Clinical trial NCT03642626: MT2017-45: CAR-T Cell Therapy for Heme Malignancies
Official title: Chimeric Antigen Receptor (CAR)-T Cell Therapy for Patients With Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia
Large B-cell Lymphoma
Keywords: ALL
CAR-T
CAR19-T
chimeric antigen receptor T cells
Lead sponsor: Masonic Cancer Center, University of Minnesota
Sponsor class: OTHER
First posted: 2018-08-22
Enrollment: 144
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: ARM A (Kymriah) and Arm G (Tecartus) :Refractory/relapsed B-cell acute lymphoblastic leukemia expressing CD19

Inclusion Criteria:

* Age and Disease Status

  * Must be age 0-25 years (for Arm A Kymriah) or \>18 years (Arm G Tecartus)
  * 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

  \* Arm A: Karnofsky (age ≥16 years) or Lansky (age \< 16 years) performance status ≥ 50% at screening; Arm G: ECOG 0, 1 or 2
* 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

ARM E: Breyanzi "lisocabtagene maraleucel" for relapsed or refractory large B-cell lymphoma

Inclusion Criteria:

* Age and Disease Status

  * Adult patients (age ≥ 18 years)
  * with relapsed or refractory disease after two or more lines of systemic therapy, including

    * diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma),
    * high-grade B-cell lymphoma,
    * primary mediastinal large B-cell lymphoma,
    * follicular lymphoma grade 3B
* Performance Status

  \*ECOG performance status 0-2
* Organ Function

  * Renal function defined as:

    * A serum creatinine of ≤1.5 x ULN OR
    * eGFR ≥ 30 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 ≥ 40% 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

ARM F: Abecma "Idecabtagene Vicleucel" for relapsed or refractory multiple myeloma

Inclusion Criteria:

* Age and Disease Status

  * Adult patients (age ≥ 18 years)
  * Relapsed (progression after prior partial or complete remission) or refractory multiple myeloma
  * Evidence of active disease (medullary or extramedullary)
  * Prior therapy (Failure or intolerance to) with an immunomodulatory agent, a proteasome inhibitor, and an antiCD38 monoclonal antibody
* Performance Status

  \*ECOG performance status 0-1
* Organ Function

  * Renal function defined as:

    * A serum creatinine of ≤2 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

Primary outcomes:
measure: Arm A&G: Complete Remission (CR)
timeFrame: Day 28
measure: Arm A&G: CRi (complete remission without count recovery)
timeFrame: Day 28
measure: Arms B & C&D& E&F: Overall Response Rate (ORR)
timeFrame: Week 8
Secondary outcomes:
measure: Arm A: MRD-negative CR (or CRi)
timeFrame: Day 28
measure: Arm A: Proportion of patients who are alive but not in remission
timeFrame: Day 28
measure: Treatment Related Mortality (TRM)
timeFrame: Day 28
measure: Treatment Related Mortality (TRM)
timeFrame: Day 100
measure: Treatment Related Mortality (TRM)
timeFrame: 1 Year
measure: Relapse-free Survival (RFS)
timeFrame: At complete remission to relapse or death
measure: Event-Free Survival (EFS)
timeFrame: 1 Year post treatment
measure: Overall Survival (OS)
timeFrame: Date of Death
measure: Toxicity
timeFrame: Day 28
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: Masonic Cancer Center at University of Minnesota
state: Minnesota
Study officials:
affiliation: Masonic Cancer Center, University of Minnesota
name: Veronika Bachanova, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: