Clinical Trials /

Chimeric Antigen Receptor T-cells for The Treatment of AML Expressing CLL-1 Antigen

NCT04219163

Description:

Patients eligible for this study have a type of blood cancer Acute Myeloid Leukemia (AML) which has come back or has not gone away after treatment. The body has different ways of fighting disease and infection, and this research study combines two different ways of fighting cancer with antibodies and T cells with the hope that they will work together. T cells (also called T lymphocytes) are special infection-fighting blood cells that can kill other cells including tumor cells. Antibodies are types of proteins that protect the body from bacterial and other infectious diseases. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients when used alone. T lymphocytes 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 targets CLL-1. This antibody sticks to AML cells because of a substance (protein) on the outside of these cells called CLL-1. For this study, the antibody to CLL-1 has been changed so that instead of floating free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is joined to them, they are called chimeric antigen receptor T-cells or CAR-T cells. In the laboratory, the investigators have also found that T cells work better if proteins that stimulate T cells are also added, 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. In this study we are going to attach the CLL-1 chimeric receptor that has CD28 added to it to the patient's T cells. We will then test how long the cells last. These CLL-1 chimeric antigen receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.

Related Conditions:
  • Acute Myeloid Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Chimeric Antigen Receptor T-cells for The Treatment of AML Expressing CLL-1 Antigen
  • Official Title: Chimeric Antigen Receptor T-cells for The Treatment of Acute Myeloid Leukemia Expressing CLL-1 Antigen

Clinical Trial IDs

  • ORG STUDY ID: H-43516-CARMEN
  • NCT ID: NCT04219163

Conditions

  • Acute Myeloid Leukemia

Interventions

DrugSynonymsArms
CLL-1.CAR T cellsCLL-1.CAR

Purpose

Patients eligible for this study have a type of blood cancer Acute Myeloid Leukemia (AML) which has come back or has not gone away after treatment. The body has different ways of fighting disease and infection, and this research study combines two different ways of fighting cancer with antibodies and T cells with the hope that they will work together. T cells (also called T lymphocytes) are special infection-fighting blood cells that can kill other cells including tumor cells. Antibodies are types of proteins that protect the body from bacterial and other infectious diseases. Both antibodies and T cells have been used to treat patients with cancers; they have shown promise, but have not been strong enough to cure most patients when used alone. T lymphocytes 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 targets CLL-1. This antibody sticks to AML cells because of a substance (protein) on the outside of these cells called CLL-1. For this study, the antibody to CLL-1 has been changed so that instead of floating free in the blood, it is now joined to the T cells. When T-cells contain an antibody that is joined to them, they are called chimeric antigen receptor T-cells or CAR-T cells. In the laboratory, the investigators have also found that T cells work better if proteins that stimulate T cells are also added, 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. In this study we are going to attach the CLL-1 chimeric receptor that has CD28 added to it to the patient's T cells. We will then test how long the cells last. These CLL-1 chimeric antigen receptor T cells with CD28 are investigational products not approved by the Food and Drug Administration.

Detailed Description

      To make the CLL1-CD28 chimeric antigen receptor T cells, the investigators will collect the
      patient's blood and stimulate them with growth factors to make the cells grow. To get the
      CLL-1 antibody and CD28 to attach to the surface of the T cell, we put the antibody gene into
      the T cell. This is done using 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 they are injected. Because the patient will have
      received cells with a new gene in them the patient will be followed for a total of 15 years
      to see if there are any long term side effects of gene transfer.

      When the patient enrolls on this study, the patient will be assigned a dose of CLL-1 chimeric
      antigen receptor- T cells. Several studies suggest that the T cells that we give to the
      patient need room to be able to grow and work well and that this may not happen if there are
      too many other T cells already in circulation the patient's body. Because of that, the
      patient will receive two chemotherapy medications before receiving the CLL-1 chimeric antigen
      receptor- T cells.

      One medication is called cyclophosphamide and the other fludarabine. The patient will receive
      3 daily doses of each drug, ending at least one day before receiving the chimeric antigen
      receptor- T cells. These drugs will lower the numbers of the patient's T cells before we give
      them the CLL-1 chimeric antigen receptor T cells and will also help lower the number of other
      cells that may block the chimeric antigen receptor- T cells from working well. Although we do
      not expect any effect on the patient's cancer with the doses that will be received, these
      drugs are part of many treatment plans that are used to treat leukemia.

      Patients will be given an injection of cells into the vein through an IV at the assigned
      dose. The injection will take from 1 to 10 minutes. Before patients receive the injection,
      they may be given a dose of Benadryl and Tylenol. The treatment will be given by the Center
      for Cell and Gene Therapy at Texas Children's Hospital or Houston Methodist Hospital.

      Investigators will monitor 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 have
      any side effects, they may have to be admitted to the hospital for evaluation and management.
      If after a 4 week evaluation period following the infusion, the patient has achieved a
      complete response, his/her cancer doctors may decide if you should go on to have a bone
      marrow transplant, at which time the patient will be removed from the treatment portion of
      the study.

      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

        -  Pregnancy test for female patients who are of child bearing potential -Measurements of
           your tumor by bone marrow studies

        -  Imaging such as PET scans, CT scans or MRIs will be obtained if needed

      PATIENTS WILL RECEIVE STANDARD MEDICAL TESTS DURING TREATMENT AND AFTER:

        -  Physical exams and History

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

        -  Measurements of your tumor by bone marrow studies 4-6 weeks after the infusion, possibly
           12 weeks after the infusion and then per standard of care.

        -  Imaging such as PET scans, CT scans or MRIs will be obtained if needed 4-6 weeks
           following the infusion

      To learn more about the way the CLL-1 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 amount is
      considered safe but may be lowered if you are anemic. This blood may be taken from a central
      line if you have one. Blood will be taken before the chemotherapy drugs, several hours after
      the T cell infusion, at 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, and 8 weeks after the
      infusion, at 3 months, 6 months, 9 months, at 1 year, every 6 months for 4 years, then yearly
      for a total of 15 years.

      If patients have a bone marrow exam while they are on this study, we may ask to have a sample
      of bone marrow to look for CLL-1 chimeric receptor- T cells.

      If a patient decides to withdraw at any time during the study, both samples and data
      collected during his/her participation will be kept.
    

Trial Arms

NameTypeDescriptionInterventions
CLL-1.CARExperimentalGroup A
  • CLL-1.CAR T cells

Eligibility Criteria

        PROCUREMENT

        Inclusion Criteria:

          1. Diagnosis of primary refractory or relapsed Acute Myeloid Leukemia (AML) AND suitable
             for consideration of allogeneic Hematopoietic Stem Cell Transplant with confirmation
             of an identified eligible donor by a FACT accredited transplant center and with
             confirmation that the center plans to proceed with transplant if CLL-1.CAR treatment
             induces response they consider adequate to proceed to allogeneic HSCT

          2. CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or
             immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology
             laboratory

          3. Age ≤75 years NOTE: The first six (6) patients treated on the study will be adults
             (≥18 yrs of age).

          4. Hgb ≥ 7.0 g/dL(can be transfused)

          5. Life expectancy greater than 12 wks

          6. If apheresis required to collect blood

               -  PT and APTT <1.5x ULN

               -  Serum Creatinine < 1.5 x ULN

               -  AST < 1.5 x ULN

          7. Informed consent

        Exclusion Criteria:

          1. Active infection (bacterial, fungal or viral) requiring ongoing treatment without
             improvement.

          2. Active infection with HIV or HTLV

          3. Active second cancer (except non-melanoma skin cancer or in situ breast cancer or
             cervix cancer)or other cancer treated ≤ 2 years prior to enrollment

          4. Ongoing treatment with immune suppression for prophylaxis or treatment of GVHD
             including high dose steroids (eg prednisone > 0.25mg/kg)

             -

        TREATMENT

        Inclusion Criteria:

          1. Diagnosis of primary refractory or relapsed Acute Myeloid Leukemia (AML). Patients
             with targetable mutations should have failed or be ineligible for targeted therapies
             (e.g. FLT3 inhibitors, IDH inhibitors, or anti-CD33 drug conjugate). AND patients
             should be suitable for consideration of allogeneic Hematopoietic Stem Cell Transplant
             with confirmation of an identified eligible donor by a FACT accredited transplant
             center and with confirmation that the center plans to proceed with transplant if
             CLL-1.CAR treatment induces a response they consider adequate to proceed to allogeneic
             HSCT.

          2. CLL-1 positive tumor with at least 30% CLL-1 blasts by flow cytometry or
             immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology
             laboratory

          3. Age ≤75 years NOTE: The first six (6) patients treated on the study will be adults
             (≥18 yrs of age).

          4. AST/ALT less than 5 times the upper limit of normal

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

          6. Estimated GFR ≥ 60ml/min

          7. Pulse oximetry of > 92% on room air

          8. Karnofsky/Lansky ≥ 60

          9. Recovered from all acute toxic effects of prior chemotherapy at least one week before
             study entry and off systemic chemotherapy at least 2 weeks prior to study entry

         10. Available autologous transduced activated peripheral blood T-cell product with ≥ 20%
             expression of CLL-1.CAR.28z by flow cytometry

         11. Life expectancy > 12 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.

        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. Active infection with HIV or HTLV.

          5. Clinically significant bacterial, viral or fungal infection requiring ongoing
             antifungal therapy without improvement,.

          6. Cardiac criteria: Prolonged QTc with maximum interval as defined by age with ;
             Uncontrolled atrial fibrillation/flutter; Myocardial infarction within the last 6
             months; Cardiac echocardiography with LVSF<30% or LVEF<50% or clinically significant
             pericardial effusion; Cardiac dysfunction NYHA III or IV; CNS abnormalities: Presence
             of CNS disease defined as detectable cerebrospinal blast cells in a sample of CSF with
             ≥ 5 WBCs per mm3 or chloroma on imaging, History or presence of an underlying CNS
             disorder such as a seizure disorder requiring current use of antiepileptic
             medications, cerebrovascular ischemia/hemorrhage within prior 6 months, dementia,
             cerebellar disease, or any autoimmune disease with CNS involvement.

          7. Use of serotherapy with Campath or Anti-Thymocyte Globulin (ATG) within the last 28
             days

          8. Use of Donor Lymphocyte Infusion (DLI) or other cellular therapy product within 30
             days

          9. Acute GVHD ≥ Grade 2 or moderate to severe (formerly extensive) chronic GVHD

         10. Aministration of high dose steroids >1 mg/kg within the preceding 5 days or currently
             receiving > 0.25 mg/kg of Prednisone equivalent

         11. Hyperleukocytosis (WBC ≥50K) or rapidly progressive disease that in the estimation of
             the investigator would compromise the ability of the patient to complete the study.
      
Maximum Eligible Age:74 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) rate
Time Frame:4 weeks post T cell infusion
Safety Issue:
Description:To assess dose limiting toxicities per protocol-defined CLL-1.CAR T related adverse events and CTCAE v5.0

Secondary Outcome Measures

Measure:Overall Response Rate
Time Frame:4 weeks post T cell infusion
Safety Issue:
Description:To measure the anti-tumor effects of CLL-1.CAR T-cells in patients with acute myeloid malignancies.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Baylor College of Medicine

Trial Keywords

  • AML

Last Updated

August 28, 2020