Study of Tisagenlecleucel in Chinese Pediatric and Young Adult Subjects With Relapsed or Refractory B-cell ALL

Overview

This is a single arm, multi-center, phase II study to evaluate the efficacy and safety of tisagenlecleucel in Chinese pediatric and young adult subjects with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL)

Full Title of Study: “A Phase II, Single Arm, Multi-center Trial to Evaluate the Efficacy and Safety of Tisagenlecleucel in Chinese Pediatric and Young Adult Patients With Relapsed or Refractory B-cell Acute Lymphoblastic Leukemia”

Study Type

  • Study Type: Interventional
  • Study Design
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: January 17, 2022

Detailed Description

The study will have the following sequential phases for all subjects:

- Screening

- Pre-Treatment (Cell Product Preparation and Lymphodepleting Chemotherapy)

- Treatment and Follow-up Tisagenlecleucel infusion should occur within 16 weeks of informed consent. The total duration of the study is 5 years. After tisagenlecluecel infusion, efficacy will be assessed monthly for the first 6 months, then quarterly up to 2 years and semi-annually afterwards up to 5 years, or until the subject relapses.

Interventions

  • Biological: Tisagenlecleucel
    • A single intravenous (i.v.) infusion of CAR-positive viable T cells.

Arms, Groups and Cohorts

  • Experimental: Tisagenlecleucel
    • All patients eligible for treatment with tisagenlecleucel will receive a single dose of tisagenlecleucel. For subjects ≤ 50 kg, tisagenlecleucel will be administered as a single infusion of 0.2 to 5.0 x 10^6 CAR positive viable T cells per kg body weight. For subjects > 50 kg, tisagenlecleucel will be administered as a single infusion of 0.1 to 2.5 x 10^8 CAR positive viable T cells.

Clinical Trial Outcome Measures

Primary Measures

  • Overall Remission Rate (ORR)
    • Time Frame: From first dosing (single administration, Day 1) up to Month 3
    • Evaluate the efficacy of tisagenlecleucel using overall remission rate (ORR) during the 3 months after tisagenlecleucel administration as assessed by the investigator. The ORR is defined as the proportion of subjects with a best overall disease response of Complete Remission (CR) or Complete Remission with Incomplete blood count recovery (CRi), where the best overall disease response is defined as the best disease response recorded from tisagenlecleucel infusion until the start of new anticancer therapy. Best response will be assigned according to the following order: CR CRi No response (NR) Unknown

Secondary Measures

  • Remission with Minimal Residual Disease (MRD) negative bone marrow
    • Time Frame: From first dosing (single administration, Day 1) up to Month 3
    • The percentage of subjects who receive tisagenlecleucel and achieve a BOR of CR or CRi with a MRD negative bone marrow by central analysis using flow cytometry during the 3 months after tisagenlecleucel infusion will be evaluated.
  • Percentage of subjects who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment
    • Time Frame: Month 6
    • The percentage of subjects who achieve CR or CRi at Month 6 without SCT (Stem Cell Transplantation) post tisagenlecleucel infusion between tisagenlecleucel infusion and Month 6 response assessment will be evaluated.
  • Duration of remission (DOR)
    • Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months
    • DOR is defined as the duration from the date when the response criteria of CR or CRi is first met to the date of relapse or death due to underlying cancer. In case a subject does not have relapse or death due to ALL prior to data cutoff, DOR will be censored at the date of the last adequate assessment on or prior to the earliest censoring event.
  • Relapse free survival (RFS)
    • Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months
    • RFS is measured by the time from achievement of CR or CRi whatever occurs first to relapse or death due to any cause during CR or CRi. In case a subject does not have relapse or death due to any cause prior to data cutoff, RFS will be censored at the date of the last adequate assessment on or prior to the earliest censoring event.
  • Event free survival (EFS)
    • Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months
    • EFS is the time from date of tisagenlecleucel infusion to the earliest of of the following: death from any cause after remission, relapse or treatment failure. In case of treatment failure, the event date will be set to study Day 1 (CHMP 2010). In case a subject does not have an event, as defined above, prior to data cutoff, EFS is censored at the last adequate response assessment date on or prior to the earliest censoring event (except for Stem Cell Transplantation (SCT)).
  • Overall survival (OS)
    • Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months
    • OS is the time from date of first tisagenlecleucel infusion to the date of death due to any reason. In case a subject is alive at the date of last contact on or before data cutoff, OS is censored at the date of last contact. Subjects will be followed-up for survival also in case of Stem Cell Transplantation (SCT).
  • Proportion of patients with Response at Day 28
    • Time Frame: Day 28 (+/- 4 days)
    • The proportion of subjects attaining CR or CRi at Day 28 +/- 4 days post tisagenlecleucel infusion will be evaluated.
  • Tisagenlecleucel immunogenicity (humoral)
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Day -14 to Day -2 (Lymphodepleting chemotherapy), Day 28, Months 3, 6, 12 and 24
    • The humoral immunogenicity assay will be evaluated to measure the antibody titers specific to the tisagenlecleucel molecule prior to and following infusion. Data will be further fractionated to determine proportion of subjects who make transient versus sustained antibody responses.
  • Tisagenlecleucel immunogenicity (cellular)
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Day -14 to Day -2 (Lymphodepleting chemotherapy), Day 28, Months 3, 6, 12 and 24
    • The cellular immunogenicity assay will be evaluated to assess the presence of T lymphocytes activated by the tisagenlecleucel protein.
  • AUC0-28d and/or AUC0-84d of Tisagenlecleucel PK
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 36, 48 and 60
    • The AUC from time zero to day 28 and/or day 84 and or other disease assessment days, in peripheral blood (%*days or days*copies/ μg)
  • Tmax of Tisagenlecleucel PK
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 36, 48 and 60
    • The time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days)
  • Cmax of Tisagenlecleucel PK
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 36, 48 and 60
    • The maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration (% or copies/ μg)
  • T1/2 of Tisagenlecleucel PK
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 36, 48 and 60
    • The half-life associated with the elimination phase slope of a semi logarithmic concentrationtime curve (days) in peripheral blood
  • Tlast of Tisagenlecleucel PK
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 36, 48 and 60
    • The time of last observed quantifiable concentration in peripheral blood (days)
  • Clast of Tisagenlecleucel PK
    • Time Frame: Week -16 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 36, 48 and 60
    • The last observed quantifiable concentration in peripheral blood (% or copies/μg)
  • Concentration of Tocilizumab PK in tocilizumab treated subjects during CRS
    • Time Frame: up to Day 7 after tocilizumab infusion
    • Characterize the tocilizumab PK by CRS grade and investigate the impact of tocilizumab administration on cellular kinetics
  • Serum ILib Level
    • Time Frame: From first dosing (single administration, Day 1) up to Month 3
    • The concentrations of soluble factors in blood and its correlation with CRS grade, neurologic toxicity and other clinical response (e.g., CR rate, MRD negativity rate, ORR, etc.) will be evaluated.
  • Serum IL2 Level
    • Time Frame: From first dosing (single administration, Day 1) up to Month 3
    • The concentrations of soluble factors in blood and its correlation with CRS grade, neurologic toxicity and other clinical response (e.g., CR rate, MRD negativity rate, ORR, etc.) will be evaluated.
  • Serum IL6 Level
    • Time Frame: From first dosing (single administration, Day 1) up to Month 3
    • The concentrations of soluble factors in blood and its correlation with CRS grade, neurologic toxicity and other clinical response (e.g., CR rate, MRD negativity rate, ORR, etc.) will be evaluated.
  • Serum TNFa Level
    • Time Frame: From first dosing (single administration, Day 1) up to Month 3
    • The concentrations of soluble factors in blood and its correlation with CRS grade, neurologic toxicity and other clinical response (e.g., CR rate, MRD negativity rate, ORR, etc.) will be evaluated.
  • Normal B cell Level
    • Time Frame: Days 7, 14, and 21,
    • The effect of tisagenlecleucel therapy on normal B cell levels will be measured in peripheral blood and bone marrow aspirate to assess the on target effect on these CD19 positive cells

Participating in This Clinical Trial

Key Inclusion Criteria:

1. Chinese patients age ≤25 years at the time of informed consent form (ICF) signature.

2. Relapsed or refractory B-cell ALL

1. 2nd or greater bone marrow (BM) relapse OR

2. Any BM relapse after allogeneic SCT and must be ≥ 3 months from SCT at the time of screening OR

3. Primary refractory as defined as not achieving a CR after 2 cycles of a standard first line chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapsed leukemia OR

4. Subjects with Ph+ ALL are eligible if they are intolerant to or relapsed/refractory after two lines of tyrosine kinase inhibitor (TKI) therapy, or if TKI therapy is contraindicated OR

5. Ineligible for allogeneic SCT because of: comorbid disease; other contraindications to allogeneic SCT conditioning regimen; lack of suitable donor; prior SCT; subject declines allogeneic SCT as a therapeutic option after documented discussion about the role of SCT with a BMT physician not part of the study team

3. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of screening

4. Bone marrow with ≥ 5% lymphoblasts on local morphologic assessment at screening

5. Adequate performance status, cardiac, hepatic, renal and pulmonary function at screening

6. Must have a leukapheresis material of non-mobilized cells accepted for manufacturing

7. Once all other eligibility criteria are confirmed, must have a leukapheresis material of non-mobilized cells received and accepted for manufacturing. Note: Leukapheresis product will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other clinical eligibility criteria is received

Key Exclusion Criteria:

1. Isolated extra-medullary disease relapse

2. Subjects with concomitant genetic syndromes associated with bone marrow failure states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Subjects with Down syndrome will not be excluded.

3. Subjects with Burkitt's lymphoma/leukemia (i.e. subjects 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)

4. Prior anti-CD19 directed therapy, gene therapy or adoptive T cell therapy

5. Active central nervous system (CNS) involvement by ALL

6. Active neurological autoimmune or inflammatory disorders (e.g. Guillain-Barre syndrome)

7. History or presence of clinically relevant CNS pathology, e.g., epilepsy, paresis, aphasia, stroke, severe brain injuries, cerebellar disease, organic brain syndrome, or psychosis.

8. Investigational medicinal product within the last 30 days or five half-lives (whichever is longer) prior to screening NOTE: Investigational therapies must not be used at any time while on study until the first progression following tisagenlecleucel infusion.

9. Previous or concurrent malignancy except for curatively treated non-melanoma skin cancers, in situ carcinoma (e.g. cervix, skin), and cancers in complete remission for at least 3 years and without evidence of recurrence

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: 25 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Novartis Pharmaceuticals
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Novartis Pharmaceuticals, Study Director, Novartis Pharmaceuticals
  • Overall Contact(s)
    • Novartis Pharmaceuticals, +41613241111, novartis.email@novartis.com

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