Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

Study Overview
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Brief Summary
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This was a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of an experimental therapy called CTL019 T-cells in pediatric patients with B-cell acute lymphoblastic leukemia, who were refractory to standard chemotherapy regimen or relapsed after allogeneic stem cell transplant.

Official Title
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A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell Acute Lymphoblastic Leukemia

Conditions
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B-cell Acute Lymphoblastic Leukemia, Relapsed B-cell Acute Lymphoblastic Leukemia, Refractory B-cell Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Biological: CTL019 T-cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsed or refractory pediatric B-cell ALL and lymphoblastic lymphoma: 2nd or greater Bone Marrow (BM) relapse OR Any BM relapse after allogeneic SCT and must be > 6 months from SCT at the time of CTL019 infusion OR 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 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 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: 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 Alanine Aminotransferase (ALT) <= 5 times the upper limit of normal (ULN) for age; Bilirubin < 2.0 mg/dL; Must have a minimum level of pulmonary reserve defined as ≤Grade 1 dyspnea and pulse oxygenation > 91% on room air 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: 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 Allogeneic cellular therapy: Any donor lymphocyte infusions (DLI) must be completed > 6 weeks prior to CTL019 infusion 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) 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 infusion (e.g. intrathecal methotrexate) f. Radiotherapy: Non-CNS site of radiation must be completed > 2 weeks prior to CTL019 infusion CNS directed radiation must be completed > 8 weeks prior to CTL019 infusion g. Anti T-cell Antibodies: Administration of any T cell lytic or toxic antibody (e.g. alemtuzumab) within 8 weeks prior to CTL019 is prohibited since residual lytic levels may destroy the infused CTL019 cells and/or prevent their in vivo expansion. If such an agent has been administered within 8 weeks prior to CTL019, contact the Sponsor, consider consultation with an pharmacology expert, and consider measuring residual drug levels, if feasible, prior to CTL019 infusion Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CTL019 infusion. Highly effective contraception methods include: Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of contraception Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception Use of IUDs are excluded due to increased risks of infection and bleeding in this population. However, IUD inserted prior to consent may remain in place, and a second method of contraception is mandated In case of use of oral contraception, women must be stable on the same pill for a minimum of 3 months before taking study treatment. 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 CTL019 or if CAR cells are present in the blood by PCR. 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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: tisagenlecleucel (CTL019)<br>Pediatric patients with relapsed/refractory B-cell ALL | Biological: CTL019 T-cells<br>* A target dose of CTL019 transduced cells will consist of a single infusion of 2.0 to 5.0 x 10^6 CTL019 transduced cells per kg body weight (for patients ≤ 50 kg) and 1.0 to 2.5 x 10^8 CTL019 transduced viable T cells (for patients > 50 kg). The following cell dose ranges may be infused if all other safety release criteria are met: 0.2 to 5.0 x 10^6 CTL019 transduced viable T cells per kg body weight (for patient ≤ 50 kg) and 0.1 to 2.5 x 10^8 CTL019 transduced viable T cells (for patients > 50 kg).<br>* Other names: tisagenlecleucel;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Remission Rate (ORR) Per Independent Review Committee (IRC) (for ALL Participants) | ORR is defined as the percentage of participants with a best overall disease response of complete remission (CR) or Complete remission with incomplete blood count recovery (CRi), where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until the start of new anticancer therapy. Best response was assigned in the following order: CR, CRi, CR or CRi with residual mediastinal disease, No response and Unknown. | within 6 months after CTL019 infusion | 
| Overall Remission Rate (ORR) Per Local Investigator Assessment (for Lymphoblastic Lymphoma Patients Only) | Overall Remission Rate (ORR), which includes Complete Remission (CR) and Complete Remission with Incomplete Blood Count Recovery (CRi), as determined by assessments of peripheral blood, bone marrow, CNS symptoms, physical exam (PE) and cerebrospinal fluid (CSF). This primary endpoint was based on the local investigator assessment. No participants with lymphoblastic lymphoma were infused in this study. | 6 months after CTL019 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Clinical Response Without Stem Cell Transplantation (SCT) at Month 6 - Per IRC Assessment | Evaluate the percentage of participants who achieved CR or CRi at Month 6 without SCT between tisagenlecleucel infusion and Month 6 response assessment. | Month 6 | 
| Percentage of Subjects Who Achieved CR or CRi and Then Proceeded to SCT While in Remission Prior to Month 6 Response - Per IRC Assessment | Evaluate the percentage of subjects who achieved CR or CRi and then proceeded to SCT while in remission prior to Month 6 response assessment. | prior to Month 6 | 
| Duration of Remission (DOR) Per Local and IRC Assessment | DOR is the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to ALL | From CR or CRi to relapse or death up to 60 months | 
| Percentage of Participants With CR or CRi With Minimum Residual Disease (MRD) Negative Bone Marrow 6 Months After CTL019 Infusion | Percentage of participants with best overall response (BOR) of CR or CRi with MRD negative bone marrow status 6 months after CTL019 infusion among all participants who achieved CR or CRi per Local Investigator & IRC assessment | within 6 months | 
| Relapse-free Survival (RFS) for Responders Per Local and IRC Assessment | RFS is the time from achievement of CR or CRi whichever occurs first to relapse or death due to any cause during CR or CRi. | 60 Months | 
| Event-free Survival (EFS) Per Local and IRC Assessment | EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure. Treatment failure is defined as no response in the study and discontinuation from the study due to any of the following reasons: death, AE, lack of efficacy, new anticancer therapy. | 60 Months | 
| Overall Survival (OS) | OS is the time from date of CTL019 infusion to the date of death due to any reason | 60 Months | 
| Secondary Outcome: Percentage of Participants Attaining CR or CRi With MRD Negative Bone Marrow Status at Day 28 +/- 4 Days After CTL019 Infusion | Percentage of participants attaining CR or CRi with MRD negative bone marrow status at Day 28 +/- 4 days after CTL019 infusion per Local Investigator and IRC assessment. BM MRD were only collected and measured only within responders. | Day 28 | 
| CTL019 Transgene Levels by qPCR CTL019 Cells by in qPCR Blood and Bone Marrow | Characterize the in vivo cellular pharmacokinetic (PK) profile (levels,persistence, trafficking) of CTL019 cells in target tissues | 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 | 
| Humoral Immunogenicity Interpretation by Day 28 Disease Response Per IRC (Anti-CTL019 Antibodies) | Humoral immunogenicity was measured by anti-CTL019 antibodies in human serum using a flow cytometry method. (Prevalence and incidence of immunogenicity to CTL019) | Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24, Month 36 | 
| ORR by Low Baseline Bone Marrow Burden Within 6 Months Post CTL019 Infusion | ORR within 6 months after infusion of CTL019 per Local & IRC assessment by baseline bone marrow tumor burden presence. | Within 6 months | 
| ORR by High Baseline Bone Marrow Burden Within 6 Months Post CTL019 Infusion | ORR within 6 months after infusion of CTL019 per Local Investigator & IRC assessment by high baseline bone marrow tumor burden presence. | Within 6 months | 
| ORR by Baseline Extramedullary Disease Presence of Yes Within 6 Months Post CTL019 Infusion | ORR within 6 months after infusion of CTL019 per Local Investigator & IRC assessment by baseline extramedullary disease presence of Yes. | Within 6 months | 
| ORR by Baseline Extramedullary Disease Presence of No Within 6 Months Post CTL019 Infusion | ORR within 6 months after infusion of CTL019 per Local Investigator & IRC assessment by baseline extramedullary disease presence of No. | Within 6 months | 
| Bone Marrow (BM) Minimum Residual Disease (MRD) Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by High Baseline Bone Marrow Tumor Burden | BM MRD status was by Local Investigator and IRC assessment within 6 months after infusion of CTL019 by baseline bone marrow tumor burden. BM MRD were collected and measured only within responders. | Within 6 months | 
| Bone Marrow MRD Status Was by Flow Cytometry Within 6 Months Post CTL019 Infusion by Low Baseline Bone Marrow Tumor Burden | BM MRD status was per Local Investigator and IRC assessment within 6 months after infusion of CTL019 by low baseline bone marrow tumor burden. BM MRD were collected and measured only within responders. | Within 6 months | 
| Bone Marrow MRD Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by Baseline Extramedullary Disease Presence: Yes | BM MRD status was by Local Investigator and IRC assessment within 6 months after infusion pf CTL019 by baseline extramedullary disease presence of Yes. BM MRD were collected and measured only within responders. | Within 6 months | 
| Bone Marrow MRD Status by Flow Cytometry Within 6 Months Post CTL019 Infusion by Baseline Extramedullary Disease Presence: No | BM MRD status WAS per Local Investigator and IRC assessment within 6 months after infusion pf CTL019 by baseline extramedullary disease presence of No. BM MRD were collected and measured only within responders. | Within 6 months | 
| Duration of Remission (DoR) Censoring Hematopoietic Stem Cell Transplantation (HSCT) by Low Baseline Bone Marrow Tumor Burden | DoR per Local Investigator & IRC assessment by low baseline marrow tumor burden | Within 6 months | 
| Duration of Remission (DoR) Censoring HSCT by High Baseline Bone Marrow Tumor Burden | DoR per Local Investigator & IRC assessment by high baseline bone marrow tumor burden | Within 6 months | 
| Duration of Remission (DoR) Censoring HSCT by Baseline Extramedullary Disease Presence: Yes | DoR per Local Investigator & IRC assessment by baseline extramedullary disease presence of Yes. | Within 6 months | 
| Duration of Remission (DoR) Censoring HSCT by Baseline Extramedullary Disease Presence: No | DoR per Local Investigator & IRC assessment by baseline extramedullary disease presence of No | Within 6 months | 
| Participants Achieving Cellular Immunogenicity Net Response by Day 28 Response Per IRC | Activation of T cells in PBMC collected from subjects in response to mCAR19 -derived peptides was used to assess the cellular immunogenicity against tisagenlecleucel. CD4 and CD8 T cell net responses (in %) were calculated for 2 non-overlapping CTL019 peptide pools (i.e., Pool 1 and Pool 2). (Lymphocyte subsets of B and T cells and description of associated safety events) | Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24, Month 36 | 
| Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: AUC0-28d and AUC0-84d | Characterize the in vivo cellular pharmacokinetic (PK) profile. AUC0-28d and AUC0-84d is defined as the AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood (% or copies/μg x days). Data was only reported for evaluable PK parameters. The Overall Number of Participants Analyzed represents all participants for which a baseline assessment was collected for this Outcome Measure, and therefore these participants did contribute data to this estimation parameter, whereas the Number Analyzed per Row represents the number of participants with data available at either 28 or 84 days. | 0 - 28 days post-infusion for AUC0-28d and 0 - 84 days post-infusion for AUC0-84d | 
| Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Cmax | Characterize the in vivo cellular pharmacokinetic (PK) profile. Cmax is defined as the maximum (peak) observed in peripheral blood drug concentration after single dose administration (% or copies/μg). | Day 28 | 
| Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Tmax | Characterize the in vivo cellular pharmacokinetic (PK) profile. Tmax is defined as the time to reach maximum (peak) peripheral blood drug concentration after single dose administration (days) | Day 28 | 
| Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: T1/2 | Characterize the in vivo cellular pharmacokinetic (PK) profile. T1/2 is defined as the half-life associated with the disposition phase slopes (alpha, beta, gamma etc.) of a semi logarithmic concentration-time curve (days) in peripheral blood | Day 28 | 
| Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Clast | Characterize the in vivo cellular pharmacokinetic (PK) profile. Clast is defined as the last observed quantifiable concentration in peripheral blood (% or copies/ug) | Day 28 | 
| Peripheral Blood PK Parameters for Tisagenlecleucel Transgene Levels by qPCR, by Day 28 Disease Response by Local & IRC Assessment: Tlast | Characterize the in vivo cellular pharmacokinetic (PK) profile. Tlast is defined as the time of last observed quantifiable concentration in peripheral blood (days) | Day 28 | 
| CD19 Status of Bone Marrow/Blood Relapse in FAS Patients Who Achieved CR or CRi and Then Relapsed | The CD19 status of bone marrow/blood relapse was categorized as follows: CD19 positive, CD19 dim, CD19 negative, CD19 positive/negative & CD19 unknown | At time of relapse up to 60 months | 
| Site of Initial Relapse Among FAS Patients Who Achieved CR/CRi and Then Relapsed | This is the site of involvement of initial relapse after achieving a best overall response of CR/CRi. | At time of relapse up to 60 months | 
| Time to B-cell Recovery in Participants Who Achieved CR or CRi by IRC | Time to B cell recovery was defined as the time from onset of remission to the earliest time when the percentage of CD19+ total B cell among viable WBC is ≥ 1% or among lymphocyte is at least 3%. | during the whole study, up to 60 months | 
| Percentage of CD19+ B Cell Levels in Peripheral Blood by Day 28 Disease Response by IRC Assessment | The levels (%) of CD19+ total B cells amongst viable white blood cells (WBC) in peripheral blood | 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 | 
| Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: C Reactive Protein (CRP) | C-Reactive Protein at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3 | Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3 | 
| Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Ferritin | Ferritin at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3 | Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3 | 
| Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: INF-gamma | INF-gamma at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3 | Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3 | 
| Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Interleukin-6 (IL-6) | IL-6 at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3 | Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3 | 
| Key Inflammatory Markers and Cytokine Parameters in Blood Within 1 Month by Maximum Cytokine Release Syndrome (CRS) Grade: Interleukin-2 (IL-2) | IL-2 at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3 | Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsed/refractory, Philadelphia chromosome positive acute lymphoblastic leukemia, Pharmaceuticals, Philadelphia chromosome positive, Acute Lymphoid Leukemia (ALL), Acute Lymphocytic Leukemia (ALL), CTL019, tisagenlecleucel