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

Overview

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.

Full Title of Study: “Chimeric Antigen Receptor (CAR)-T Cell Therapy for Patients With Hematologic Malignancies”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: July 2028

Interventions

  • Drug: KYMRIAH
    • FDA approved CD19-directed genetically modified autologous T cell immunotherapy comprised of autologous T cells
  • Drug: YESCARTA
    • CD19-directed genetically modified autologous T cell immunotherapy
  • Drug: Fludarabine
    • 30 mg/m2 IV daily for 4 doses
  • Drug: Cyclophosphamide
    • 500 mg/m2 IV daily for 2 doses starting with the first dose of fludarabine
  • Drug: Fludarabine
    • 30 mg/m2 IV daily for 3 doses
  • Drug: Cyclophosphamide
    • 500 mg/m2 IV daily for 3 doses starting with the first dose of fludarabine
  • Drug: Fludarabine
    • 25 mg/m2 i.v. daily for 3 days
  • Drug: Cyclophosphamide
    • 250 mg/m2 IV daily for 3 days starting with the first dose of fludarabine

Arms, Groups and Cohorts

  • ARM A: Refractory/relapsed B-cell acute lymphoblastic leuk
  • ARM B: Yescarta for Refractory diffuse large B cell lymphom
  • ARM C: Kymriah for Refractory diffuse large B cell lymphom

Clinical Trial Outcome Measures

Primary Measures

  • Arm A: Complete Remission (CR)
    • Time Frame: Day 28
    • Incidence of CR
  • Arm A: CRi (complete remission without count recovery)
    • Time Frame: Day 28
    • Incidence of CRi
  • Arms B & C: Overall Response Rate (ORR)
    • Time Frame: Week 8
    • ORR defined by complete response + partial response by Lugano

Secondary Measures

  • Arm A: MRD-negative CR (or CRi)
    • Time Frame: Day 28
    • Proportion of patients with MRD-negative CR (or CRi)
  • 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
  • Arm A: Treatment Related Mortality (TRM)
    • Time Frame: Day 28
    • Incidence of treatment related mortality (in absence of disease relapse/progression)
  • Arm A: Treatment Related Mortality (TRM)
    • Time Frame: Day 100
    • Incidence of treatment related mortality (in absence of disease relapse/progression)
  • Arm A: Treatment Related Mortality (TRM)
    • Time Frame: 1 Year
    • Incidence of treatment related mortality (in absence of disease relapse/progression)
  • Arm A: Relapse-free Survival (RFS)
    • Time Frame: At complete remission, relapse, death
    • Incidence of Relapse-free Survival (RFS)
  • 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
  • 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.
  • Arm A: Toxicity
    • Time Frame: Day 28
    • Proportion of patients with grade 3 or 4 targeted toxicity of CRS and/or neurotoxicity
  • Arms B/C: Complete Remission (CR)
    • Time Frame: Day 28
    • Proportion of patients with Complete Remission by Lugano criteria
  • Arms B/C: Treatment Related Mortality (TRM)
    • Time Frame: Day 28
    • Incidence of treatment related mortality
  • Arms B/C: Treatment Related Mortality (TRM)
    • Time Frame: Day 100
    • Incidence of treatment related mortality
  • Arms B/C: Treatment Related Mortality (TRM)
    • Time Frame: 1 Year
    • Incidence of treatment related mortality
  • Arms B/C: Relapse-free Survival (RFS)
    • Time Frame: At complete remission, relapse, or death
    • Incidence of Relapse-free Survival (RFS)
  • 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
  • Arms B/C: 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
  • Arms B/C: Toxicity
    • Time Frame: Day 28
    • Proportion of patients developing grade 3, 4 targeted toxicity of CRS and/or neurotoxicity

Participating in This Clinical Trial

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

  • 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 – 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

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Masonic Cancer Center, University of Minnesota
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Contact(s)
    • Timothy Krepski, RN, 612-273-2800, tkrepsk1@fairview.org

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