Chimeric Antigen Receptor (CAR)-T Cell Therapy for Patients with B-Cell Blood Cancers

Inclusion Criteria

• ARM A (KYMRIAH) and ARM G (TECARTUS): Must be age 0- =< 25 years (for Arm A Kymriah) or > 18 years (Arm G Tecartus)
• ARM A (KYMRIAH) and ARM G (TECARTUS): Disease Status: Relapsed and refractory 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 * First relapse following remission lasting < 12 months * Patients in 2nd or greater relapse of B-ALL or * Down syndrome or other congenital diseases assuming that they fit the criteria for second or greater relapse or refractory leukemia, or * Patients with Philadelphia chromosome positive (Ph+) ALL who have failed or are intolerant to two lines of tyrosine kinase inhibitor (TKI) assuming they fit the criteria for second or greater relapse or are considered refractory * Relapsed or refractory ALL after allogeneic stem cell transplantation and off immunosuppression
• ARM A (KYMRIAH) and ARM G (TECARTUS): Arm A: Karnofsky (age >= 16 years) or Lansky (age < 16 years) performance status >= 50% at screening; Arm G: Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2
• ARM A (KYMRIAH) and ARM G (TECARTUS): A serum creatinine of =< 1.5 x upper limit of normal (ULN) OR estimated glomerular filtration rate (eGFR) >= 40 mL/min/1.73 m^2
• ARM A (KYMRIAH) and ARM G (TECARTUS): Alanine aminotransferase (ALT) =< 5 times the ULN for age (unless due to disease)
• ARM A (KYMRIAH) and ARM G (TECARTUS): 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
• ARM A (KYMRIAH) and ARM G (TECARTUS): Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygenation oxygen saturation (SpO2) > 88% on room air
• ARM A (KYMRIAH) and ARM G (TECARTUS): Hemodynamically stable and left ventricular ejection fraction (LVEF) >= 40% confirmed by echocardiogram or multigated acquisition scan (MUGA)
• ARM A (KYMRIAH) and ARM G (TECARTUS): Life expectancy >= 12 weeks
• ARM A (KYMRIAH) and ARM G (TECARTUS): 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
• ARM A (KYMRIAH) and ARM G (TECARTUS): 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
• ARM B: Adult patients (age >= 18 years)
• ARM B: 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 * Follicular lymphoma any grade
• ARM B: 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 hematopoietic cell transplantation (HCT) (and failed at least 2 prior lines of therapy including high dose chemotherapy). If salvage therapy is given post autologous (auto)HCT, the subject must have no complete response, or relapse after the last line of therapy
• ARM B: Measurable disease at time of apheresis : * Nodal lesions or extranodal lesion
• ARM B: ECOG performance status 0-1 (ECOG 2 permissible for follicular lymphoma [FL])
• ARM B: A serum creatinine of =< 1.5 x ULN OR eGFR >= 40 mL/min/1.73 m^2
• ARM B: ALT =< 5 times the ULN for age (unless due to disease)
• ARM B: 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
• ARM B: Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
• ARM B: Hemodynamically stable and LVEF >= 45% confirmed by echocardiogram or MUGA
• ARM B: Absolute neutrophil count (ANC) > 1.000/mm^3 (only for non-Hodgkin lymphoma [NHL])
• ARM B: Platelets >= 30.000/mm^3 (transfusion support can be provided)
• ARM B: Hemoglobin > 8.0 mg/dl (transfusion support can be provided)
• ARM B: Life expectancy >= 12 weeks
• ARM B: 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
• ARM B: 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
• ARM C: Adult patients (age >= 18 years)
• ARM C: Relapsed or refractory (r/r) large B-cell lymphoma, including * Diffuse large B-cell lymphoma (DLBCL) not otherwise specified, * High grade B-cell lymphoma * DLBCL arising from follicular lymphoma
• ARM C: Disease status: * After two or more lines of systemic therapy or * Relapse after autologous HCT
• ARM C: ECOG performance status 0-2
• ARM C: A serum creatinine of =< 1.5 x ULN OR eGFR >= 30 mL/min/1.73 m^2
• ARM C: ALT =< 5 times the ULN for age (unless due to disease)
• ARM C: 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
• ARM C: Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
• ARM C: Hemodynamically stable and LVEF >= 40% confirmed by echocardiogram or MUGA
• ARM C: Absolute neutrophil count (ANC) > 1.000/mm^3 (only for NHL)
• ARM C: Platelets >= 30.000/mm^3 (transfusion support can be provided)
• ARM C: Hemoglobin > 8.0 mg/dl (transfusion support can be provided)
• ARM C: Life expectancy >= 12 weeks
• ARM C: 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
• ARM C: 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
• ARM D: Adult patients (age >= 18 years)
• ARM D: Relapsed or refractory (r/r) mantle cell lymphoma, including * Prior 1st line therapy (containing anthracycline or bendamustine or cytarabine or other) * Prior rituximab or other CD20 directed antibody (or inability to treat with CD20 monoclonal antibody [MoAb]) * Not a candidate or relapse after autologous HCT * Active disease at enrollment
• ARM D: ECOG performance status 0-1
• ARM D: A serum creatinine of =< 1.5 x ULN OR eGFR >= 50 mL/min/1.73 m^2
• ARM D: ALT =< 5 times the ULN for age (unless due to disease)
• ARM D: 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
• ARM D: Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
• ARM D: Hemodynamically stable and LVEF >= 45% confirmed by echocardiogram or MUGA
• ARM D: Absolute neutrophil count (ANC) > 1.000/mm^3 (only for NHL) (unless marrow infiltrated by disease)
• ARM D: Platelets >= 30.000/mm^3 (transfusion support can be provided) (unless marrow infiltrated by disease)
• ARM D: Hemoglobin > 8.0 mg/dl (transfusion support can be provided) (unless marrow infiltrated by disease)
• ARM D: Life expectancy >= 12 weeks
• ARM D: 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
• ARM D: 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
• ARM E: Adult patients (age >= 18 years)
• ARM E: 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
• ARM E: ECOG performance status 0-2
• ARM E: A serum creatinine of =< 1.5 x ULN OR eGFR >= 350 mL/min/1.73 m^2
• ARM E: ALT =< 5 times the ULN for age (unless due to disease)
• ARM E: 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
• ARM E: Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
• ARM E: Hemodynamically stable and LVEF >= 40% confirmed by echocardiogram or MUGA
• ARM E: Absolute neutrophil count (ANC) > 1,000/mm^3 (only for NHL)
• ARM E: Platelets >= 30,000/mm^3 (transfusion support can be provided)
• ARM E: Hemoglobin > 8.0 mg/dl (transfusion support can be provided)
• ARM E: Life expectancy >= 12 weeks
• ARM E: 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
• ARM E: 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
• ARM F: 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 anti-CD38 monoclonal antibody
• ARM F: Performance status ECOG 0-1 (2 is permitted if due to effects of myeloma)
• ARM F: A serum creatinine of =< 2 x ULN or eGFR >= 50 mL/min/1.73 m^2
• ARM F: ALT =< 5 times the ULN for age (unless due to disease)
• ARM F: 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
• ARM F: Must have a minimum level of pulmonary reserve defined as =< grade 1 dyspnea and pulse oxygenation SpO2 > 91% on room air
• ARM F: Hemodynamically stable and LVEF >= 45% confirmed by echocardiogram or MUGA
• ARM F: Platelets >= 30,000/mm^3 (transfusion support can be provided)
• ARM F: Hemoglobin > 8.0 mg/dl (transfusion support can be provided)
• ARM F: Life expectancy >= 12 weeks
• ARM F: 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
• ARM F: 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
• Women who are not of reproductive potential (defined as either < 11 years of age, Tanner Stage 1, post-menopausal for at least 24 consecutive months (i.e. have had no menses) or have undergone hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy) are eligible without requiring the use of contraception. Women who are not yet of reproductive potential are to agree to use acceptable forms of contraception when they reach reproductive potential if within 1 year of CAR-T infusion. Acceptable documentation includes written or oral documentation communicated by clinician or clinician’s staff of one of the following: * Demographics show age < 11 * Physical examination indicates Tanner Stage 1 * Physician report/letter * Operative report or other source documentation in the patient record * Discharge summary * Follicle stimulating hormone measurement elevated into the menopausal range
• Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, must agree to use highly effective methods of contraception for the duration of treatment and a period of 1 year after the CAR-T infusion. According to the World Health Organization and the United States Center for Disease Control and Prevention, the most effective forms of birth control include complete abstinence, surgical sterilization (both male and female), intrauterine devices (IUDs), and the contraceptive implant. The next most effective forms of birth control include injectables, oral contraceptive pills, the contraceptive ring, or the contraceptive patch. Acceptable, but least effective, methods of birth control include male condoms (with or without spermicide) and female condoms

Exclusion Criteria

• ARM A (KYMRIAH) and ARM G (TECARTUS): 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
• ARM A (KYMRIAH) and ARM G (TECARTUS): 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)
• ARM A (KYMRIAH) and ARM G (TECARTUS): Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 1 week prior to apheresis
• ARM A (KYMRIAH) and ARM G (TECARTUS): Uncontrolled active hepatitis B or hepatitis C
• ARM A (KYMRIAH) and ARM G (TECARTUS): Active human immunodeficiency virus (HIV) infection
• ARM A (KYMRIAH) and ARM G (TECARTUS): Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive =< 72 hours prior to infusion)
• ARM A (KYMRIAH) and ARM G (TECARTUS): Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
• ARM A (KYMRIAH) and ARM G (TECARTUS): Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
• ARM A (KYMRIAH) and ARM G (TECARTUS): Intolerance to the excipients of the CAR-T cell product
• ARM A (KYMRIAH) and ARM G (TECARTUS): Patient has taken one of the prohibited concomitant medications
• ARM B: 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
• ARM B: Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD). All GVHD medication must be stopped 1 week prior to apheresis
• ARM B: Uncontrolled active hepatitis B or hepatitis C
• ARM B: Active HIV infection (controlled HIV is permissible)
• ARM B: Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive =< 72 hours prior to infusion)
• ARM B: Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
• ARM B: Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
• ARM B: Intolerance to the excipients of the CAR-T cell product
• ARM B: Any immunosuppressive medication must be stopped >= 2 weeks prior to apheresis (steroids must be stopped > 72 hours prior to apheresis)
• ARM B: Patient has taken one of the prohibited concomitant medications
• ARM C: 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
• ARM C: 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
• ARM C: Uncontrolled active hepatitis B or hepatitis C
• ARM C: Active or inactive HIV infection
• ARM C: Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive =< 72 hours prior to infusion)
• ARM C: Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
• ARM C: Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
• ARM C: Intolerance to the excipients of the CAR-T cell product
• ARM C: Any immunosuppressive medication must be stopped >= 2 weeks prior to apheresis (steroids must be stopped > 72 hours prior to apheresis)
• ARM C: Patient has taken one of the prohibited concomitant medications
• ARM D: 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
• ARM D: 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
• ARM D: Uncontrolled active hepatitis B or hepatitis C
• ARM D: Active HIV infection
• ARM D: Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive =< 72 hours prior to infusion)
• ARM D: Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
• ARM D: Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
• ARM D: Intolerance to the excipients of the CAR-T cell product
• ARM D: Any immunosuppressive medication must be stopped >= 2 weeks prior to apheresis (steroids must be stopped > 72 hours prior to apheresis)
• ARM D: Patient has taken one of the prohibited concomitant medications
• ARM E: 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
• ARM E: 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
• ARM E: Uncontrolled active hepatitis B or hepatitis C
• ARM E: Active HIV infection
• ARM E: Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive =< 72 hours prior to infusion)
• ARM E: Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
• ARM E: Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
• ARM E: Intolerance to the excipients of the CAR-T cell product
• ARM E: Any immunosuppressive medication must be stopped >= 2 weeks prior to apheresis (steroids must be stopped > 72 hours prior to apheresis)
• ARM E: Patient has taken one of the prohibited concomitant medications within the timeframe
• ARM F: 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
• ARM F: 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
• ARM F: Uncontrolled active hepatitis B or hepatitis C
• ARM F: Active HIV infection
• ARM F: Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive =< 72 hours prior to infusion)
• ARM F: Unstable angina and/or myocardial infarction within 1 month prior to CAR-T infusion
• ARM F: Investigational medicinal product within the last 7 days prior to apheresis or CAR-T infusion
• ARM F: Intolerance to the excipients of the CAR-T cell product
• ARM F: Any immunosuppressive medication must be stopped ≥ 2 weeks prior to apheresis (steroids must be stopped > 72 hours prior to apheresis)
• ARM F: Patient has taken one of the prohibited concomitant medications within the timeframe