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

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. 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.

- See sections 4.4 and 4.5 for additional criteria involving pregnancy and
contraception.

- 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 0-1

- 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 June
6ly 10, 2018 Page 20 of 69 2017LS118

- 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. 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.

- See sections 4.4 and 4.5 for additional criteria involving pregnancy and
contraception.

- 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 outlined in section 6.1

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 0-1

- 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 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 June 6ly 10, 2018 Page 22 of 69
2017LS118

- 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. 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.

- See sections 4.4 and 4.5 for additional criteria involving pregnancy and
contraception.

- 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 outlined in section 6.1