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

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

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)

Study Overview

• Status: Withdrawn
• Conditions: B-cell Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: Tisagenlecleucel

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.

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 25 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 meet the institutional criteria to undergo leukapheresis
7. Once all other eligibility criteria are confirmed, must have a leukapheresis material of non-mobilized cells received and accepted for manufacturing.

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. CNS involvement by ALL, defined as CNS-2 and CNS-3 disease per National Comprehensive Cancer Network guidelines NCCN 2018 v1
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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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.

Biological: Tisagenlecleucel; A single intravenous (i.v.) infusion of CAR-positive viable T cells.; Other Names: CTL019

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Remission Rate (ORR)	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)	From first dosing (single administration, Day 1) up to Month 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
CR or CRi rate at month 6	Evaluate the percentage of participants who achieve CR or CRi at Month 6 without SCT after tisagenlecleucel infusion	Month 6
CR or CRi rate at Day 28	Evaluate the percentage of participants who achieve CR or CRi at Day 28 after tisagenlecleucel infusion	Day 28
Best Overall Response (BOR) of CR or CRi with a MRD negative bone marrow	Evaluate the percentage of participants who achieve a BOR of CR or CRi with a MRD negative bone marrow during the 3 months after tisagenlecleucel infusion	From first dosing (single administration, Day 1) up to Month 3
Duration of remission (DOR)	DOR, i.e. the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to ALL	Average of 60 Months
Relapse free survival (RFS)	RFS, i.e. the time from achievement of CR or CRi whichever occurs first to relapse or death due to any cause during CR or CRi	Avarage of 60 Months
Event free survival (EFS)	EFS, i.e. the time from date of Tisagenlecleucel infusion to the earliest of death, relapse or treatment failure	Average of 60 Months
Overall survival (OS)	OS, i.e. the time from date of tisagenlecleucel infusion to the date of death due to any reason	Average of 60 Months
Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Deaths	Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) parameters.	From Screening up to Month 60
In vivo cellular PK profile of tisagenlecleucel	qPCR and flow cytometry will be used to measure tisagenlecleucel transgene concentration in blood, bone marrow and other matrices/tissues	Up to Month 60
Serum cytokine	Concentrations of soluble factors (such as IL-10, iFN-y, IL-6) in blood will be summarized by participant and time point	Up to Month 60
Levels of pre-existing and treatment induced humoral immunogenicity	The humoral immunogenicity assay measures the antibody titers specific to tisagenlecleucel prior to and following infusion	Up to Month 60
Tociluzumab PK	Concentrations of tocilizumab	Up to Day 7 after tocilizumab infusion
Levels of prexisting and treatment induced cellular immunogenicity	The cellular immunogenicity assay will assess the presence of T lymphocyte activated by the tisagenlecleucel protein	Up to Month 60

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Anticipated): November 30, 2021
• Primary Completion (Anticipated): November 30, 2022
• Study Completion (Anticipated): November 30, 2027

Study Registration Dates

• First Submitted: October 23, 2019
• First Submitted That Met QC Criteria: November 6, 2019
• First Posted (Actual): November 7, 2019

Study Record Updates

• Last Update Posted (Estimate): March 9, 2023
• Last Update Submitted That Met QC Criteria: March 7, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: China; ALL; CTL019; Tisagenlecleucel; Relapsed/Refractory B-cell Acute Lymphoblastic Leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid
• Other Study ID Numbers: CCTL019B2210

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD 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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No