Using modified T-cells to treat certain blood cancers

Phase 1 Therapy With Manufactured Autologous T-Cells Expressing a Second Generation Chimeric Antigen Receptor (CAR) for Treatment of T-Cell Malignancies Expressing CD5 Antigen

This study is testing a new way to treat certain blood cancers by using modified T-cells from patients to see if they can better fight the cancer after chemotherapy.

Quick facts

• Phase: PHASE1
• Study type: Interventional
• Enrollment: 54 (estimated)
• Ages: N/A to 75 Years
• Sex: All
• Sponsor: Baylor College of Medicine (other)
• Drugs / interventions: CAR T, chemotherapy, prednisone, Rituximab, cyclophosphamide, fludarabine
• Locations: 2 sites (Houston, Texas and 1 other locations)
• Trial ID: NCT03081910 on ClinicalTrials.gov

What this trial studies

This clinical trial focuses on patients with T-cell malignancies, specifically T-cell acute lymphoblastic leukemia and lymphoma. It involves extracting T-cells from the patient's blood or a previous donor, modifying them with a gene that enhances their ability to target cancer cells, and then infusing these engineered T-cells back into the patient. Prior to the infusion, patients will receive chemotherapy to reduce their existing T-cell population, allowing the modified cells to proliferate effectively. The study will monitor patients for long-term effects of this gene therapy approach over a period of 15 years.

Who should consider this trial

Good fit: Ideal candidates include individuals diagnosed with recurrent T-cell acute lymphoblastic leukemia, T-cell acute lymphoblastic lymphoma, or T-non-Hodgkin lymphoma.

Not a fit: Patients with other types of blood cancers or those who are not eligible for T-cell modification may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new, effective option for patients with difficult-to-treat T-cell malignancies.

How similar studies have performed: Other studies using CAR T-cell therapy have shown promising results, indicating that this approach may be effective for similar conditions.

Eligibility criteria

Procurement Inclusion Criteria for the Patient

Referred patients (Group A - NOW CLOSED) or their previous HSCT donors (Group B) will initially be consented for procurement of blood for generation of the transduced ATL. Patient 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

   Group A (auto arm - NOW CLOSED): Transplant naïve or relapsed post-allogeneic HSCT OR

   Group B (allo arm): Relapsed post-allogeneic HSCT with previous HSCT donor from whom allogeneic MAGENTA CAR T cells can be manufactured

   AND
   * Suitable for allogeneic hematopoietic stem cell transplant (HSCT) with confirmation of an identified eligible allo-HSCT donor by FACT accredited institution
   * Confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission.

     * For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated.
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 ≤75 years old. NOTE: The first six (6) patients treated on the study should be adults (\>18 yrs of age).
4. Life expectancy of greater than 12 weeks.
5. Patients must have an available partially-HLA matched allogeneic EBV-specific T cell line on a BCM IRB approved protocol which can be used as treatment in the event of uncontrolled EBV reactivation
6. Informed consent explained to, understood by and signed by patient/guardian. Patient/guardian given copy of informed consent.
7. Hgb greather than or equal to 7.0 g/dL (can be transfused)
8. 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

Procurement Exclusion Criteria for the Patient (Group A)

1. Active infection requiring antibiotics.
2. Active infection with HIV
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.

Procurement Inclusion Criteria for Normal Healthy Donor (Group B):

1. Donor must be prior hematopoietic stem cell transplant donor for patients relapsed post-allogeneic HSCT. Prior transplant donors will be screened with the standard blood bank donor questionnaire, medical history, and testing for infectious disease markers (IDMs; which may be pending at the time of blood collection). Medical history may be obtained by the patient's primary/referring transplant team if collection is being done remotely. The physician assessment, donor questionnaire, and IDMs will be reviewed by the principle investigator or appropriate designee to confirm/provide final eligibility determination and documented in the donor's medical record.
2. Informed consent explained to, understood by and signed by donor/LAR. Donor/LAR given copy of informed consent.

Treatment Inclusion Criteria

Patients must meet the following eligibility criteria to be included for treatment:

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

   Group A (auto arm - NOW CLOSED): Transplant naïve or relapsed post-allogeneic HSCT OR

   Group B (allo arm): Relapsed post-allogeneic HSCT with previous HSCT donor from whom allogeneic MAGENTA CAR T cells can be manufactured

   AND
   * Suitable for allogeneic hematopoietic stem cell transplant (HSCT) with confirmation of an identified eligible allo-HSCT donor by FACT accredited institution
   * Confirmation that the center plans to proceed with transplant if CD5.CAR treatment induces a complete remission.

     * For T-NHL subjects, eligibility will be confined to disease stages where allogeneic HSCT is indicated.
2. CD5-positive tumor. \>50% CD5 + blasts by flow cytometry or immunohistochemistry (tissue) assessed by a CLIA certified Flow Cytometry/Pathology laboratory.
3. Age \<75 years old. NOTE: The first six (6) patients treated on the study should 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. ≥ 60 days post-allogeneic HSCT at time of treatment.
11. Patients must have an available partially-HLA matched allogeneic EBV-specific T cell line on a BCM IRB approved protocol which can be used as treatment in the event of uncontrolled EBV reactivation.
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.
6. Clinically significant viral infection or uncontrolled viral reactivation of EBV, CMV, Adv, BK-virus, or HHV-6.
7. Evidence of acute GVHD \> Grade II or active chronic GVHD \> mild global severity score
8. Currently taking corticosteroids for therapy of GVHD at a dose of \>0.5mg/kg prednisone equivalent
9. Patients who have received Immunosuppressive Treatment (IST) for GVHD within 28 days of infusion
10. Patients who have received donor lymphocyte infusion (DLI) within 28 days of infusion
11. 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 within 12 months of treatment)
12. CNS abnormalities: Presence of CNS-3 disease defined as detectable cerebrospinal blast cells in a sample of CSF with ≥ 5 WBCs per mm3; History or presence of any CNS disorder such as a uncontrolled seizure disorder, cerebrovascular ischemia/hemorrhage within prior 6 months, dementia, cerebellar disease, or any autoimmune disease with CNS involvement.

Where this trial is running

Houston, Texas and 1 other locations

• Houston Methodist Hospital — Houston, Texas, United States (RECRUITING)
• Texas Children's Hospital — Houston, Texas, United States (RECRUITING)

Study contacts

• Principal investigator: Rayne Rouce, MD — Baylor College of Medicine
• Study coordinator: Rayne Rouce, MD

Conditions: T-cell Acute Lymphoblastic Lymphoma, T-non-Hodgkin Lymphoma, T-cell Acute Lymphoblastic Leukemia, Autologous CAR T cells, T-cell acute lymphoblastic lymphoma, Allogeneic CAR T cells