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

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ClinicalTrials.gov Identifier: NCT03690011
Recruitment Status : Not yet recruiting
First Posted : October 1, 2018
Last Update Posted : October 1, 2018
Sponsor:
Collaborators:
The Methodist Hospital System
Texas Children's Hospital
Center for Cell and Gene Therapy, Baylor College of Medicine
Information provided by (Responsible Party):
Rayne Rouce, Baylor College of Medicine

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
T-cell Acute Lymphoblastic Leukemia T-cell Acute Lymphoblastic Lymphoma T-non-Hodgkin Lymphoma Genetic: CD7.CAR/28zeta CAR T cells Drug: Fludarabine Drug: Cytoxan Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 21 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cell Therapy for High Risk T-Cell Malignancies Using CD7-specific CAR Expressed On Autologous T Cells (CRIMSON)
Estimated Study Start Date : March 1, 2019
Estimated Primary Completion Date : May 1, 2023
Estimated Study Completion Date : May 1, 2038


Arm Intervention/treatment
Experimental: CD7.CAR/28zeta CAR T Cells
Three dose levels will be evaluated. The T cells will be administered with Cytoxan and fludarabine.
Genetic: CD7.CAR/28zeta CAR T cells
Three dose levels will be evaluated: Dose level one: 1×10^7 cells/m^2, Dose level two: 3×10^7 cells/m^2, Dose level three: 1×10^8 cells/m^2

Drug: Fludarabine
Patients will receive 3 daily doses of fludarabine (30 mg/m^2) to induce lymphopenia, finishing at least 24 hours before T cell infusion. Infusions should be given following hospital/pharmacy recommendations (including dose adjustments as appropriate per institutional guidelines) however at a minimum the fludarabine should be infused over 30 minutes. Mesna, IV hydration and anti-emetics should also be provided following local institutional guidelines.
Other Name: Fludara

Drug: Cytoxan
Patients will receive 3 daily doses of cyclophosphamide (500 mg/m^2/day) to induce lymphopenia, finishing at least 24 hours before T cell infusion. Infusions should be given following hospital/pharmacy recommendations (including dose adjustments as appropriate per institutional guidelines); however at a minimum, the cyclophosphamide should be infused over 1 hour. Mesna, IV hydration and anti-emetics should also be provided following local institutional guidelines.
Other Name: cyclophosphamide




Primary Outcome Measures :
  1. Number of patients with dose limiting toxicity [ Time Frame: 6 weeks ]
    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 :
  1. Overall Response Rate [ Time Frame: 6 weeks ]
    To measure the anti-tumor effects of CD7.CAR-ATLs in patients with T-cell leukemia or lymphoma.



Information from the National Library of Medicine

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Ages Eligible for Study:   up to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03690011


Contacts
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Contact: LaQuisa Hill, MD 713-441-1450 LaQuisa.Hill@bcm.edu
Contact: Rayne Rouce, MD 832-824-4716 rhrouce@txch.org

Locations
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United States, Texas
Houston Methodist Hospital Not yet recruiting
Houston, Texas, United States, 77030
Contact: LaQuisa HIll, MD    832-824-4670    LaQuisa.Hill@bcm.edu   
Contact: Jacqueline Castello    713-441-1450    jxcastel@txch.org   
Texas Children's Hospital Not yet recruiting
Houston, Texas, United States, 77030
Contact: Rayne Rouce, MD    832-824-4716    rhrouce@txch.org   
Contact: Jacqueline Castello    832-824-4391    jxcastel@txch.org   
Sponsors and Collaborators
Baylor College of Medicine
The Methodist Hospital System
Texas Children's Hospital
Center for Cell and Gene Therapy, Baylor College of Medicine
Investigators
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Principal Investigator: Rayne Rouce, MD Pediatrics, Baylor College of Medicine
Principal Investigator: LaQuisa Hill, MD Baylor College of Medicine
Principal Investigator: Maksim Mamonkin, PhD Baylor College of Medicine
Principal Investigator: Malcolm K Brenner, MB, PhD Baylor College of Medicine

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Responsible Party: Rayne Rouce, Professor, Baylor College of Medicine
ClinicalTrials.gov Identifier: NCT03690011     History of Changes
Other Study ID Numbers: H-43761 - CRIMSON
First Posted: October 1, 2018    Key Record Dates
Last Update Posted: October 1, 2018
Last Verified: September 2018

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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 Rayne Rouce, Baylor College of Medicine:
Autologouse CAR T cells
T-cell Acute Lymphoblastic Leukemia
T-cell acute lymphoblastic lymphoma
T-non-Hodgkin lymphoma

Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Non-Hodgkin
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia
Cyclophosphamide
Fludarabine phosphate
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antimetabolites, Antineoplastic
Antimetabolites