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Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL (ELIANA)

This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals ) Identifier:
First received: April 16, 2015
Last updated: July 12, 2017
Last verified: July 2017
This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL.

Condition Intervention Phase
Lymphoblastic Leukemia, Acute, Childhood Genetic: Single dose of CTL019 Phase 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: No masking
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

Resource links provided by NLM:

Further study details as provided by Novartis ( Novartis Pharmaceuticals ):

Primary Outcome Measures:
  • Overall remission rate (ORR) = CR + CRi [ Time Frame: After 50 pts have received CTL019 infuson and completed 6 months from study day 1 infusion or discontinued earlier ]
    Efficacy of CTL019 therapy as measured by overall remission rate during the 6 months after CTL019 administration, which includes CR and CR with incomplete blood count recovery (CRi) as determined by IRC assessment.

Secondary Outcome Measures:
  • Percentage of patients who achieve best overall response (BOR) or CR or CRi with an MRD negative bone marrow by central analysis using qPCR [ Time Frame: 60 months ]
  • Percentage of patients who achieve CR or CRi at month 6 without SCT between CTL019 infusion and Month 6 response assessment. [ Time Frame: 60 months ]
  • Duration of remission (DOR) [ Time Frame: 60 months ]
  • Percentage of patients who achieve CR or CRi with minimal residual disease negative bone marrow [ Time Frame: 60 months ]
  • Relapse-free survival [ Time Frame: 60 months ]
  • Event-free survival [ Time Frame: 60 months ]
  • Overall survival [ Time Frame: 60 months ]
  • Response at Day 28 +/- 4 days [ Time Frame: 60 months ]
  • Impact of baseline tumor burden on response [ Time Frame: 60 months ]
  • Percentage of patient who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment [ Time Frame: 60 months ]
  • Quality of response using MRD disease assessments before treatment at day 28 +/-4 days after treatment using central assessments by qPCR and before SCT by local assessment (flow or PCR) [ Time Frame: 60 months ]
  • Safety of CTL019 therapy [ Time Frame: 60 months ]
  • Characterize in vivo cellular PK profile of CTL019 cells in target tissues [ Time Frame: 60 months ]
  • Prevalence and incidence of immunogenicity to CTL019 [ Time Frame: 60 months ]
  • Effects of CTL019 therapy on Patient Reported Outcomes [ Time Frame: 60 months ]
  • Derivation of a score to predict cytokine release syndrome [ Time Frame: 60 months ]
  • Describe the profile of soluable immune factors that may be key to cytokine release syndrome [ Time Frame: 60 months ]
  • Describe levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring [ Time Frame: 60 months ]

Estimated Enrollment: 72
Study Start Date: April 2015
Estimated Study Completion Date: January 2023
Estimated Primary Completion Date: January 2023 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Single dose of CTL019
2 to 5 x 10(6) autologous CTL019 transduced cells per kg body weight, with a maximum dose of 2.5 x 10(8) autologous CTL019 transduced cells via intravenous infusion.
Genetic: Single dose of CTL019
2 to 5 x 10(6) autologous CTL019 transduced cells per kg body weight, with a maximum dose of 2.5 x 10(8) autologous CTL019 transduced cells via intravenous infusion.

Detailed Description:
This is a single arm, open-label, multi-center, phase II study to determine the efficacy and safety of CTL019 in pediatric patients with r/r B-cell ALL. The study will have the following sequential phases: Screening, Pre-Treatment (Cell Product Preparation & Lymphodepleting Chemotherapy), Treatment and Primary Follow-up, Secondary Follow-up (if applicable) and Survival Follow-up. The total duration of the study is 5 years from CTL019 cell infusion.

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.

    1. 2nd or greater Bone Marrow (BM) relapse OR.
    2. Any BM relapse after allogeneic stem cell transplantation (SCT) and must be ≥ 6 months from SCT at the time of CTL019 infusion OR.
    3. Primary refractory as defined by not achieving a CR after 2 cycles of a standard chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapsed 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, documentation of 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:

      A serum creatinine based on age/gender as follows:

      Maximum Serum Creatinine (mg/dL). Age Male Female

      1. to < 2 years 0.6 0.6
      2. to < 6 years 0.8 0.8

      6 to < 10 years 1.0 1.0 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

      ≥ 16 years 1.7 1.4.

    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 as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air.
    5. Left Ventricular Shortening Fraction (LVSF) ≥ 28% confirmed by echocardiogram (ECHO), or Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multiple Uptake Gated Acquisition (MUGA).
  • Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
  • Life expectancy > 12 weeks.
  • Age 3 at the time of screening to age 21 at the time of initial diagnosis
  • Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.
  • Must have an apheresis product of non-mobilized cells received and accepted by the manufacturing site.

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 [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
  • Treatment with any prior gene therapy product
  • Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
  • Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
  • Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening
  • Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD).
  • Active CNS involvement by malignancy, defined by CNS-3 per NCCN guidelines.
  • Patient has an investigational medicinal product within the last 30 days prior to screening.
  • Pregnant or nursing women.
  • 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) 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. BOTH of the following forms of contraception must be utilized:

      • 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.
      • Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository
    5. Use of IUDs are excluded due to increased risks of infection and bleeding in this population.
    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 or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy) are eligible without requiring the use of contraception. 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
  • The following medications are excluded:

    1. Steroids: Therapeutic 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 drug used for GVHD must be stopped > 4 weeks prior to CTL019 infusion (e.g. calcineurin inhibitors, methotrexate or other chemotherapy drugs, mycophenolyate, rapamycin, thalidomide, or immunosuppressive antibodies such as anti-CD20 (rituximab), anti-TNF, anti-IL6 or anti-IL6R)
    4. Chemotherapy:

      The following drugs must be stopped > 1 week prior to CTL019 infusion and should not be administered concomitantly or following lymphodepleting chemotherapy: hydroxyurea, 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), excluding the required lymphodepleting chemotherapy drugs Pegylated-asparaginase must be stopped > 4 weeks prior to CTL019 infusion

    5. CNS disease prophylaxis:

      CNS prophylaxis treatment must be stopped > 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)

  • Anti T-cell therapy: Administration of any T cell or toxic agent is strongly discouraged since residual lytic levels may destroy the infused CTL019 cell or prevent their in vivo expansion.

Other protocol-defined inclusion/exclusion may apply.

  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02435849

  Show 26 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis Pharmaceuticals Identifier: NCT02435849     History of Changes
Other Study ID Numbers: CCTL019B2202
Study First Received: April 16, 2015
Last Updated: July 12, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Pediatric, ALL, Cell therapy

Additional relevant MeSH terms:
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases processed this record on July 21, 2017