Clinical Trials /

Phase III B in Acute Lymphoblastic Leukemia

NCT03123939

Description:

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.

Related Conditions:
  • B-Cell Acute Lymphoblastic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Phase III B in Acute Lymphoblastic Leukemia
  • Official Title: Phase IIIb Study for Relapsed/Refractory Pediatric/Young Adult Acute Lymphoblastic Leukemia Patients to be Treated With CTL019

Clinical Trial IDs

  • ORG STUDY ID: CCTL019B2001X
  • SECONDARY ID: 2016-001991-31
  • NCT ID: NCT03123939

Conditions

  • Acute Lymphoblastic Leukemia

Interventions

DrugSynonymsArms
CTL019CTL019 - traetment arm

Purpose

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.

Trial Arms

NameTypeDescriptionInterventions
CTL019 - traetment armExperimentalall enrolled subjects will get the study treatment.
  • CTL019

Eligibility 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
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:3 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Number of participants with Adverse Events (AEs)
Time Frame:patient followed up for one year post infusion
Safety Issue:
Description:Safety will be determined by type, frequency and severity of adverse events (AEs) and laboratory abnormalities

Secondary Outcome Measures

Measure:Complete Remission (CR)
Time Frame:6 months after administration
Safety Issue:
Description:CR includes CR + CR with incomplete blood count recovery (CRi).
Measure:Percentage of patients who achieve CR or CRi at Month 6 without step cell transplantation (SCT)
Time Frame:Month 6
Safety Issue:
Description:Percentage of patients who achieve CR or CRi at Month 6 without stem cell transplantation (SCT) between CTL019 infusion and Month 6 response assessment.
Measure: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
Safety Issue:
Description: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
Measure:Duration of response (DOR)
Time Frame:Month 6, Month 12
Safety Issue:
Description:DOR is the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to acute lymphoblastic leukemia (ALL).
Measure:Relapse-free survival (RFS)
Time Frame:Up to 24 weeks
Safety Issue:
Description: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.
Measure:Event-free survival (EFS)
Time Frame:Up to 24 weeks
Safety Issue:
Description:EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure.
Measure:Overall survival (OS)
Time Frame:Up to 24 weeks
Safety Issue:
Description:OS is the time from date of CTL019 infusion to the date of death due to any reason.
Measure:Prevalence and incidence of immunogenicity of antibodies against CTL019
Time Frame:Week -16 to Day -1, Month 12
Safety Issue:
Description:Describe the prevalence and incidence of immunogenicity of antibodies against CTL019
Measure:Persistence of CTL019 in the blood
Time Frame:Day 28, Month 3
Safety Issue:
Description: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
Measure:Correlation of Cmax and AUC0-28d of CTL019 in the blood with CRS grade
Time Frame:Day 28
Safety Issue:
Description:Evaluate the relationship between exposure to CTL019 with Cytokine Release Syndrome (CRS) grades
Measure:Percentage of patients attaining CR or CRi at Day 28
Time Frame:Day 28 ± 4 days post CTL019 infusion
Safety Issue:
Description:
Measure:Response as a function of baseline tumor burden (tumor load) (minimal residual disease (MRD), extramedullary disease, etc.)
Time Frame:Day 28 ± 4 days
Safety Issue:
Description:
Measure:Maximum concentration (Cmax) kinetic parameter of CTL019 in the blood
Time Frame:Up to 28 days
Safety Issue:
Description:
Measure:Time to peak concentration (Tmax) kinetic parameter of CTL019 in the blood
Time Frame:Day 28, Month 3
Safety Issue:
Description:
Measure:Area under the curve (AUC) kinetic parameter of CTL019 in the blood
Time Frame:0-28 days
Safety Issue:
Description:
Measure:MRD quantitative result (% leukemic cells) and qualitative result
Time Frame:Day 28
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Novartis Pharmaceuticals

Trial Keywords

  • ALL
  • Acute Lymphoblastic Leukemia
  • CTL019
  • relapsed/refractory pediatric/young adult

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