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Study of Efficacy and Safety of CTL019 in Pediatric ALL Patients

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02228096
Recruitment Status : Completed
First Posted : August 28, 2014
Last Update Posted : August 28, 2019
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is 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 are refractory to standard chemotherapy regimen or relapsed after allogeneic stem cell transplant

Condition or disease Intervention/treatment Phase
B-cell Acute Lymphoblastic Leukemia Relapsed B-cell Acute Lymphoblastic Leukemia Refractory B-cell Acute Lymphoblastic Leukemia Biological: CTL019 T-cells Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : August 14, 2014
Actual Primary Completion Date : May 29, 2018
Actual Study Completion Date : May 24, 2019

Arm Intervention/treatment
Experimental: CTL019
Pediatric patients with relapsed/refractory B-cell ALL
Biological: CTL019 T-cells
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).
Other Name: tisagenlecleucel

Primary Outcome Measures :
  1. Overall Remission Rate (ORR) er independent review committee (IRC) (for ALL patients) [ Time Frame: 6 months after CTL019 administration ]
    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). The primary endpoint was based on the independent review committee (IRC) assessment.

  2. Overall Remission Rate (ORR) per local Investigator assessment (for lymphoblastic lymphoma patients only) [ Time Frame: 6 months after CTL019 administration ]
    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.

Secondary Outcome Measures :
  1. Percentage of patients who achieve CR or CRi without stem cell transplantation (SCT) [ Time Frame: Month 6 ]
    Evaluate the percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment

  2. Percentage of patients who achieve CR or CRi and then proceed to SCT while in remission [ Time Frame: prior to Month 6 ]
    Percentage of patients who achieve CR or CRi and then proceed to SCT while in remission prior to Month 6 response assessment. In addition, all patients that proceed to SCT after CTL019 infusion will be described.

  3. Duration of response (DOR) [ Time Frame: From CR or CRi to relapse or death ]
    DOR is the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to ALL

  4. Percentage of patients with best overall response (BOR) of CR or CRi with minimal residual disease (MRD) negative bone marrow 6 months after CTL019 infusion [ Time Frame: 6 months after CTL019 infusion ]
    Evaluate the quality of response by assessing BOR of CR or CRi with MRD negative bone marrow 6 months after CTL019 infusion and at Day 28 by central analysis.

  5. Relapse-free survival (RFS) [ Time Frame: 60 Months ]
    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.

  6. Event-free survival (EFS) [ Time Frame: 60 Months ]
    EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure

  7. Overall survival (OS) [ Time Frame: 60 Months ]
    OS is the time from date of CTL019 infusion to the date of death due to any reason

  8. Percentage of patients attaining CR or CRi t Day 28 +/- 4 days post CTL019 infusion [ Time Frame: Day 28 +/- 4 days post CTL019 infusion ]
    Evaluate the response at Day 28 +/- 4 days

  9. Response as a function of baseline tumor burden (tumor load) (MRD, extramedullary disease, etc.) [ Time Frame: 60 Months ]
    Evaluate the impact of baseline tumor burden on response

  10. CTL019 transgene levels by qPCR CTL019 cells by in qPCR blood, bone marrow and CSF if [ Time Frame: 60 Months ]
    Characterize the in vivo cellular pharmacokinetic (PK) profile (levels,persistence, trafficking) of CTL019 cells in target tissues

  11. Prevalence and incidence of immunogenicity to CTL019 [ Time Frame: 60 Months ]
    Describe the prevalence and incidence of immunogenicity to CTL019

  12. Frequent monitoring of concentrations of soluble immune factors in blood [ Time Frame: 60 Months ]
    Describe the profile of soluble immune factors that may be key to cytokine release syndrome

  13. Lymphocyte subsets of B and T cells and description of associated safety events [ Time Frame: 60 Months ]
    Describe the levels of B and T cells (peripheral blood and bone marrow) prior to and following CTL019 in safety monitoring

  14. Persistence of CTL019 in blood, bone marrow and CSF [ Time Frame: 60 Months ]
    Persistence based on Time > Limit of Quantification [LOQ], Time > other threshold CTL019 levels, Mean Residence Time [MRT] last).

  15. Maximum extent of expansion of CTL019 in blood (Cmax/Cpost-infusion, hr [ Time Frame: 60 Months ]
    Characterize the in vivo cellular pharmacokinetic (PK) profile

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   3 Years to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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 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:

    1. 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
    2. 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
    3. 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
    4. 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
    5. 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
    6. 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:

  1. Demographics show age < 11
  2. Physical examination indicates Tanner Stage 1
  3. Physician report/letter
  4. Operative report or other source documentation in the patient record
  5. Discharge summary
  6. Follicle stimulating hormone measurement elevated into the menopausal range

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02228096

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United States, California
Childrens Hospital Los Angeles SC
Los Angeles, California, United States, 90027
Stanford University Medical Center
Palo Alto, California, United States, 94304
United States, Georgia
Children's Healthcare of Atlanta SC-2
Atlanta, Georgia, United States, 30342
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109-5941
United States, Minnesota
University of Minnesota Medical Center
Minneapolis, Minnesota, United States, 55455
United States, Missouri
Mercy Children's Kansas University
Kansas City, Missouri, United States, 64108
United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27708
United States, Ohio
Cincinnati Children's Hospital
Cincinnati, Ohio, United States, 45230
United States, Oregon
Oregon Health and Science University SC
Portland, Oregon, United States, 97239
United States, Pennsylvania
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
University of Texas Southwestern Medical Center SC
Dallas, Texas, United States, 75390-9034
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84113
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
Novartis Pharmaceuticals
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
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Responsible Party: Novartis Pharmaceuticals Identifier: NCT02228096    
Other Study ID Numbers: CCTL019B2205J
First Posted: August 28, 2014    Key Record Dates
Last Update Posted: August 28, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Philadelphia chromosome positive acute lymphoblastic leukemia
Philadelphia chromosome positive
Acute Lymphoid Leukemia (ALL)
Acute Lymphocytic Leukemia (ALL)
Additional relevant MeSH terms:
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Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases