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MT2017-45: CAR-T Cell Therapy for Heme Malignancies

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03642626
Recruitment Status : Recruiting
First Posted : August 22, 2018
Last Update Posted : May 25, 2021
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota

Brief Summary:
This is a phase II study of FDA-approved CAR-T products for patients with hematologic malignancies. Patients will be assigned to Arm A and B based on age and diagnosis. Overall remission rate, safety events and other endpoints will be calculated for Arm A and B separately.

Condition or disease Intervention/treatment
Acute Lymphoblastic Leukemia Large B-cell Lymphoma Drug: KYMRIAH Drug: YESCARTA Drug: Fludarabine 30mg/m2 4 doses Drug: Cyclophosphamide 500 mg/m2; 2 doses Drug: Fludarabine 30mg/m2 3 doses Drug: Cyclophosphamide 500 mg/m2; 3 doses Drug: Fludarabine 25mg/m2 3 days Drug: Cyclophosphamide 250 mg/m2; 3 days Drug: Tecartus

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Study Type : Observational
Estimated Enrollment : 120 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Chimeric Antigen Receptor (CAR)-T Cell Therapy for Patients With Hematologic Malignancies
Actual Study Start Date : December 18, 2018
Estimated Primary Completion Date : July 2028
Estimated Study Completion Date : July 2028


Group/Cohort Intervention/treatment
ARM A: Refractory/relapsed B-cell acute lymphoblastic leukemia (ALL) Drug: KYMRIAH
FDA approved CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells
Other Name: tisagenlecleucel

Drug: Fludarabine 30mg/m2 4 doses
30 mg/m2 IV daily for 4 doses

Drug: Cyclophosphamide 500 mg/m2; 2 doses
500 mg/m2 IV daily for 2 doses starting with the first dose of fludarabine

ARM B: Yescarta for Refractory diffuse large B cell lymphoma (DLBCL) Drug: YESCARTA
CD19-directed genetically modified autologous T cell immunotherapy

Drug: Fludarabine 30mg/m2 3 doses
30 mg/m2 IV daily for 3 doses

Drug: Cyclophosphamide 500 mg/m2; 3 doses
500 mg/m2 IV daily for 3 doses starting with the first dose of fludarabine

ARM C: Kymriah for Refractory diffuse large B cell lymphoma (DLBCL) Drug: KYMRIAH
FDA approved CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells
Other Name: tisagenlecleucel

Drug: Fludarabine 25mg/m2 3 days
25 mg/m2 i.v. daily for 3 days

Drug: Cyclophosphamide 250 mg/m2; 3 days
250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine

Arm D: Tecartus CAR-T product for Mantle Cell Leukemia (MCL) Drug: Fludarabine 30mg/m2 3 doses
30 mg/m2 IV daily for 3 doses

Drug: Cyclophosphamide 500 mg/m2; 3 doses
500 mg/m2 IV daily for 3 doses starting with the first dose of fludarabine

Drug: Tecartus
TECARTUS is a CD19-directed genetically modified autologous T cell immunotherapy, binds to CD19-expressing cancer cells and normal B cells
Other Name: Brexucabtagene Autoleucel




Primary Outcome Measures :
  1. Arm A: Complete Remission (CR) [ Time Frame: Day 28 ]
    Incidence of CR

  2. Arm A: CRi (complete remission without count recovery) [ Time Frame: Day 28 ]
    Incidence of CRi

  3. Arms B & C&D: Overall Response Rate (ORR) [ Time Frame: Week 8 ]
    ORR defined by complete response + partial response by Lugano


Secondary Outcome Measures :
  1. Arm A: MRD-negative CR (or CRi) [ Time Frame: Day 28 ]
    Proportion of patients with MRD-negative CR (or CRi)

  2. Arm A: Proportion of patients who are alive but not in remission [ Time Frame: Day 28 ]
    Proportion of patients who are alive but not in remission

  3. Arm A: Treatment Related Mortality (TRM) [ Time Frame: Day 28 ]
    Incidence of treatment related mortality (in absence of disease relapse/progression)

  4. Arm A: Treatment Related Mortality (TRM) [ Time Frame: Day 100 ]
    Incidence of treatment related mortality (in absence of disease relapse/progression)

  5. Arm A: Treatment Related Mortality (TRM) [ Time Frame: 1 Year ]
    Incidence of treatment related mortality (in absence of disease relapse/progression)

  6. Arm A: Relapse-free Survival (RFS) [ Time Frame: At complete remission, relapse, death ]
    Incidence of Relapse-free Survival (RFS)

  7. Arm A: Event-Free Survival (EFS) [ Time Frame: 1 Year post treatment ]
    Incidence of event-free survival (EFS) from the date of the CAR-T infusion through 1 year post treatment

  8. Arm A: Overall Survival (OS) [ Time Frame: Date of Death ]
    Incidence of Overall Survival (OS) from the date of the CAR-T infusion through the date of patient death for any reason.

  9. Arm A: Toxicity [ Time Frame: Day 28 ]
    Proportion of patients with grade 3 or 4 targeted toxicity of CRS and/or neurotoxicity

  10. Arms B/C/D: Complete Remission (CR) [ Time Frame: Day 28 ]
    Proportion of patients with Complete Remission by Lugano criteria

  11. Arms B/C/D: Treatment Related Mortality (TRM) [ Time Frame: Day 28 ]
    Incidence of treatment related mortality

  12. Arms B/C/D: Treatment Related Mortality (TRM) [ Time Frame: Day 100 ]
    Incidence of treatment related mortality

  13. Arms B/C/D: Treatment Related Mortality (TRM) [ Time Frame: 1 Year ]
    Incidence of treatment related mortality

  14. Arms B/C/D: Relapse-free Survival (RFS) [ Time Frame: At complete remission, relapse, or death ]
    Incidence of Relapse-free Survival (RFS)

  15. Arms B/C: Event-free Survival (EFS) [ Time Frame: 1 Year post treatment ]
    Event-free survival (EFS) from the date of the CAR-T infusion through 1 year post treatment

  16. Arms B/C/D: Overall Survival (OS) [ Time Frame: Date of Death ]
    Incidence of Overall Survival (OS) from the date of the CAR-T infusion through the date of patient death for any reason

  17. Arms B/C/D: Toxicity [ Time Frame: Day 28 ]
    Proportion of patients developing grade 3, 4 targeted toxicity of CRS and/or neurotoxicity



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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Study entry is open to patients 0 through 75 years of age with hematologic malignancies.
Criteria

ARM A: Kymriah for Refractory/relapsed B-cell acute lymphoblastic leukemia expressing CD19

Inclusion Criteria:

  • Age and Disease Status

    • Must be age 0-25 years
    • Disease status: Relapsed and refractory pediatric B-cell ALL defined by one of these:

      • Primary induction failure with no complete remission after ≥2 cycles of induction chemotherapy, or
      • Patients with persistent minimal residual disease (MRD >0.01% by flow cytometry or persistent by cytogenetic or molecular assays) after ≥2 cycles of consolidation chemotherapy, or
      • Patients in 2nd or greater relapse of B-ALL or
      • Patients with persistent CNS leukemia, or
      • Down Syndrome or other congenital diseases assuming that they fit the criteria for second or greater relapse or refractory leukemia, or
      • Patients with Ph+ ALL are eligible if theywho have failed or are intolerant to two lines of TKI assuming they fit the criteria for second or greater relapse or are considered refractory.
  • Performance Status

    • Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50% at screening
    • ALC >500/uL at screening (prior to apheresis) and absolute lymphocyte count >/= 150/uL
  • Organ Function

    • Renal function defined as:

      • A serum creatinine of ≤1.5 x ULN OR
      • eGFR ≥ 50 mL/min/1.73 m2
    • Liver function defined as:

      ** ALT ≤ 5 times the ULN for age (unless due to disease)

      ** Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN

    • Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
    • Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA
  • Other Inclusion Criteria

    • Life expectancy ≥12 weeks
    • Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use adequate birth control for the duration of treatment.
    • Written voluntary consent (adults) or parental/guardian consent (minors or adults with diminished capacity) prior to the performance of any research related tests or procedures.

Exclusion Criteria:

  • Pregnant or breastfeeding - Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
  • Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)
  • CNS 2A
  • CAR-T is not indicated for the treatment of patients with primary central nervous system lymphoma.
  • Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 2 weeks prior to apheresis.
  • Uncontrolled active hepatitis B or hepatitis C
  • Active HIV infection
  • Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
  • Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
  • Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
  • Intolerance to the excipients of the CAR-T cell product
  • Any immunosuppressive medication must be stopped ≥ 2 weeks prior to enrollment.
  • Patient has taken one of the prohibited concomitant medications within the timeframe outlined in section 6.1

ARM B: Yescarta for Relapsed or Refractory diffuse large B cell lymphoma

Inclusion Criteria:

  • Age and Disease Status

    • Adult patients (age ≥ 18 years)Patients must be ≥18 years of age
    • One of the following histologies and expression of CD19 by tumor cells:

      ** diffuse large B-cell lymphoma (DLBCL) not otherwise specified, or

      ** primary mediastinal large B-cell lymphoma, or

      ** high grade B-cell lymphoma, or

      ** DLBCL arising from follicular lymphoma

    • Disease status:

      ** Chemotherapy refractory disease after ≥2 lines of chemotherapy, or

      ** Relapsed with no remission after ≥1 lines of salvage chemotherapy, or

      ** Relapsed following autologous HCT (and failed at least 2 prior lines of therapy including high dose chemotherapy). If salvage therapy is given post autoHCT, the subject must have no response or relapse after the last line of therapy

    • Measurable disease at time of apheresis: Nodal lesions or extranodal lesion
    • ECOG performance status 0-2
    • ALC >/=100/uL at screening (prior to apheresis)
    • Renal function defined as:

      ** A serum creatinine of ≤1.5 x ULN OR

      ** eGFR ≥ 50 mL/min/1.73 m2

    • Liver function defined as:

      • ALT ≤ 5 times the ULN for age (unless due to disease)
      • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
    • Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
    • Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA
    • Adequate bone marrow reserve (unless marrow infiltrated by disease) defined as :

      • Absolute neutrophil count (ANC) > 1.000/mm3 (only for NHL)
      • Platelets ≥ 50.000/mm3 (transfusion support can be provided)
      • Hemoglobin >8.0 mg/dl (transfusion support can be provided)
    • Life expectancy ≥12 weeks
    • Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use adequate birth control for the duration of treatment.
    • Written voluntary consent (adults) or parental/guardian consent (minors or adults with diminished capacity) prior to the performance of any research related tests or procedures.

Exclusion Criteria:

  • Pregnant or breastfeeding - Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
  • Active CNS involvement by malignancy (no evidence of disease in CSF by flow cytometry) CAR-T is not indicated for the treatment of patients with primary central nervous system lymphoma.
  • Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 2 weeks prior to apheresis.
  • Uncontrolled active hepatitis B or hepatitis C
  • Active HIV infection (controlled HIV is permissible)
  • Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
  • Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
  • Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
  • Intolerance to the excipients of the CAR-T cell product
  • Any immunosuppressive medication must be stopped ≥ 2 weeks prior to apheresis.
  • Patient has taken one of the prohibited concomitant medications within the timeframe.

ARM C: Kymriah for rRelapsed or rRefractory diffuse large B cell lymphoma

Inclusion Criteria:

  • Age and Disease Status

    • Adult patients (age ≥ 18 years)
    • with relapsed or refractory (r/r) large B-cell lymphoma, including

      • diffuse large B-cell lymphoma (DLBCL) not otherwise specified,
      • high grade B-cell lymphoma
      • and DLBCL arising from follicular lymphoma.
    • Disease status:

      • after two or more lines of systemic therapy or
      • relapse after autologous HCT
  • Performance Status

    • ECOG performance status 0-2
    • ALC >/=100/uL at screening (prior to apheresis)
  • Organ Function

    • Renal function defined as:

      • A serum creatinine of ≤1.5 x ULN OR
      • eGFR ≥ 50 mL/min/1.73 m^2
    • Liver function defined as:

      • ALT ≤ 5 times the ULN for age (unless due to disease)
      • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
    • Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
    • Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA
    • Adequate bone marrow reserve (unless marrow infiltrated by disease) defined as :

      • Absolute neutrophil count (ANC) > 1.000/mm3 (only for NHL)
      • Platelets ≥ 50.000/mm3 (transfusion support can be provided)
      • Hemoglobin >8.0 mg/dl (transfusion support can be provided)
  • Other Inclusion Criteria

    • Life expectancy ≥12 weeks
    • Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use adequate birth control for the duration of treatment.
    • Written voluntary consent (adults) or parental/guardian consent (minors or adults with diminished capacity) prior to the performance of any research related tests or procedures.

Exclusion Criteria:

  • Pregnant or breastfeeding - Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
  • Active CNS involvement by malignancy (no evidence of disease in CSF by flow cytometry) CAR-T is not indicated for the treatment of patients with primary central nervous system lymphoma.
  • Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 2 weeks prior to apheresis.
  • Uncontrolled active hepatitis B or hepatitis C
  • Active or inactive HIV infection
  • Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
  • Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
  • Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
  • Intolerance to the excipients of the CAR-T cell product
  • Any immunosuppressive medication must be stopped ≥ 2 weeks prior to apheresis.
  • Patient has taken one of the prohibited concomitant medications within the timeframe

ARM D: Tecartus (Brexucabtagene Autoleucel) for relapsed or refractory mantle cell lymphoma

Inclusion Criteria:

  • Age and Disease Status

    * with relapsed or refractory (r/r) mantle cell lymphoma, including

    • prior anthracycline or Bendamustine containing therapy
    • prior Rituximab or other CD20 directed antibody (or inability to treat with CD20 MoAb)
    • not a candidate or relapse after autologous HCT
    • active disease at enrollment
  • Performance Status

    *ECOG performance status 0-1

  • Organ Function

    • Renal function defined as:

      • A serum creatinine of ≤1.5 x ULN OR
      • eGFR ≥ 50 mL/min/1.73 m2
    • Liver function defined as:

      • ALT ≤ 5 times the ULN for age (unless due to disease)
      • Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert syndrome; may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN
  • Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
  • Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA
  • Adequate bone marrow reserve (unless marrow infiltrated by disease) defined as:
  • Absolute neutrophil count (ANC) > 1,000/mm^3 (only for NHL)
  • Platelets ≥ 50,000/mm^3 (transfusion support can be provided)
  • Hemoglobin >8.0 mg/dl (transfusion support can be provided)

Other Inclusion Criteria:

  • Life expectancy ≥12 weeks
  • Women of child bearing potential and sexually active males with partners of child bearing potential must agree to use adequate birth control for the duration of treatment. See section 4.5 for definitions of child bearing potential and section 4.6 for definitions of adequate birth control.
  • Written voluntary consent (adults) or parental/guardian consent (minors or adults with diminished capacity) prior to the performance of any research related tests or procedures.

Exclusion Criteria:

  • Pregnant or breastfeeding - Females of childbearing potential must have a blood test or urine study within 14 days prior to registration to rule out pregnancy.
  • Active CNS involvement by malignancy (no evidence of disease in CSF by flow cytometry) CAR-T is not indicated for the treatment of patients with primary central nervous system lymphoma.
  • Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 2 weeks prior to apheresis.
  • Uncontrolled active hepatitis B or hepatitis C
  • Active HIV infection
  • Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
  • Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
  • Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
  • Intolerance to the excipients of the CAR-T cell product
  • Any immunosuppressive medication must be stopped ≥ 2 weeks prior to apheresis (steroids must be stopped >72 hours prior to apheresis).
  • Patient has taken one of the prohibited concomitant medications within the timeframe

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): NCT03642626


Contacts
Layout table for location contacts
Contact: Tamy Grainger, RN 612-273-2800 tgraing1@fairview.org
Contact: Carol Rose 612-273-2800 crose1@faireview.org

Locations
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United States, Minnesota
Masonic Cancer Center at University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
Contact: Tamy Grainger, RN    612-273-2800    tgraing1@fairview.org   
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
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Principal Investigator: Veronika Bachanova, MD, PhD Masonic Cancer Center, University of Minnesota
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Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT03642626    
Other Study ID Numbers: 2017LS118
MT2017-45 ( Other Identifier: University of Minnesota Masonic Cancer Center )
First Posted: August 22, 2018    Key Record Dates
Last Update Posted: May 25, 2021
Last Verified: May 2021

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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
Keywords provided by Masonic Cancer Center, University of Minnesota:
ALL
CAR-T
CAR19-T
chimeric antigen receptor T cells
Additional relevant MeSH terms:
Layout table for MeSH terms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Vidarabine
Cyclophosphamide
Fludarabine
Fludarabine phosphate
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
Antiviral Agents
Anti-Infective Agents