Clinical Trials /

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

NCT02435849

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.

Related Conditions:
  • Acute Lymphoblastic Leukemia
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Determine Efficacy and Safety of <span class="go-doc-concept go-doc-intervention">CTL019</span> in Pediatric Patients With Relapsed and Refractory B-cell <span class="go-doc-concept go-doc-disease">ALL</span>

Title

  • Brief Title: Determine Efficacy and Safety of CTL019 in Pediatric Patients With Relapsed and Refractory B-cell ALL
  • 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
  • Clinical Trial IDs

    NCT ID: NCT02435849

    ORG ID: CCTL019B2202

    Trial Conditions

    Lymphoblastic Leukemia, Acute, Childhood

    Trial Interventions

    Drug Synonyms Arms

    Trial Purpose

    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.

    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.

    Trial Arms

    Name Type Description Interventions
    Single dose of CTL019 Experimental 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.

    Eligibility Criteria

    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.

    Minimum Eligible Age: 3 Years

    Maximum Eligible Age: 33 Years

    Eligible Gender: Both

    Primary Outcome Measures

    Overall remission rate (ORR) = CR + CRi

    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

    Percentage of patients who achieve CR or CRi at month 6 without SCT between CTL019 infusion and Month 6 response assessment.

    Duration of remission (DOR)

    Percentage of patients who achieve CR or CRi with minimal residual disease negative bone marrow

    Relapse-free survival

    Event-free survival

    Overall survival

    Response at Day 28 +/- 4 days

    Impact of baseline tumor burden on response

    Percentage of patient who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment

    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)

    Safety of CTL019 therapy

    Characterize in vivo cellular PK profile of CTL019 cells in target tissues

    Prevalence and incidence of immunogenicity to CTL019

    Effects of CTL019 therapy on Patient Reported Outcomes

    Derivation of a score to predict cytokine release syndrome

    Describe the profile of soluable immune factors that may be key to cytokine release syndrome

    Describe levels of B and T cells (blood and bone marrow) prior to and following CTL019 infusion for safety monitoring

    Trial Keywords

    Pediatric, ALL, Cell therapy