CD4CAR for CD4+ Leukemia and Lymphoma

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Brief Title

CD4CAR for CD4+ Leukemia and Lymphoma

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

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

Detailed Description

      The study will be performed as a dose-escalation protocol. Due to the relatively low
      incidence and prevalence of cluster of differentiation 4-positive (CD4+) hematological
      malignancies and the associated aggressive nature of these diseases and the sequel of
      treatment failure, the investigators expect to recruit 20 subjects at Stony Brook with an
      expected dropout rate of 25% primarily due to rapid progression or death and screen and or
      manufacturing failure. Taking this into account, the investigators expect to treat 15
      patients. The study will utilize autologous CD4CAR T-cells that are engineered to express a
      chimeric antigen receptor (CAR) targeting CD4 that is linked to the cluster of
      differentiation 28 (CD28), 4-1BB, cluster of differentiation 3-zeta (CD3ζ) signaling chains
      (third generation CAR).

      At entry, disease status will be staged and investigators will determine if the subject has
      the minimal T cell number adequate for apheresis (screening step) and for manufacturing
      CD4CAR cells. qualifying subjects will be leukapheresed to obtain large numbers of peripheral
      blood mononuclear cells (PBMC) for the manufacturing. Next, participants will receive
      conditioning chemotherapy. If tumor burden is sufficiently reduced (screening step),
      participants will receive CD4CAR cells by infusion on Day 0 of treatment.

      For cell harvest, 12-15-liter apheresis procedure will be performed at the apheresis center
      with the intention to harvest at least 50x10^9-nucleated cells to manufacture CD4CAR T-cells.
      A portion of the pheresed cells will also be cryopreserved for FDA look-back requirements and
      for further research. The T-cells will be purified from the PBMC, transduced with CD4CAR
      lentiviral vector, expanded in vitro, and then frozen for administration. Each dose will be
      stored in either one or two bags. The route of administration is by IV infusion and the
      duration of infusion will be approximately 20 minutes. Each bag will contain an aliquot
      (30-50 mL) of liquid suitable for freezing, and containing the following infusible grade
      reagents (% v/v): 62.5cc Plasmalyte-A 5% dextrose; 7.5cc Pure dimethylsulfoxide (DMSO), 20cc
      of 25% Human Serum Albumin, and 10cc Dextran 40. The cell product is expected to be ready for
      release approximately 3-4 weeks after apheresis.

      If the disease progresses during the manufacturing period participants may be excluded from
      the study. Minimal chemotherapy to keep the disease under control in the meanwhile is allowed
      if deemed necessary by investigators.

      A single dose of CD4CAR transduced T cells will consist of the cell number for the dose level
      to be infused.

      Post-infusion monitoring: on days 1, 3, 5, 7, 14, and 28 following infusion of CD4CAR
      T-cells, evaluation of leukemic cell killing and CD4CAR Trafficking will be done. Cytokines
      levels will be evaluated on Day 2, 4, 7, 11, 14, 21, 28 and every 8 hours during active
      cytokine release syndrome (CRS). Active monitoring of fungal and viral infections during
      treatment while utilizing standard prophylaxis recommended for HIV-positive patients with
      T-cell aplasia and those undergoing allogeneic stem cell transplant. Investigators plan to
      collect data about clinicoradiologic measurements of residual tumor burden starting on day 6
      and weekly afterward until remission and then monthly for 6 months. This will be followed by
      quarterly clinical evaluations for the next two (2) years with a medical history, physical
      examination, and comprehensive blood testing. After these short- and intermediate-term
      evaluations are performed, these patients will enter a rollover study to assess for
      disease-free survival (DFS), relapse, and the development of other health problems or
      malignancies for annual where follow-up will by phone and a questionnaire for an additional
      thirteen (13) years. The treating physician will decide to proceed with allogeneic or
      autologous transplant when needed.

      Dose of CD4CAR description: the main objective of this study is to establish a recommended
      dose and/or schedule of CD4CAR. The guiding principle for dose escalation in phase I is to
      avoid unnecessary exposure of patients to sub-therapeutic doses (i.e., to treat as many
      patients as possible within the therapeutic dose range) while preserving safety and
      maintaining rapid accrual. Investigators will use the rule-based traditional Phase I "3+3"
      design for the evaluation of safety. Based on lab experience in mice the starting dose (dose
      level 1) for the first cohort of three patients in phase I portion of the study will be
      8x10^5 cells. The dose escalation or de-escalation will follow a modified Fibonacci sequence
      as below.

      If more than one patient out of the first cohort of three patients in dose level 1 experience
      dose limiting toxicity (DLT), the trial will be placed on hold. If zero or one out of three
      patients in the first cohort of dose level 1 experience DLT, three more patients will be
      enrolled at dose level 1; the dose escalation continues until at least two patients among a
      cohort of six patients experience DLT (i.e., ≥33% of patients with a DLT at this dose level)

        -  If one of the first three patients in dose level 1 experiences a DLT, three more
           patients will be treated at dose level 1.

        -  If none of the three patients or only one of the 6 patients in the dose level 1
           experiences a DLT, the dose escalation continues to the dose level 2

        -  If one of the first three patients in dose level 2 experience a DLT, three more patients
           will be treated at dose level 2

        -  If none of the three patients or only one of the 6 patients in the dose level2
           experiences a DLT, the dose escalation continues to the dose level 3

        -  If one of the first three patients in dose level 3 experiences a DLT, three more
           patients will be treated at dose level 3

        -  If none of the three patients or only one of the 6 patients in the dose level 3
           experiences a DLT, dose level 3 will be declared the maximum tolerated dose (MTD) and
           will be used as the recommended phase II dose (RP2D) for the phase II portion of the

      In summary, the dose escalation continues until at least two patients among a cohort of six
      patients experience DLT (i.e., ≥33% of patients with a DLT at that dose level). The
      recommended dose for phase II trials is defined as one dose level below this toxic dose
      level. Since some grade 3 and possibly 4 toxicities are highly likely to be reversible, grade
      3 infectious, hematological and vascular toxicities will not be considered DLTs mandating
      dose reduction. Also allergic or infusion-related reactions ≤ grade 3 will not be counted as
      DLTs. There will be no intra-patient dose escalation or reduction.

      To allow for full spectrum toxicity duration evaluation and reporting, no patients within the
      same or a different cohort will be initiated on lymphodepleting chemotherapy sooner than 28
      days from the initiation date of the preceding patient.

Study Phase

Phase 1

Study Type


Primary Outcome

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Secondary Outcome

 Duration of in vivo survival of the CD4CAR.


T-cell Lymphoma



Study Arms / Comparison Groups

Description:  Redirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells)


* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information

Recruitment Status


Estimated Enrollment


Start Date

June 18, 2019

Completion Date

December 2037

Primary Completion Date

December 2022

Eligibility Criteria

        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

               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

          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




18 Years - N/A

Accepts Healthy Volunteers



Huda Salman, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations



Organization ID


Secondary IDs


Responsible Party


Study Sponsor

Huda Salman


 iCell Gene Therapeutics

Study Sponsor

Huda Salman, MD, Study Chair, Indiana University

Verification Date

December 2021