman, Director, Hematologic Malignancies Service and Director, CAR T Cellular Therapy Program, Indiana University
ClinicalTrials.gov Identifier: NCT03829540    
Other Study ID Numbers: CTO-IUSCCC-ICG122-101
FD-R-006820-01 ( Other Grant/Funding Number: FDA OOPD )
First Posted: February 4, 2019    Key Record Dates
Last Update Posted: September 21, 2022
Last Verified: September 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Huda Salman, Indiana University:
CD4; T-cell; lymphoma; leukemia; chimeric antigen; CAR-T
Additional relevant MeSH terms:
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Leukemia, T-Cell
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, Lymphoid