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Key inclusion & exclusion criteria
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Inclusion Criteria:
- Relapsed or refractory pediatric B-cell ALL and lymphoblastic lymphoma:
1. 2nd or greater Bone Marrow (BM) relapse OR
2. Any BM relapse after allogeneic SCT and must be > 6 months from SCT at the time
of CTL019 infusion OR
3. Refractory as defined by not achieving a CR after 2 cycles of a standard
chemotherapy regimen chemotherapy regimen or chemorefractory as defined by not
achieving a CR after 1 cycle of standard chemotherapy for relapse leukemia OR
4. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are
intolerant to or have failed 2 lines of tyrosine kinase inhibitor therapy (TKI),
or if TKI therapy is contraindicated OR
5. Ineligible for allogeneic SCT
- For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral
blood by flow cytometry within 3 months of study entry
- Adequate organ function defined as:
1. Renal function defined as (Calculated creatinine clearance or radioisotope
Glomerular Filtration Rate (GFR) > 60 mL/min/1.73 m2 OR serum creatinine based on
age/gender
2. Alanine Aminotransferase (ALT) <= 5 times the upper limit of normal (ULN) for
age;
3. Bilirubin < 2.0 mg/dL;
4. Must have a minimum level of pulmonary reserve defined as =Grade 1 dyspnea and
pulse oxygenation > 91% on room air
5. Left Ventricular Shortening Fraction (LVSF) = 28% confirmed by echocardiogram, or
Left Ventricular Ejection Fraction (LVEF) = 45% confirmed by echocardiogram or
MUGA within 7 days of screening
- Bone marrow with = 5% lymphoblasts by morphologic assessment at screening
- Life expectancy > 12 weeks
- Age 3 at the time of screening per protocol to age 21 at the time of initial diagnosis
- Karnofsky (age = 16 years) or Lansky (age < 16 years) performance status = 50 at
screening
- Signed written informed consent and assent forms (if applicable) must be obtained
prior to any study procedures
- Once all other eligibility criteria are confirmed, must have an apheresis product of
non-mobilized cells received and accepted by the manufacturing site. Note: Apheresis
product will not be shipped to or assessed for acceptance by the manufacturing site
until documented confirmation of all other eligibility criteria is received.
- Patients with active CNS leukemia involvement defined as CNS-3 by CSF findings only
are eligible but will have their CTL019 infusion delayed until CNS disease is reduced
to CNS-1 or CNS-2 by CSF findings. Patients with other forms of active CNS-3 leukemic
involvement such as CNS parenchymal or ocular disease, cranial nerve involvement or
significant leptomeningeal disease are not eligible. However, such patients with other
forms of CNS-3 leukemic involvement (non-CSF involvement) are eligible if there is
documented evidence of disease stabilization for at least 3 months prior to CTL019
infusion. Patients must have no acute/ongoing neurologic toxicity > Grade 1 with the
exception of a history of controlled seizures or fixed neurologic deficits that have
been stable/improving over the past 3 months.
Exclusion Criteria:
- Isolated extra-medullary disease relapse
- Patients with concomitant genetic syndrome: such as patients with Fanconi anemia,
Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome.
Patients with Down Syndrome will not be excluded.
- Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL,
leukemia with B-cell [surface Immunoglobulin (sIg) positive and kappa or lambda
restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)
- Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative
intent and with no evidence of active disease
- Prior treatment with gene therapy product
- Treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
- Presence of Grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD)
- Patient has participated in an investigational research study using an investigational
agent within the last 30 days prior to screening
- Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive
potential must have a negative serum or urine pregnancy test performed within 48 hours
before infusion
- Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening),
or any uncontrolled infection at screening
- HIV positive test within 8 weeks of screening
- The following medications are excluded:
1. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior
to CTL019 infusion. However, the following physiological replacement doses of
steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent
2. Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be
completed > 6 weeks prior to CTL019 infusion
3. GVHD therapies: Any systemic drug used for GVHD must be stopped > 4 weeks prior
to CTL019 infusion to confirm that GVHD recurrence is not observed (e.g.
calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolate,
rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20
(rituximab), anti-tumor necrosis factor [anti-TNF], anti-interleukin 6 [anti-IL6]
or anti-interleukin 6 receptor [anti-IL6R], systemic steroids)
4. Chemotherapy:
- Tyrosine kinase inhibitors and hydroxyurea must be stopped > 72 hours prior to CTL019
infusion
- The following drugs must be stopped > 1 week prior to CTL019 infusion and should not
be administered concomitantly or following lymphodepleting chemotherapy: vincristine,
6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg/m2, cytosine arabinoside < 100
mg/m2/day, asparaginase (non-pegylated)
- The following drugs must be stopped >2 weeks prior to CTL019 infusion: salvage
chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines,
cyclophosphamide, methotrexate = 25 mg/m2), excluding the required lymphodepleting
chemotherapy drugs
- Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion e. CNS
disease prophylaxis:
- CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 inf
Age minimum:
3 Years
Age maximum:
21 Years
Gender:
All
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Secondary Outcome(s)
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Bone Marrow (BM) Minimum Residual Disease (MRD) Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by High Baseline Bone Marrow Tumor Burden
[Time Frame: Within 6 months]
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Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Interleukin-6 (IL-6)
[Time Frame: Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3]
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ORR by Baseline Extramedullary Disease Presence of Yes Within 6 Months Post CTL019 Infusion
[Time Frame: Within 6 months]
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Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: AUC0-28d and AUC0-84d
[Time Frame: 0 - 28 days post-infusion for AUC0-28d and 0 - 84 days post-infusion for AUC0-84d]
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Bone Marrow MRD Status Was by Flow Cytometry Within 6 Months Post CTL019 Infusion by Low Baseline Bone Marrow Tumor Burden
[Time Frame: Within 6 months]
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Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Ferritin
[Time Frame: Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3]
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ORR by High Baseline Bone Marrow Burden Within 6 Months Post CTL019 Infusion
[Time Frame: Within 6 months]
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Percentage of Participants With Clinical Response Without Stem Cell Transplantation (SCT) at Month 6 - Per IRC Assessment
[Time Frame: Month 6]
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Percentage of Subjects Who Achieved CR or CRi and Then Proceeded to SCT While in Remission Prior to Month 6 Response - Per IRC Assessment
[Time Frame: prior to Month 6]
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Duration of Remission (DoR) Censoring Hematopoietic Stem Cell Transplantation (HSCT) by Low Baseline Bone Marrow Tumor Burden
[Time Frame: Within 6 months]
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Event-free Survival (EFS) Per Local and IRC Assessment
[Time Frame: 60 Months]
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ORR by Low Baseline Bone Marrow Burden Within 6 Months Post CTL019 Infusion
[Time Frame: Within 6 months]
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Duration of Remission (DoR) Censoring HSCT by Baseline Extramedullary Disease Presence: No
[Time Frame: Within 6 months]
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Bone Marrow MRD Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by Baseline Extramedullary Disease Presence: No
[Time Frame: Within 6 months]
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Duration of Remission (DoR) Censoring HSCT by Baseline Extramedullary Disease Presence: Yes
[Time Frame: Within 6 months]
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Relapse-free Survival (RFS) for Responders Per Local and IRC Assessment
[Time Frame: 60 Months]
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Bone Marrow MRD Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by Baseline Extramedullary Disease Presence: Yes
[Time Frame: Within 6 months]
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CTL019 Transgene Levels by qPCR CTL019 Cells by in qPCR Blood and Bone Marrow
[Time Frame: Enrollment; D1; D4; D7; D11; D14; D21; D28; M3; M6; M9, M12; M18; M24, M30, M36, M42, M48 for transgene levels in blood; Screening, D28, M3, M6 for transgene levels in bone marrow]
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Overall Survival (OS)
[Time Frame: 60 Months]
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Participants Achieving Cellular Immunogenicity Net Response by Day 28 Response Per IRC
[Time Frame: Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24, Month 36]
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Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: C Reactive Protein (CRP)
[Time Frame: Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3]
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CD19 Status of Bone Marrow/Blood Relapse in FAS Patients Who Achieved CR or CRi and Then Relapsed
[Time Frame: At time of relapse up to 60 months]
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Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: INF-gamma
[Time Frame: Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3]
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ORR by Baseline Extramedullary Disease Presence of No Within 6 Months Post CTL019 Infusion
[Time Frame: Within 6 months]
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Time to B-cell Recovery in Participants Who Achieved CR or CRi by IRC
[Time Frame: during the whole study, up to 60 months]
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Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Tlast
[Time Frame: Day 28]
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Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: T1/2
[Time Frame: Day 28]
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Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Clast
[Time Frame: Day 28]
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Site of Initial Relapse Among FAS Patients Who Achieved CR/CRi and Then Relapsed
[Time Frame: At time of relapse up to 60 months]
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Duration of Remission (DoR) Censoring HSCT by High Baseline Bone Marrow Tumor Burden
[Time Frame: Within 6 months]
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Duration of Remission (DOR) Per Local and IRC Assessment
[Time Frame: From CR or CRi to relapse or death up to 60 months]
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Humoral Immunogenicity Interpretation by Day 28 Disease Response Per IRC (Anti-CTL019 Antibodies)
[Time Frame: Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24, Month 36]
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Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Interleukin-2 (IL-2)
[Time Frame: Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3]
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Percentage of CD19+ B Cell Levels in Peripheral Blood by Day 28 Disease Response by IRC Assessment
[Time Frame: Enrollment/Pre-Chemotherapy; Pre-infusion; Baseline; Day 7; Day 14; Day 21; Day 28; Month 3; Month 6; Month 9; Month 12; Month 24; Month 36]
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Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Cmax
[Time Frame: Day 28]
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Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Tmax
[Time Frame: Day 28]
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Secondary Outcome: Percentage of Participants Attaining CR or CRi With MRD Negative Bone Marrow Status at Day 28 +/- 4 Days After CTL019 Infusion
[Time Frame: Day 28]
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Percentage of Participants With CR or CRi With Minimum Residual Disease (MRD) Negative Bone Marrow 6 Months After CTL019 Infusion
[Time Frame: within 6 months]
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