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Autologous T-Cells Expressing a Second Generation CAR for Treatment of T-Cell Malignancies Expressing CD5 Antigen (MAGENTA)

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ClinicalTrials.gov Identifier: NCT03081910
Recruitment Status : Recruiting
First Posted : March 16, 2017
Last Update Posted : March 15, 2019
Sponsor:
Collaborators:
Center for Cell and Gene Therapy, Baylor College of Medicine
The Methodist Hospital System
Texas Children's Hospital
Information provided by (Responsible Party):
Rayne Rouce, Baylor College of Medicine

Tracking Information
First Submitted Date  ICMJE March 8, 2017
First Posted Date  ICMJE March 16, 2017
Last Update Posted Date March 15, 2019
Actual Study Start Date  ICMJE November 1, 2017
Estimated Primary Completion Date July 15, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 10, 2017)
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 CD5 molecule (CD5.CAR) in combination with lymphodepletion in patients with relapsed/refractory T-cell malignancies.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03081910 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 17, 2017)
Overall Response Rate [ Time Frame: 6 weeks ]
To measure the anti-tumor effects of CD5.CAR-ATLs in patients with T-cell leukemia or lymphoma.
Original Secondary Outcome Measures  ICMJE
 (submitted: March 10, 2017)
Overall Response Rate [ Time Frame: 6 weeks ]
1.10.1. To measure the anti-tumor effects of CD5.CAR-ATLs in patients with T-cell leukemia or lymphoma.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Autologous T-Cells Expressing a Second Generation CAR for Treatment of T-Cell Malignancies Expressing CD5 Antigen
Official Title  ICMJE Phase 1 Therapy of Manufactured Autologous T-Cells Expressing a Second Generation Chimeric Antigen Receptor (CAR) for Treatment of T-Cell Malignancies Expressing CD5 Antigen
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. No one way seems perfect for fighting cancers. This research study combines two different ways of fighting disease, antibodies and T cells, hoping that they will work together. Antibodies are types of proteins that protect the body from bacterial and other diseases. T cells, also called 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 patients with cancers; they have shown promise, but have not been strong enough to cure most patients.

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 is called anti-CD5. It first came from mice that have developed immunity to human leukemia. This antibody sticks to T-cell leukemia or lymphoma cells because of a substance on the outside of these cells called CD5. CD5 antibodies have been used to treat people with T-cell leukemia and lymphoma. For this study, anti-CD5 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, 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 investigators are going to attach the CD5 chimeric receptor with CD28 added to it to the patient's T cells. The investigators will then test how long the cells last. These CD5 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. To get the CD5 antibody and CD28 to attach to the surface of the T cell, investigators 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 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 is enrolled on this study, they will be assigned a dose of CD5 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 circulation . Because of that, the patient will receive two chemotherapy medications prior to receiving the CD5 chimeric 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 the patient receives the chimeric receptor-T cells. These drugs will decrease the numbers of the patient's own T cells before the CD5 chimeric receptor T cells are infused and also will help decrease the number of other cells that may interfere with the chimeric receptor-T cells working well. Although we do not expect any effect on the patient's tumor with the doses that the patient will receive, these drugs are part of many regimens that are used to treat leukemia or lymphoma.

The patient 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 the patient receives 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.

The patient will be followed in the clinic after the injection for up to 3 hours, and the patient will have to remain locally for at least 3 weeks after the infusion. If the patient experiences any side effects, they may have to be hospitalized for evaluation and management.

If after a 6-8 week evaluation period after the infusion, the patient has achieved a complete response (measured by bone marrow or radiology scans), the patient's primary oncology doctors may decide the patient should proceed to bone marrow transplant, at which time the patient will be removed from the treatment portion of the study.

Before being treated, the patient 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 the patient's tumor by scans and/or bone marrow studies

The patient will also receive standard medical tests during treatment 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 6-8 weeks after the infusion and then per standard of care.

To learn more about the way the CD5 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 the patient is anemic. This blood may be drawn from a central line if the patient has one. Blood will be taken before the chemotherapy drugs, several hours after the T cell infusion, at 1 week, 2 weeks, 3 weeks (optional), 4 weeks, 6 weeks and 8 weeks (optional) 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. We will also test blood to check for signs of viral infection at the following time points: within 1 to 2 weeks prior to chemotherapy drugs, prior to T cell infusion, then at weeks 1, 2, 3, 4, 6, 8 for all patients, and months 3, 6, 9, 12 for patients who do not proceed to bone marrow transplant. The total blood drawn during participation in this study will not exceed 280 teaspoons.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • T-cell Acute Lymphoblastic Lymphoma
  • T-non-Hodgkin Lymphoma
  • T-cell Acute Lymphoblastic Leukemia
Intervention  ICMJE
  • Genetic: CD5.CAR/28zeta CAR T cells

    Three dose levels will be evaluated:

    Dose level one: 1×10^7 cells/m2

    Dose level two: 5×10^7 cells/m2

    Dose level three: 1×10^8 cells/m2

    The first six (6) patients treated on the study will be adults (>18 yrs of age). Six adolescents (age 12-18) will be treated before children (>3 yrs of age) are eligible.

    Three dose levels will be evaluated. The T cells will be administered with Cytoxan and fludarabine.

  • Drug: Fludarabine
    Patients will receive 3 daily doses of fludarabine (30 mg/m2) 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/m2/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
Study Arms  ICMJE Experimental: CD5.CAR/28zeta CAR T cells
Three dose levels will be evaluated. The T cells will be administered with Cytoxan and fludarabine.If patients have experienced either a partial response or stable disease and completed the 6 week toxicity evalution without evidence of DLT or other infectious complications, they will be eligible to receive up to 3 additional infusions of CD5 CAR.T cells. Patients remain eligible for up to 3 additional infusions as long as they continue to have a clinical response and absence of safety concerns. If patients experience a complete response following an additional infusion, investigators will recommend they proceed to allogeneic HSCT.
Interventions:
  • Genetic: CD5.CAR/28zeta CAR T cells
  • Drug: Fludarabine
  • Drug: Cytoxan
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: August 17, 2017)
21
Original Estimated Enrollment  ICMJE
 (submitted: March 10, 2017)
14
Estimated Study Completion Date  ICMJE June 1, 2036
Estimated Primary Completion Date July 15, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 Suitable for allogeneic HSCT with confirmation of an identified eligible allo-HSCT donor by a FACT accredited transplant center

    AND with confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission.

  2. CD5-positive tumor (result can be pending at this time). > 50% CD5 + blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory.
  3. Age less than or equal to 75 years old. NOTE: The first six (6) patients treated on the study will be adults (>18 yrs of age). Six adolescents (age 12-18) will be treated before children (>3 yrs of age) are eligible.
  4. Hgb greater than or equal to 7.0 (can be transfused)
  5. Life expectancy greater than 12 weeks
  6. If pheresis required to collect blood:

    • Creatinine <1.5 × upper limit normal
    • AST <1.5 × 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. Clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV, Adv, BK-virus, or HHV-6.
  4. 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 less than or equal to 30% or LVEF less than or equal to 50% or clinically significant pericardial effusion; Cardiac dysfunction NYHA III or IV (Confirmation of absence of these conditions within 12 months of treatment).
  5. 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 suitable for allogeneic HSCT with confirmation of an identified eligible allo-HSCT donor by a FACT accredited transplant center

    AND with confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission.

  2. CD5-positive tumor: >50% CD5+ blasts by flow cytometry or immunohistochemistry (tissue) assessed in a CLIA certified Flow Cytometry/Pathology laboratory.
  3. Age less than or equal to 75 years old. NOTE: The first six (6) patients treated on the study will be adults (>18 yrs of age). Six adolescents (age 12-18) will be treated before children (>3 yrs of age) are eligible.
  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 greater than or equal to 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 greater than or equal to 20% expression of CD5.CAR.28 zeta and <0.5% gene-modified malignant T blasts by flow cytometry.
  11. Life expectancy of greater than 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.

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.
  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. Cardiac criteria: Prolonged QT syndrome; Atrial fibrillation/flutter; Myocardial infarction within the last 12 months; Cardiac echocardiography with LVSF less than or equal to 30% or LVEF less than or equal to 50%; Cardiac dysfunction NYHA III or IV; Cardiac echocardiography with clinically significant pericardial effusion.
  8. CNS abnormalities: Presence of CNS-3 disease defined as detectable cerebrospinal blast cells in a sample of CSF with greater than or equal to 5 WBCs per mm3; History or presence of any CNS disorder such as a seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 75 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Rayne Rouce, MD 832-824-4716 rhrouce@txch.org
Contact: Josalind Randall 832-824-6835 jxrandal@txch.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03081910
Other Study ID Numbers  ICMJE H-40466, MAGENTA
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Rayne Rouce, Baylor College of Medicine
Study Sponsor  ICMJE Baylor College of Medicine
Collaborators  ICMJE
  • Center for Cell and Gene Therapy, Baylor College of Medicine
  • The Methodist Hospital System
  • Texas Children's Hospital
Investigators  ICMJE
Principal Investigator: Rayne Rouce, MD Baylor College of Medicine
PRS Account Baylor College of Medicine
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP