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Phase III B in Acute Lymphoblastic Leukemia

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ClinicalTrials.gov Identifier: NCT03123939
Recruitment Status : Recruiting
First Posted : April 21, 2017
Last Update Posted : September 24, 2019
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Brief Summary:
This is a single arm, open-label, multi-center, phase III B study to determine the safety and efficacy of CTL019 in pediatric/young adult patients with r/r B-cell ALL.

Condition or disease Intervention/treatment Phase
Acute Lymphoblastic Leukemia Biological: CTL019 Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase IIIb Study for Relapsed/Refractory Pediatric/Young Adult Acute Lymphoblastic Leukemia Patients to be Treated With CTL019
Actual Study Start Date : April 24, 2017
Estimated Primary Completion Date : August 21, 2020
Estimated Study Completion Date : December 30, 2020


Arm Intervention/treatment
Experimental: CTL019 - traetment arm
all enrolled subjects will get the study treatment.
Biological: 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.




Primary Outcome Measures :
  1. Number of participants with Adverse Events (AEs) [ Time Frame: patient followed up for one year post infusion ]
    Safety will be determined by type, frequency and severity of adverse events (AEs) and laboratory abnormalities


Secondary Outcome Measures :
  1. Complete Remission (CR) [ Time Frame: 6 months after administration ]
    CR includes CR + CR with incomplete blood count recovery (CRi).

  2. Percentage of patients who achieve CR or CRi at Month 6 without step cell transplantation (SCT) [ Time Frame: Month 6 ]
    Percentage of patients who achieve CR or CRi at Month 6 without stem cell transplantation (SCT) between CTL019 infusion and Month 6 response assessment.

  3. Percentage of patients who achieve CR or CRi and then proceed to SCT while in remission prior to month 6 [ 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

  4. Duration of response (DOR) [ Time Frame: Month 6, Month 12 ]
    DOR is the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to acute lymphoblastic leukemia (ALL).

  5. Relapse-free survival (RFS) [ Time Frame: Up to 24 weeks ]
    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: Up to 24 weeks ]
    EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure.

  7. Overall survival (OS) [ Time Frame: Up to 24 weeks ]
    OS is the time from date of CTL019 infusion to the date of death due to any reason.

  8. Prevalence and incidence of immunogenicity of antibodies against CTL019 [ Time Frame: Week -16 to Day -1, Month 12 ]
    Describe the prevalence and incidence of immunogenicity of antibodies against CTL019

  9. Persistence of CTL019 in the blood [ Time Frame: Day 28, Month 3 ]
    • Maximum concentration (Cmax), time to peak concentration (Tmax), area under the curve (AUC) and other relevant kinetic parameters of CTL019 in the blood
    • Persistence of CTL019 in the blood

  10. Correlation of Cmax and AUC0-28d of CTL019 in the blood with CRS grade [ Time Frame: Day 28 ]
    Evaluate the relationship between exposure to CTL019 with Cytokine Release Syndrome (CRS) grades

  11. Percentage of patients attaining CR or CRi at Day 28 [ Time Frame: Day 28 ± 4 days post CTL019 infusion ]
  12. Response as a function of baseline tumor burden (tumor load) (minimal residual disease (MRD), extramedullary disease, etc.) [ Time Frame: Day 28 ± 4 days ]
  13. Maximum concentration (Cmax) kinetic parameter of CTL019 in the blood [ Time Frame: Up to 28 days ]
  14. Time to peak concentration (Tmax) kinetic parameter of CTL019 in the blood [ Time Frame: Day 28, Month 3 ]
  15. Area under the curve (AUC) kinetic parameter of CTL019 in the blood [ Time Frame: 0-28 days ]
  16. MRD quantitative result (% leukemic cells) and qualitative result [ Time Frame: Day 28 ]


Information from the National Library of Medicine

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

Inclusion Criteria:

  1. Relapsed or refractory B-cell ALL in pediatric or young adult patients:

    1. Second or greater bone marrow relapse OR
    2. Any bone marrow relapse after allogeneic 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 (TKI) therapy, or if TKI therapy is contraindicated OR
    5. Ineligible for allogeneic SCT
  2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of program entry
  3. Adequate organ function defined as:

    1. A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL). Age Male Female: to < 2 years 0.6 0.6; 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. ALT ≤ 5 times the upper limit of normal (ULN) for age.
    3. Bilirubin < 2.0 mg/dL.
    4. Minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air.
    5. Left Ventricular Shortening Fraction ≥ 28% by echocardiogram, or Left Ventricular Ejection Fraction ≥ 45% by echocardiogram or Multiple Uptake Gated Acquisition (MUGA).
  4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
  5. Life expectancy > 12 weeks.
  6. Age 3 years at the time of screening to age 21 years at the time of initial diagnosis.
  7. Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.
  8. Patients previously treated with blinatumomab who have detectable leukemia and documented CD19+ expression (via flow cytometry) and confirmed absence of CD19- leukemic blasts at Screening may be included. In this case, at least 1 week washout period must be applied from last dose of blinatumomab to start of leukapheresis. Patients previously treated with blinatumomab with no detectable MRD (i.e. MRD negative demonstrated by leukemic blasts < 0.01%) will be excluded.
  9. Must have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site.

Exclusion criteria

  1. Isolated extra-medullary disease relapse.
  2. Concomitant genetic syndromes associated with bone marrow failure states: Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.
  3. 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).
  4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
  5. Prior treatment with any gene therapy product.
  6. Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab
  7. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening
  8. Human immunodeficiency virus (HIV) positive test within 8 weeks of screening.
  9. Presence of grade 2 to 4 acute or extensive chronic GVHD.
  10. Uncontrolled acute life threatening bacterial, viral or fungal infection atScreening
  11. Active central nervous system involvement by malignancy, defined as CNS-3 per NCCN guidelines.
  12. Investigational medicinal product within the last 30 days prior to screening.

12. Pregnant or nursing women. 13. Women of child-bearing potential and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CTL019 infusion.

14. The following medications are excluded:

  1. Steroids: Therapeutic systemic doses of steroids must be stopped > 72 hours prior to CTL019 infusion.
  2. Allogeneic cellular therapy: Any donor lymphocyte infusions 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.
  4. Chemotherapy:

    • TKIs and hydroxyurea must be stopped > 72 hours prior to CTL019 infusion.
    • must be stopped > 1 week prior to CTL019 infusion: vincristine, 6-mercaptopurine, 6-thioguanine, methotrexate < 25 mg/m2, cytosine arabinoside < 100 mg/m2/day, asparaginase (non pegylated).
    • 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).
    • 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).
  6. 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.
  7. Anti T-cell antibodies: Administration of any T cell lytic or toxic antibody (e.g. alemtuzumab) within 8 weeks prior to CTL019 is prohibited Other protocol-defined inclusion/exclusion may apply

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 ClinicalTrials.gov identifier (NCT number): NCT03123939


Contacts
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Contact: Novartis Pharmaceuticals +41613241111 novartis.email@novartis.com
Contact: Novartis Pharmaceuticals +81337978748

Locations
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Austria
Novartis Investigative Site Recruiting
Wien, Austria, A 1090
Belgium
Novartis Investigative Site Recruiting
Gent, Belgium, 9000
Canada, Ontario
Novartis Investigative Site Recruiting
Toronto, Ontario, Canada, M5G 1X8
Canada, Quebec
Novartis Investigative Site Recruiting
Montreal, Quebec, Canada, H3T 1C5
France
Novartis Investigative Site Completed
Paris Cedex 10, France, 75475
Novartis Investigative Site Completed
Paris Cedex, France, 75019
Germany
Novartis Investigative Site Completed
Frankfurt, Germany, 60590
Italy
Novartis Investigative Site Recruiting
Monza, MB, Italy, 20900
Japan
Novartis Investigative Site Active, not recruiting
Sakyo Ku, Kyoto, Japan, 606 8507
Norway
Novartis Investigative Site Active, not recruiting
Oslo, Norway, 0424
Spain
Novartis Investigative Site Active, not recruiting
Esplugues de Llobregat, Barcelona, Spain, 08950
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
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Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

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Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT03123939     History of Changes
Other Study ID Numbers: CCTL019B2001X
2016-001991-31 ( EudraCT Number )
First Posted: April 21, 2017    Key Record Dates
Last Update Posted: September 24, 2019
Last Verified: September 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 www.clinicalstudydatarequest.com


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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
ALL
Acute Lymphoblastic Leukemia
CTL019
relapsed/refractory pediatric/young adult
Additional relevant MeSH terms:
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Leukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases