Clinical Trials /

CD4CAR for CD4+ Leukemia and Lymphoma

NCT03829540

Description:

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.

Related Conditions:
  • Adult T-Cell Leukemia/Lymphoma
  • Angioimmunoblastic T-Cell Lymphoma
  • Peripheral T-Cell Lymphoma
  • Primary Cutaneous T Cell Non-Hodgkin Lymphoma
  • Sezary Syndrome
  • T-Cell Acute Lymphoblastic Leukemia
  • T-Cell Large Granular Lymphocyte Leukemia
  • T-Cell Prolymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 1259208
  • NCT ID: NCT03829540

Conditions

  • T-cell Lymphoma
  • T-cell Leukemia

Interventions

DrugSynonymsArms
CD4CARTreatment

Purpose

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.

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
           study.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
TreatmentExperimentalRedirected autologous T cells transduced with the anti-CD4 lentiviral vector (referred to as "CD4CAR" cells)
  • CD4CAR

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. ALT/AST < 3 x ULN

          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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
Time Frame:18-24 months
Safety Issue:
Description: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

Measure:Duration of in vivo survival of the CD4CAR.
Time Frame:18-24 months
Safety Issue:
Description:Persistence of CD4CAR will be monitored by measuring the CD4CAR transgene copy number at variable time points.
Measure:Rate of manufacturing failure
Time Frame:18-24 months
Safety Issue:
Description: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.
Measure:Clinical Response
Time Frame:18-24 months
Safety Issue:
Description: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.
Measure:trafficking of CD4CAR at tumor sites and at sites with significant toxicity
Time Frame:18-24 months
Safety Issue:
Description:Quantification of both of CD4CAR by flowcytometry and transgene copy number by 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.
Measure:Number of participants with immune reactions against CD4CAR
Time Frame:18-24 months
Safety Issue:
Description: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.
Measure:Serum cytokines levels
Time Frame:18-24 months
Safety Issue:
Description: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
Measure:determine CD4CAR cell subsets during proliferation
Time Frame:18-24 months
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Stony Brook University

Trial Keywords

  • CD4; T-cell; lymphoma; leukemia; chimeric antigen; CAR-T

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