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