Clinical Trials /

Human AntiCD19 Chimeric Antigen Receptor T Cells for Relapsed or Refractory Lymphoid Malignancies

NCT04732845

Description:

The purpose of this study is to determine if it is possible to treat relapsed or refractory lymphoid malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia) with a new type of T cell-based immunotherapy (therapy that uses the immune system to treat the cancer).

Related Conditions:
  • Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia
  • Non-Hodgkin Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Human AntiCD19 Chimeric Antigen Receptor T Cells for Relapsed or Refractory Lymphoid Malignancies
  • Official Title: Phase I Clinical Trial of Human AntiCD19 Chimeric Antigen Receptor T Cells for Treatment of Relapsed or Refractory Lymphoid Malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia)

Clinical Trial IDs

  • ORG STUDY ID: CASE2419
  • NCT ID: NCT04732845

Conditions

  • Non Hodgkin Lymphoma
  • Acute Lymphoblastic Leukemia
  • Chronic Lymphocytic Leukemia

Interventions

DrugSynonymsArms
Fully human anti CD19 CAR-T Cell DoseGroup A - NHL/CLL
FludarabineFludaraGroup A - NHL/CLL
CyclophosphamideCytoxan, Endoxan, Neosar, Procytox, Revimmune, CycloblastinGroup A - NHL/CLL

Purpose

The purpose of this study is to determine if it is possible to treat relapsed or refractory lymphoid malignancies (Non-Hodgkin Lymphoma, Acute Lymphoblastic Leukemia, Chronic Lymphocytic Leukemia) with a new type of T cell-based immunotherapy (therapy that uses the immune system to treat the cancer).

Detailed Description

      This study seeks to determine the safety of the treatment of relapsed or refractory B cell
      lymphomas, relapsed/ refractory chronic lymphocytic leukemia and relapsed/refractory acute
      lymphoblastic leukemia with chimeric antigen receptor T cells targeting CD19 and to find the
      recommended phase II dose for this cellular therapy.

      T cells are a type of white blood cell that helps the body fight infections. This treatment
      uses T cells already present within the body that have been modified outside of the body by a
      lentivirus and then returned to the participant by an infusion to target the cancer.
      Lentivirus is a family of viruses that can be used by scientists to alter cells, which then
      could be used to change the course of a disease. This type of treatment is sometimes referred
      to as adoptive cell transfer (ACT). In this study the specific type of cells that will be
      used is called human chimeric antigen receptor T cells (CAR-T cells). The CAR-T cells that
      will be reinfused to the body are modified using a lentivirus that is no longer active. The
      CAR-T cells will be returned to the body through an intravenous (IV) infusion. Another
      purpose of this study is to learn about the side effects and toxicities related to this
      treatment. Human CAR-T cell therapy is investigational (experimental) and works by removing T
      cells from the blood and modifying them to be able to target the cancer.
    

Trial Arms

NameTypeDescriptionInterventions
Group A - NHL/CLLExperimentalUpon enrollment, peripheral blood mononuclear cells will be collected, and T-cell selection and manufacture of CAR-T cells will be done. Participants will receive 60 mg/Kg/IV Cyclophosphamide on day -6 and 25 mg/m^2 Fludarabine from day -5 to day -3. Participants with CD19+ lymphomas and chronic lymphocytic leukemia will be enrolled on this arm sequentially in a 3 + 3 design starting with infusion of CAR-T cells at dose level 1 (DL1) on day 0. The maximum tolerated dose (MTD) will be determined and then 6 additional participants will be enrolled at the MTD.
  • Fully human anti CD19 CAR-T Cell Dose
  • Fludarabine
  • Cyclophosphamide
Group B - ALLExperimentalUpon enrollment, peripheral blood mononuclear cells will be collected, and T-cell selection and manufacture of CAR-T cells will be done. Participants will receive 60 mg/Kg/IV Cyclophosphamide on day -6 and 25 mg/m^2 Fludarabine from day -5 to day -3. Participants with Acute Lymphoblastic Leukemia (and lymphoblastic lymphoma as a solid tumor equivalent) will be enrolled on this arm sequentially in a 3 + 3 design starting with infusion of CAR-T cells at DL1 on day 0 and 7. The maximum tolerated dose (MTD) will be determined and then 6 additional participants will be enrolled at the MTD.
  • Fully human anti CD19 CAR-T Cell Dose
  • Fludarabine
  • Cyclophosphamide

Eligibility Criteria

        Inclusion Criteria:

          -  Must have relapsed or refractory non-Hodgkin lymphoma (NHL) (Group A - NHL/CLL),
             chronic lymphocytic leukemia (Group A - NHL/CLL) or acute lymphoblastic leukemia
             (Group B - ALL) treated with at least two lines of therapy. Disease must have either
             progressed after the last regimen or presented failure to achieve complete remission
             with the last regimen.

          -  The participant's lymphoid malignancy must be cluster of differentiation antigen 19
             (CD19) positive, either by immunohistochemistry or flow cytometry analysis on the last
             biopsy available or peripheral blood for circulating disease.

          -  Eastern Cooperative Oncology Group (ECOG) Performance status ≤ 2

          -  Total bilirubin ≤ 1.5 times the institutional upper limit of normal

          -  AST (SGOT) ≤ 3 X institutional upper limit of normal

          -  ALT (SGPT) ≤ 3 X institutional upper limit of normal

          -  Serum Creatinine ≤ 2 X the institutional upper limit of normal unless bilirubin rise
             is due to Gilbert's syndrome (maximum 2 times normal) or of non - hepatic origin.

          -  Must have adequate pulmonary function as defined as pulse oximetry ≥ 92% on room air.

          -  Must have adequate cardiac function as defined as left ventricular ejection fraction≥
             40% in the most recent echocardiogram.

          -  Absolute Lymphocyte Count >100/microliter (uL)

          -  Participants (or legal guardians) must have the ability to understand and the
             willingness to sign a written informed consent document.

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
             per year during the treatment period and for at least 90 days after the human
             anti-CD19 CAR-T cell infusion. A woman is considered to be of childbearing potential
             if she is postmenarcheal, has not reached a postmenopausal state (< 12 continuous
             months of amenorrhea with no identified cause other than menopause), and has not
             undergone surgical sterilization (removal of ovaries and/or uterus). Examples of
             contraceptive methods with a failure rate of < 1% per year include bilateral tubal
             ligation, male sterilization, hormonal contraceptives that inhibit ovulation,
             hormone-releasing intrauterine devices, and copper intrauterine devices. The
             reliability of sexual abstinence should be evaluated in relation to the duration of
             the clinical trial and the preferred and usual lifestyle of the patient. Periodic
             abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and
             withdrawal are not acceptable methods of contraception.

          -  For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use
             contraceptive measures, and agreement to refrain from donating sperm, as defined
             below: With female partners of childbearing potential, men must remain abstinent or
             use a condom plus an additional contraceptive method that together result in a failure
             rate of < 1% per year during the treatment period and for at least 6 months after the
             human anti-CD19 CAR-T cell infusion. Men must refrain from donating sperm during this
             same period. With pregnant female partners, men must remain abstinent or use a condom
             during the treatment period and for at least 6 months after the human antiCD19 CAR-T
             cell infusion to avoid potential embryonal or fetal exposure. The reliability of
             sexual abstinence should be evaluated in relation to the duration of the clinical
             trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,
             calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not
             acceptable methods

        Exclusion Criteria:

          -  Autologous transplant within 6 weeks of planned CAR-T cell infusion.

          -  Allogeneic stem cell transplant within 3 months of planned CAR-T cell infusion and
             patients must be off immunosuppressive agents.

          -  Active graft versus host disease.

          -  Active central nervous system or meningeal involvement by lymphoma or leukemia.
             Subjects with untreated brain metastases/central nervous system (CNS) disease will be
             excluded from this clinical trial because of their poor prognosis and because they
             often develop progressive neurologic dysfunction that would confound the evaluation of
             neurologic and other adverse events.

          -  Participants with a history of CNS or meningeal involvement must be in a documented
             remission by cerebrospinal fluid (CSF) evaluation and contrast-enhanced MRI imaging
             for at least 90 days prior to registration.

          -  Active malignancy, other than non-melanoma skin cancer or carcinoma in situ (e.g.
             cervix, bladder, breast).

          -  A minimum of 28 days must have elapsed between prior treatment with investigational
             agent(s) and the day of lymphocyte collection.

          -  HIV seropositivity.

          -  Participants with uncontrolled intercurrent illness including, but not limited to
             ongoing or active infection, symptomatic congestive heart failure, unstable angina
             pectoris, cardiac arrhythmia, pulmonary abnormalities or psychiatric illness/social
             situations that would limit compliance with study requirements.

          -  Pregnant or breastfeeding women are excluded from this study because CAR-T cell
             therapy may be associated with the potential for teratogenic or abortifacient effects.
             Women of childbearing potential must have a negative serum pregnancy test. Because
             there is an unknown, but potential risk for adverse events in nursing infants
             secondary to treatment of the mother with CAR-T cells, breastfeeding should be
             discontinued. These potential risks may also apply to other agents used in this study.

          -  Evidence of myelodysplasia or cytogenetic abnormality indicative of myelodysplasia on
             any bone marrow biopsy prior to initiation of therapy

          -  Serologic status reflecting active hepatitis B or C infection. Patients that are
             positive for hepatitis B core antibody, hepatitis B surface antigen (HBsAg), or
             hepatitis C antibody must have a negative polymerase chain reaction (PCR) prior to
             enrollment. (PCR positive patients will be excluded.)

          -  Participants with history of clinically relevant CNS pathology such as epilepsy,
             seizure disorders, paresis, aphasia, uncontrolled cerebrovascular disease, severe
             brain injuries, dementia and Parkinson's disease.

          -  History of autoimmune disease (i.e. rheumatoid arthritis, systemic lupus
             erythematosus) with requirement of immunosuppressive medication within 6 months.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase II dose of human anti-CD19 CAR-T cells
Time Frame:24 months
Safety Issue:
Description:Recommended phase II dose of human anti-CD19 CAR-T cells

Secondary Outcome Measures

Measure:Number of participants experiencing grade 3 or more adverse events
Time Frame:18 months
Safety Issue:
Description:Toxicity profile for to infusion of fully human CAR-T cells, as measured by number of participants experiencing grade 3 or more adverse events
Measure:Number of participants experiencing dose limiting toxicities
Time Frame:18 months
Safety Issue:
Description:Toxicity profile for to infusion of fully human CAR-T cells, as measured by number of participants experiencing dose limiting toxicities
Measure:Overall response rate (ORR)
Time Frame:30 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:ORR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Overall response rate (ORR)
Time Frame:60 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:ORR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Overall response rate (ORR)
Time Frame:90 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:ORR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Overall response rate (ORR)
Time Frame:6 months after day 0 (first CAR-T treatment)
Safety Issue:
Description:ORR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Overall response rate (ORR)
Time Frame:12 months after day 0 (first CAR-T treatment)
Safety Issue:
Description:ORR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Complete response rate (CR)
Time Frame:30 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:CR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Complete response rate (CR)
Time Frame:60 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:CR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Complete response rate (CR)
Time Frame:90 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:CR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Complete response rate (CR)
Time Frame:6 months after day 0 (first CAR-T treatment)
Safety Issue:
Description:CR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Complete response rate (CR)
Time Frame:12 months after day 0 (first CAR-T treatment)
Safety Issue:
Description:CR relapsed B cell malignancies treated with CAR-T cells targeting CD19
Measure:Progression Free Survival (PFS)
Time Frame:30 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:PFS from time of infusion
Measure:Progression Free Survival (PFS)
Time Frame:60 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:PFS from time of infusion
Measure:Progression Free Survival (PFS)
Time Frame:90 days after day 0 (first CAR-T treatment)
Safety Issue:
Description:PFS from time of infusion
Measure:Progression Free Survival (PFS)
Time Frame:6 months after day 0 (first CAR-T treatment)
Safety Issue:
Description:PFS from time of infusion
Measure:Progression Free Survival (PFS)
Time Frame:12 months after day 0 (first CAR-T treatment)
Safety Issue:
Description:PFS from time of infusion

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Paolo Caimi, MD

Last Updated

February 1, 2021