Phase III B in Acute Lymphoblastic Leukemia

Phase IIIb Study for Relapsed/Refractory Pediatric/Young Adult Acute Lymphoblastic Leukemia Patients to be Treated With CTL019

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 Acute Lymphoblastic Leukemia (ALL).

Study Overview

• Status: Completed
• Conditions: Acute Lymphoblastic Leukemia
• Intervention / Treatment: Biological: CTL019

Detailed Description

This was a single-arm, multi-centeric Phase IIIb study provided pediatric/young adult patients with r/r B-cell ALL the opportunity to be treated with CTL019. The main purpose of this study was to assess the safety of CTL019 for up to 12 months after the CTL019 infusion. The study had the following sequential phases for all patients: Screening including leukapheresis, Pre-Treatment (Cell Product Preparation and Lymphodepleting Chemotherapy), Treatment and Follow-up, and Long-Term Follow-Up (LTFU). The end of study (EOS) was defined as the last patient's last visit, which was the last patient's Month 12 evaluation, or the time of premature withdrawal. All patients were followed in this study for up to 12 months after the CTL019 infusion.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, A 1090
    • Novartis Investigative Site
• Belgium
  • Gent, Belgium, 9000
    • Novartis Investigative Site
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Novartis Investigative Site
  • Quebec
    • Montreal, Quebec, Canada, H3T 1C5
      • Novartis Investigative Site
• France
  • Paris Cedex, France, 75019
    • Novartis Investigative Site
  • Paris Cedex 10, France, 75475
    • Novartis Investigative Site
• Germany
  • Frankfurt, Germany, 60590
    • Novartis Investigative Site
• Italy
  • MB
    • Monza, MB, Italy, 20900
      • Novartis Investigative Site
• Japan
  • Kyoto, Japan, 606 8507
    • Novartis Investigative Site
• Norway
  • Oslo, Norway, 0424
    • Novartis Investigative Site
• Spain
  • Barcelona
    • Esplugues de Llobregat, Barcelona, Spain, 08950
      • Novartis Investigative Site

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

Inclusion Criteria:

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

1. Second or greater bone marrow relapse.
2. Any bone marrow relapse after allogeneic SCT and must be ≥ 4 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

For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of program entry.For relapsed or refractory patients previously treated with blinatumomab, CD19 tumor expression must be demonstrated (via flow cytometry) at Screening.

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).

Life expectancy > 12 weeks.

Age less than 26 at the time of screening.

Karnofsky (age ≥16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.

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.

Must have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site.

Patients with active CNS leukemia involvement defined as CNS-3 by CSF findings only are eligible but will have their CTL019 infusion delayed until CNS disease is reduced to CNS-1 or CNS-2 by CSF findings. Patients with other forms of active CNS-3 leukemic involvement such as CNS parenchymal or ocular disease, cranial nerve involvement or significant leptomeningeal disease are not eligible. However, such patients with other forms of CNS-3 leukemic involvement (non-CSF involvement) are eligible if there is documented evidence of disease stabilization for at least 3 months prior to CTL019 infusion. Patients must have no acute/ongoing neurologic toxicity > Grade 1 with the exception of a history of controlled seizures or fixed neurologic deficits that have been stable/improving over the past 3 months.

Exclusion criteria Isolated extra-medullary disease relapse. 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.

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).

Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.

Prior treatment with any gene therapy product. Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab 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 GVHD. Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening Investigational medicinal product within the last 30 days prior to screening. Pregnant or nursing women.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.

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

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: CTL019; CTL019 transduced T cells were given as a single dose of 0.2 to 5.0 × 10^6 autologous CTL019 transduced viable T cells per kg body weight (for patients ≤ 50 kg) and 0.1 to 2.5 × 10^8 CTL019 transduced viable T cells (for patients > 50 kg)	Biological: CTL019; CTL019 transduced T cells were given as a single dose of 0.2 to 5.0 × 10^6 autologous CTL019 transduced viable T cells per kg body weight (for patients ≤ 50 kg) and 0.1 to 2.5 × 10^8 CTL019 transduced viable T cells (for patients > 50 kg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Treatment emergent adverse events were collected from CTL019 infusion until end of study, up to 12 months	From CTL019 infusion until end of study, up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Remission Rate (ORR)	ORR is defined as the proportion of participants with a best overall disease response of Complete remission (CR) or CR with incomplete blood count recovery (CRi), where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until Month 6.	From CTL019 infusion until Month 6
Number of Participants Who Achieved CR or CRi at Month 6 Without Stem Cell Transplantation (SCT)	Proportion of participants who achieved CR or CRi at Month 6 without stem cell transplantation between CTL019 infusion and Month 6 response assessment	Month 6
Number of Participants Who Achieved CR or CRi and Then Proceeded to Stem Cell Transplantation (SCT) While in Remission Before Month 6 Assessment	Proportion of participants who achieved CR or CRi and then proceeded to stem cell transplantation while in remission prior to Month 6 response assessment.	From CTL019 infusion until Month 6
Duration of Response (DOR)	DOR is the duration of remission from the date when the response criteria of CR or CRi was first met post CTL019 infusion to the date of relapse or death due to acute lymphoblastic leukemia (ALL), whichever occured first.	Actual reported Time Frame: up to 14.4 months post CTL019 infusion (planned follow-up period per protocol was only 12 months post CTL019 infusion)
Relapse-free Survival (RFS)	RFS is measured by the time from achievement of CR or CRi whichever occured first post CTL019 infusion, to relapse or death due to any cause during CR or CRi.	Actual reported Time Frame: up to 14.4 months post CTL019 infusion (planned follow-up period per protocol was only 12 months post CTL019 infusion)
Event-free Survival (EFS)	EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure.	Actual reported Time Frame: up to 15.1 months post CTL019 infusion (planned follow-up period per protocol was only 12 months post CTL019 infusion)
Overall Survival (OS)	OS is the time from date of CTL019 infusion to the date of death due to any reason	Actual reported Time Frame: up to 24.4 months post CTL019 infusion (planned follow-up period per protocol was only 12 months post CTL019 infusion)
Number of Participants Who Attained CR or CRi at Day 28	Proportion of participants who attained CR or CRi at Day 28 post CTL019 infusion.	Day 28
Number of Participants Who Attained CR or CRi at Day 28 by Baseline Bone Marrow Tumor Burden	Proportion of participants who attained CR or CRi at Day 28 post CTL019 infusion by baseline bone marrow tumor burden.	Day 28
Bone Marrow Minimum Residual Disease (MRD) Status by Flow Cytometry on Day 28 Post CTL019 Infusion	MRD in ALL refers to the presence of leukemic cells below the threshold of detection using conventional morphologic methods. The most frequently used methods for MRD assessment include multicolor flow cytometry to detect abnormal immunophenotypes and polymerase chain reaction (PCR) assays to detect clonal rearrangements in immunoglobulin heavy chain genes and/or T-cell receptor genes or fusion transcripts (e.g. BCR-ABL (Philadelphia chromosome)). The results include the descriptive summary of MRD qualitative result (positive/negative) before treatment and at Day 28 after treatment and before HSCT by local assessment (flow cytometry).	Enrollment/Pre-chemotherapy and Day 28
Bone Marrow Minimum Residual Disease (MRD) Status by qPCR on Day 28 Post CTL019 Infusion	MRD in ALL refers to the presence of leukemic cells below the threshold of detection using conventional morphologic methods. The most frequently used methods for MRD assessment include multicolor flow cytometry to detect abnormal immunophenotypes and polymerase chain reaction (PCR) assays to detect clonal rearrangements in immunoglobulin heavy chain genes and/or T-cell receptor genes or fusion transcripts (e.g. BCR-ABL (Philadelphia chromosome)). The results include the descriptive summary of MRD qualitative result (positive/negative) before treatment and at Day 28 after treatment and before HSCT by local assessment (qPCR).	Enrollment/Pre-chemotherapy and Day 28
Incidence of Immunogenicity Against CTL019 - Humoral Immunogenicity	The humoral immunogenicity assessment included evaluation of pre-existing (pre-treatment) and post-treatment anti-CTL019 antibodies to examine the incidence of immunogenicity with treatment.	Baseline, Day 14, Day 28, Month 3, Month 6 and Month 12
Incidence of Immunogenicity Against CTL019 - Cellular Immunogenicity	The cellular immunogenicity assessment included percentage of CD4+ and CD8+ T- cells specific for CTL019.	Baseline, Day 14, Day 28, Month 3, Month 6 and Month 12
AUC0-28d: PK Parameters for CTL019 by qPCR	Area under the concentration-time curve of CTL019 in the peripheral blood after single dose administration from time zero to Day 28 after single dose administration as measured by qPCR.	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28
AUC0-84d: PK Parameters for CTL019 by qPCR	Area under the concentration-time curve of CTL019 in the peripheral blood after single dose administration from time zero to Day 84 after single dose administration as measured by qPCR.	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28 and 84
Cmax: PK Parameters for CTL019 by qPCR	The maximum (peak) observed in peripheral blood drug concentration after single dose administration	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28, Month 3, 6, 9 and 12
Clast: PK Parameters for CTL019 by qPCR	The last observed in peripheral blood drug concentration after single dose administration.	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28, Month 3, 6, 9 and 12
Tmax: PK Parameters for CTL019 by qPCR	The time to reach maximum (peak) peripheral blood drug concentration after single dose administration.	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28, Month 3, 6, 9 and 12
T1/2: PK Parameters for CTL019 by qPCR	The half-life associated with the elimination phase slope of a semi logarithmic concentration-time curve (days) in peripheral blood.	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28, Month 3, 6, 9 and 12
Tlast: PK Parameters for CTL019 by qPCR	The time to reach the last observed quantifiable concentration in peripheral blood after single dose administration.	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28, Month 3, 6, 9 and 12
AUC0-28d by Maximum Cytokine Release Syndrome (CRS) Grade	AUC0-28d from time zero to Day 28 after single dose administration as measured by qPCR. PK results were presented by the maximum Penn Grading Scale (Grade 1 to 4): - Mild reaction; - Moderate reaction; - More severe reaction; - Life-threatening complications	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28
Cmax by Maximum Cytokine Release Syndrome (CRS) Grade	The maximum (peak) observed in peripheral blood drug concentration after single dose administration. PK results were presented by the maximum Penn Grading Scale (Grade 1 to 4): - Mild reaction; - Moderate reaction; - More severe reaction; - Life-threatening complications	Day 1 10 min post-infusion, Day 4, 7, 11, 14, 28, Month 3, 6, 9 and 12

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Laetsch TW, Maude SL, Balduzzi A, Rives S, Bittencourt H, Boyer MW, Buechner J, De Moerloose B, Qayed M, Phillips CL, Pulsipher MA, Hiramatsu H, Tiwari R, Grupp SA. Tisagenlecleucel in pediatric and young adult patients with Down syndrome-associated relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2022 Jun;36(6):1508-1515. doi: 10.1038/s41375-022-01550-z. Epub 2022 Apr 14.

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2017
• Primary Completion (Actual): October 13, 2020
• Study Completion (Actual): October 13, 2020

Study Registration Dates

• First Submitted: April 13, 2017
• First Submitted That Met QC Criteria: April 19, 2017
• First Posted (Actual): April 21, 2017

Study Record Updates

• Last Update Posted (Actual): July 21, 2021
• Last Update Submitted That Met QC Criteria: June 30, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: ALL; Acute Lymphoblastic Leukemia; CTL019; relapsed/refractory pediatric/young adult
• 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: CCTL019B2001X; 2016-001991-31 (EudraCT Number)

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: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes