Clinical Trials /

Cell Therapy for High Risk T-Cell Malignancies Using CD7-Specific CAR Expressed On Autologous T Cells

NCT03690011

Description:

Patients eligible for this study have a type of blood cancer called T-cell leukemia or lymphoma (lymph gland cancer). The body has different ways of fighting infection and disease. This study combines two different ways of fighting disease with antibodies and T cells. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, or T lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. Both antibodies and T cells have been used to treat cancer; they have shown promise, but have not been strong enough to cure most patients. T cells can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study is called anti-CD7. This antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of these cells called CD7. CD7 antibodies have been used to treat people with T-cell leukemia and lymphoma. For this study, anti-CD7 has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. In the laboratory, investigators have also found that T cells work better if they also add proteins that stimulate T cells, such as one called CD28. Adding the CD28 makes the cells grow better and last longer in the body, thus giving the cells a better chance of killing the leukemia or lymphoma cells. Finally, to make sure the T cells are able to grow and expand properly without accidentally targeting themselves (because they also have CD7 on their surface), investigators have removed the CD7 gene in the T cells using a genome editing technique called CRISPR-Cas9. Investigators have repeatedly shown in the laboratory and in our animal studies that removing the CD7 genes in T cells using CRISPR-Cas9 before adding the CAR to the cells helps them expand and kill better, and does not interfere with the other functions of the T cells. In this study, investigators attach the CD7 chimeric receptor with CD28 added to it to T cells that have had CD7 removed from their surface. Investigators will then test how long the cells last. These CD7 chimeric receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.

Related Conditions:
  • Adult T-Cell Leukemia/Lymphoma
  • Anaplastic Large Cell Lymphoma
  • Nasal Type Extranodal NK/T-Cell Lymphoma
  • T-Cell Acute Lymphoblastic Leukemia
  • T-Cell Lymphoblastic Leukemia/Lymphoma
  • T-Cell Non-Hodgkin Lymphoma
  • T-Cell Prolymphocytic Leukemia
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cell Therapy for High Risk T-Cell Malignancies Using CD7-Specific CAR Expressed On Autologous T Cells
  • Official Title: Cell Therapy for High Risk T-Cell Malignancies Using CD7-specific CAR Expressed On Autologous T Cells (CRIMSON)

Clinical Trial IDs

  • ORG STUDY ID: H-43761 - CRIMSON
  • NCT ID: NCT03690011

Conditions

  • T-cell Acute Lymphoblastic Leukemia
  • T-cell Acute Lymphoblastic Lymphoma
  • T-non-Hodgkin Lymphoma

Interventions

DrugSynonymsArms
FludarabineFludaraCD7.CAR/28zeta CAR T Cells
CytoxancyclophosphamideCD7.CAR/28zeta CAR T Cells

Purpose

Patients eligible for this study have a type of blood cancer called T-cell leukemia or lymphoma (lymph gland cancer). The body has different ways of fighting infection and disease. This study combines two different ways of fighting disease with antibodies and T cells. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, or T lymphocytes, are special infection-fighting blood cells that can kill other cells including tumor cells. Both antibodies and T cells have been used to treat cancer; they have shown promise, but have not been strong enough to cure most patients. T cells can kill tumor cells but there normally are not enough of them to kill all the tumor cells. Some researchers have taken T cells from a person's blood, grown more of them in the laboratory and then given them back to the person. The antibody used in this study is called anti-CD7. This antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of these cells called CD7. CD7 antibodies have been used to treat people with T-cell leukemia and lymphoma. For this study, anti-CD7 has been changed so that instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. In the laboratory, investigators have also found that T cells work better if they also add proteins that stimulate T cells, such as one called CD28. Adding the CD28 makes the cells grow better and last longer in the body, thus giving the cells a better chance of killing the leukemia or lymphoma cells. Finally, to make sure the T cells are able to grow and expand properly without accidentally targeting themselves (because they also have CD7 on their surface), investigators have removed the CD7 gene in the T cells using a genome editing technique called CRISPR-Cas9. Investigators have repeatedly shown in the laboratory and in our animal studies that removing the CD7 genes in T cells using CRISPR-Cas9 before adding the CAR to the cells helps them expand and kill better, and does not interfere with the other functions of the T cells. In this study, investigators attach the CD7 chimeric receptor with CD28 added to it to T cells that have had CD7 removed from their surface. Investigators will then test how long the cells last. These CD7 chimeric receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.

Detailed Description

      To make the T cells, the investigators will take the patient's blood and stimulate it with
      growth factors to make the T cells grow. Investigators will remove the CD7 gene from the
      patient's T cells using a special technique (called CRISPR-Cas) in order to make sure the T
      cells are able to grow properly. To get the CD7 antibody and CD28 to attach to the surface of
      the T cell, investigators will insert the antibody gene into the T cell. This is done with a
      virus called a retrovirus that has been made for this study and will carry the antibody gene
      into the T cell. This virus also helps investigators find the T cells in the patient's blood
      after investigators inject them. Because patients will have received cells with a new gene in
      them, patients will be followed for a total of 15 years to see if there are any long term
      side effects of gene transfer. If patients cannot visit the clinic, they may be contacted by
      the research coordinator or physician.

      When patients enroll on this study, they will be assigned a dose of CD7 chimeric receptor-T
      cells. Several studies suggest that the infused T cells need room to be able to proliferate
      (grow) and accomplish their functions and that this may not happen if there are too many
      other T cells in blood. Because of that, patients will receive two chemotherapy medications
      prior to receiving the CD7 chimeric receptor-T cells. One medication is called
      cyclophosphamide and the other fludarabine. Patients will receive 3 daily doses of each drug,
      ending at least one day before they receive the chimeric receptor-T cells. These drugs will
      decrease the numbers of the patients own T cells before investigators infuse the CD7 chimeric
      receptor T cells and also will help decrease the number of other cells that may interfere
      with the chimeric receptor-T cells working well. Although investigators do not expect any
      effect on tumors with the doses that patients will receive, these drugs are part of many
      regimens that are used to treat leukemia or lymphoma. Investigators prefer that patients do
      not receive other chemotherapy until 6 weeks after cell infusion but patients can do so if
      their doctors thinks it is medically necessary.

      Patients will be given an injection of cells into the vein through an IV at the assigned
      dose. Before patients receive the injection, they will be given a dose of Benadryl and
      Tylenol. The injection will take about 20 minutes. Investigators will follow patients in the
      clinic after the injection for up to 3 hours, and they will have to remain locally for at
      least 3 weeks after the infusion. If patients experience any side effects (see section on
      risks below), they may have to be hospitalized for evaluation and management. If after a 4-6
      week evaluation period after a patient's infusion and s/he has achieved a complete response
      (measured by bone marrow or radiology scans), the patient's primary oncology doctors may
      decide s/he should proceed to bone marrow transplant, at which time s/he will be removed from
      the treatment portion of the study.

      The treatment will be given by the Center for Cell and Gene Therapy at Texas Children's
      Hospital or Houston Methodist Hospital.

      MEDICAL TESTS BEFORE TREATMENT

      Before being treated, patients will receive a series of standard medical tests:

        -  Physical exam and History

        -  Blood tests to measure blood cells, kidney and liver function

        -  Measurements of the patient's tumor by scans and/or bone marrow studies

        -  Testing of patient's blood for certain viral infections

        -  An ultrasound of patient's heart to make sure his/her heart function is appropriate for
           the study

      MEDICAL TESTS DURING AND AFTER TREATMENT:

      Patients will receive standard medical tests when they are getting the infusion and after:

        -  Physical exams and History

        -  Blood tests to measure blood cells, kidney and liver function

        -  Measurements of the patient's tumor by scans and/or bone marrow studies 4-6 weeks after
           the infusion

      To learn more about the way the CD7 chimeric receptor-T cells are working and how long they
      last in the body, extra blood will be drawn. The total amount on any day is about 10
      teaspoons (50 mL) or no more than 3 mL per 2.2 pounds body weight in children. This volume is
      considered safe but may be decreased if patients are anemic. This blood may be drawn from a
      central line if one is available. Blood will be taken before patients start the chemotherapy
      a few days prior to the cell infusion. On the day patients receive the cells, blood will be
      taken before the cells are given and several hours afterwards. Other blood will be drawn one
      week after the infusion, 2 weeks, 3 weeks, 4 weeks and 6 weeks after the infusion, at 3
      months, at 6 months, at 9 months, at 1 year, every 6 months for 4 years, then yearly for a
      total of 15 years. The total blood drawn during a patient's participation in this study will
      not exceed 280 teaspoons.
    

Trial Arms

NameTypeDescriptionInterventions
CD7.CAR/28zeta CAR T CellsExperimentalThree dose levels will be evaluated. The T cells will be administered with Cytoxan and fludarabine.
  • Fludarabine
  • Cytoxan

Eligibility Criteria

        Procurement Inclusion Criteria:

        Referred patients will initially be consented for procurement of blood for generation of
        the transduced ATL. Eligibility criteria at this stage include:

          1. Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute
             lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including
             Angioimmunoblastic T-cell lymphoma (AITL), Enteropathy-associated T-cell lymphoma
             (EATL), Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Peripheral
             T-cell lymphoma (PTCL) NOS, Anaplastic large cell lymphoma (ALCL), Adult T-cell
             leukemia/lymphoma, T cell prolymphocytic leukemia with symptomatic disease, Extranodal
             NK/T cell lymphoma, Mycosis fungoides/ Sezary Syndrome Stage IIB or higher))

        AND

          1. suitable for allogeneic hematopoietic stem cell transplant (HSCT)

          2. with a suitable donor identified by a FACT accredited transplant center

          3. willing to proceed to transplant if the CD7.CAR treatment induces complete remission
             and the patient/donor remain suitable candidates

        Using NMDP donor assessment criteria, suitability is defined as "during the search process,
        a donor is medically fit to proceed to the next step- whether high-resolution or
        confirmatory HLA testing OR donor work-up." Documentation of suitability (including above
        criteria) will be confirmed by the investigator prior to treatment.

          -  For T-NHL subjects, eligibility will be confined to disease stages where allogeneic
             HSCT is indicated.

             2. CD7-positive tumor (≥20% CD7 positive blasts by flow cytometry or
             immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology
             laboratory).

             3. Age </=75 years old.. NOTE: The first three (3) patients treated on the study must
             be adults (>/=18 yrs of age).

             4. Hgb ≥ 7.0 (can be transfused)

             5. Life expectancy greater than 12 weeks

             6. If pheresis required to collect blood:

               -  Estimated GFR > 60 mL/min

               -  AST < 5 × upper limit normal

               -  PT and APTT <1.5 × upper limit normal

                  7. Informed consent explained to, understood by and signed by patient/guardian.
                  Patient/guardian given copy of informed consent.

        Procurement Exclusion Criteria:

          1. Active infection requiring antibiotics.

          2. Active infection with HIV or HTLV

          3. History of other cancer (except non-melanoma skin cancer or in situ breast cancer or
             cervix cancer) unless the tumor was successfully treated with curative intent at least
             2 years before trial entry.

        Treatment Inclusion Criteria:

        1. Diagnosis of recurrent T-cell acute lymphoblastic leukemia (T-ALL), T-cell acute
        lymphoblastic lymphoma (T-LLy), or T-non-Hodgkin lymphoma (T-NHL, including
        Angioimmunoblastic T-cell lymphoma (AITL), Enteropathy-associated T-cell lymphoma (EATL),
        Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), Peripheral T-cell lymphoma
        (PTCL) NOS, Anaplastic large cell lymphoma (ALCL), Adult T-cell leukemia/lymphoma, T cell
        prolymphocytic leukemia with symptomatic disease, Extranodal NK/T cell lymphoma, Mycosis
        fungoides/ Sezary Syndrome Stage IIB or higher))

        AND

          1. suitable for allogeneic hematopoietic stem cell transplant (HSCT)

          2. with a suitable donor identified by a FACT accredited transplant center

          3. willing to proceed to transplant if the CD7.CAR treatment induces complete remission
             and the patient/donor remain suitable candidates

        Using NMDP donor assessment criteria, suitability is defined as "during the search process,
        a donor is medically fit to proceed to the next step- whether high-resolution or
        confirmatory HLA testing OR donor work-up." Documentation of suitability (including above
        criteria) will be confirmed by the investigator prior to treatment.

          -  For T-NHL subjects, eligibility will be confined to disease stages where allogeneic
             HSCT is indicated.

             2. CD7-positive tumor (≥20% CD7+ blasts by flow cytometry or immunohistochemistry
             (tissue) assessed in a CLIA certified Flow Cytometry/Pathology laboratory.

             3. Age </=75 years old. NOTE: The first three (3) patients treated on the study must
             be adults (>/=18 yrs of age).

             4. Bilirubin less than 3 times the upper limit of normal.

             5. AST less than 5 times the upper limit of normal.

             6. Estimated GFR > 60 mL/min.

             7. Pulse oximetry of > 90% on room air

             8. Karnofsky or Lansky score of ≥ 60.

             9. Recovered from acute toxic effects of prior chemotherapy at least one week before
             entering this study.

             10. Available autologous activated peripheral blood T cell products with ≥ 20%
             expression of CD7.CAR.28zeta.CH3 and <0.5% gene-modified malignant T blasts by flow
             cytometry.

             11. Life expectancy of greater than 8 weeks.

             12. Sexually active patients must be willing to utilize one of the more effective
             birth control methods during the study and for 6 months after the study is concluded.
             The male partner should use a condom.

             13. Informed consent explained to, understood by, and signed by patient/guardian.
             Patient/guardian given copy of informed consent.

        Treatment Exclusion Criteria:

          1. Currently receiving any investigational agents or having received any tumor vaccines
             within the previous 6 weeks.

          2. History of hypersensitivity reactions to murine protein-containing products.

          3. Pregnant or lactating.

          4. Tumor in a location where enlargement could cause airway obstruction (per investigator
             discretion).

          5. Active infection with HIV or HTLV.

          6. Clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV,
             Adv, BK-virus, or HHV-6.

          7. Any of the following cardiac criteria: Atrial fibrillation/flutter; Myocardial
             infarction within the last 12 months; Prolonged QT syndrome or secondary prolonged QT,
             per investigator discretion. Cardiac echocardiography with LVSF<30% or LVEF<50%; or
             clinically significant pericardial effusion. Cardiac dysfunction NYHA III or IV
             (Confirmation of absence of these conditions on echocardiogram within 12 months of
             treatment).

          8. CNS abnormalities: Presence of CNS-3 disease defined as detectable cerebrospinal blast
             cells in a sample of CSF with ≥ 5 WBCs per mm3 (unless negative by the
             Steinherz/Bleyer algorithm); Presence of any CNS disorder such as an uncontrolled
             seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease,
             or any autoimmune disease with CNS involvement.
      
Maximum Eligible Age:75 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of patients with dose limiting toxicity
Time Frame:6 weeks
Safety Issue:
Description:To evaluate the safety of escalating doses of autologous peripheral blood T lymphocytes (ATLs) genetically modified to express chimeric antigen receptors (CAR) targeting the CD7 molecule (CD7.CAR) in combination with lymphodepletion in patients with relapsed/refractory T-cell malignancies.

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:6 weeks
Safety Issue:
Description:To measure the anti-tumor effects of CD7.CAR-ATLs in patients with T-cell leukemia or lymphoma.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Baylor College of Medicine

Trial Keywords

  • Autologouse CAR T cells
  • T-cell Acute Lymphoblastic Leukemia
  • T-cell acute lymphoblastic lymphoma
  • T-non-Hodgkin lymphoma

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