Phase II Open Label Trial to Determine Safety & Efficacy of Tisagenlecleucel in Pediatric Non-Hodgkin Lymphoma Patients

Non-Hodgkin Lymphoma Clinical Trial

— BIANCA  

Official title:

A Phase II, Single Arm, Multicenter Open Label Trial to Determine the Safety and Efficacy of Tisagenlecleucel in Pediatric Subjects With Relapsed or Refractory Mature B-cell Non-Hodgkin Lymphoma (NHL)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03610724
• Other study ID #: CCTL019C2202
• Secondary ID: 2017-005019-15
• Status: Completed
• Phase: Phase 2
• Start date: February 15, 2019
• Est. completion date: April 26, 2023

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of the study was to assess the efficacy and safety of tisagenlecleucel in pediatric, adolescent and young adult patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL) including Burkitt Lymphoma and Burkitt Leukemia.

For pediatric patients who have r/r B-NHL including Burkitt Lymphoma and Burkitt Leukemia, survival rates are dismal, only ~20-50% subjects are alive at 2 years with overall response rate (ORR) of 20-30% after conventional salvage chemotherapy.

Description:

This study was part of an agreed Pediatric Investigation Plan (PIP). The single-arm study design included r/r B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia subject population with poor prognosis, lack of approved effective therapies in this setting. Subject population included aggressive subtypes of B-cell NHL including Burkitt Lymphoma and Burkitt Leukemia who were allowed to receive "bridging therapy" of investigator's choice. After assessment of eligibility, subjects qualifying for the study were enrolled and were allowed to start lymphodepleting chemotherapy as recommended in protocol after which a single dose of tisagenlecleucel product was infused. The efficacy of tisagenlecleucel was evaluated through the primary endpoint of Overall Response Rate (ORR) which included complete response (CR) and partial response (PR) as determined by local assessment. Safety assessments were conducted until study completion.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 34
• Est. completion date: April 26, 2023
• Est. primary completion date: July 27, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A to 25 Years

Eligibility

Inclusion Criteria:

• Histologically confirmed pediatric mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt lymphoma/ Burkitt leukemia (BL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), gray zone lymphoma (GZL), and follicular lymphoma (FL) Note: Patients with B-cell NHL associated with Nijmegen breakage syndrome will be allowed.

• Patients <25 years of age and weighing at least 6 kg at the time of screening

• Patients who have relapsed after one or more prior therapies (can include allogeneic and autologous hematopoietic stem cell transplant) or are primary refractory (have not achieved a CR or PR after the first line of therapy)

• Measurable disease by radiological criteria in all patients at the time of screening. Patients with Burkitt leukemia who don't meet radiological criteria must have bone marrow involvement of >25% by local assessment of bone marrow aspirate and/or biopsy.

• Karnofsky (age =16 years) or Lansky (age <16 years) performance status =60.

• Adequate bone marrow reserve without transfusions (transfusion >2 weeks prior to laboratory assessment is allowed) defined as:

1. Absolute neutrophil count (ANC) >1000/mm3

2. Platelets =50000//mm3

3. Hemoglobin =8.0 g/dl

• Adequate organ function defined as:

1. a serum creatinine (sCR) based on gender/age as follows: Maximum Serum Creatinine (mg/dL) Age Male Female

1 to <2 years 0.6 0.6 2 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. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =5 times the upper limit of normal (ULN) for age

3. Total bilirubin <2 mg/dL (for Gilbert's Syndrome patients total bilirubin <4 mg/dL)

4. Adequate pulmonary function

i. Oxygen saturation of >91% on room air ii. No or mild dyspnea (=Grade 1)

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

Exclusion Criteria:

• Prior gene therapy or engineered T cell therapy.

• Prior treatment with any anti-CD19 therapy.

• Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and =4 months prior to infusion.

• Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT.

• Prior diagnosis of malignancy other than study indication, and not disease free for 5 years.

• Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)

• Presence of active hepatitis B or C as indicated by serology.

• Human Immunodeficiency Virus (HIV) positive test.

• Active neurological autoimmune or inflammatory disorders not related to B cell NHL (eg: Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)

• Active central nervous system (CNS) involvement by malignancy.

• Patients with B-cell NHL in the context of post-transplant lymphoproliferative disorders (PTLD) associated lymphomas.

Related Conditions & MeSH terms

• Lymphoma
• Lymphoma, Non-Hodgkin
• Non-Hodgkin Lymphoma

Intervention

Biological:
• Tisagenlecleucel
Tisagenlecleucel was infused once as an intravenous infustion at a dose of either 0.2 to 5 x 106 CAR-positive viable T cells per kg body weight for subjects = 50 kg or 0.1 to 2.5 x 108 CAR-positive viable T cells for subjects > 50 kg.

Drug:
• lymphodepleting chemotherapy
Prior to tisagenlecleucel infusion, each subject underwent lymphodepletion with recommended Fludarabine and cyclophosphamide (unless contra-indicated for subject)
• Bridging Therapy
Pre-treatment phase could also include bridging therapy of investigator's choice

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Parkville	Victoria
Australia	Novartis Investigative Site	Randwick	New South Wales
Austria	Novartis Investigative Site	Wien
Canada	Novartis Investigative Site	Toronto	Ontario
Denmark	Novartis Investigative Site	Copenhagen
Finland	Novartis Investigative Site	Helsinki
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Villejuif
Germany	Novartis Investigative Site	Muenster
Italy	Novartis Investigative Site	Monza	MB
Italy	Novartis Investigative Site	Roma	RM
Japan	Kyoto University Hospital	Sakyo-ku	Kyoto
Japan	Novartis Investigative Site	Setagaya-ku	Tokyo
Netherlands	Prinses Maxima Centrum voor Kinderoncologie	Utrecht	CS
Norway	Novartis Investigative Site	Oslo
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
United Kingdom	Novartis Investigative Site	London
United States	Johns Hopkins Oncology Center ORA	Baltimore	Maryland
United States	Dana Farber Cancer Institute Dept.of DFCI	Boston	Massachusetts
United States	Cinn Children Hosp Medical Center	Cincinnati	Ohio
United States	University of Texas Southwestern Medical Center .	Dallas	Texas
United States	Childrens Hospital Los Angeles	Los Angeles	California
United States	Memorial Sloan Kettering Cancer Center MSKCC (8)	New York	New York
United States	The Childrens Hospital of Philadelphia Drug Shipment	Philadelphia	Pennsylvania
United States	UCSF Medical Center	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Denmark,  Finland,  France,  Germany,  Italy,  Japan,  Netherlands,  Norway,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Response Rate (ORR) as Determined by Local Investigator	The overall response rate (ORR) is defined as the percentage of subjects with a best overall disease response of complete response (CR) or partial response (PR), where the best overall disease response is defined as the best disease response recorded from tisagenlecleucel infusion until progressive disease or start of new anticancer therapy, whichever comes first.	6 months post-tisagenlecleucel infusion
Secondary	Duration of Response (DOR)	Duration of response (DOR) is defined as the time from the date of first documented disease response (CR or PR) as determined by local investigator assessments to the date of first documented progression or death due to underlying cancer.	Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
Secondary	Event Free Survival (EFS)	Event free survival (EFS) is defined as the time from date of first tisagenlecleucel infusion to the earliest date of death from any cause, disease progression as determined by local investigator assessments, or starting new anticancer therapy for underlying cancer, excluding hematopoietic stem cell transplant (HSCT).	Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
Secondary	Relapse Free Survival (RFS)	Relapse free survival (RFS) is defined as the time from the date of first documented disease response (CR or PR) as determined by local investigator assessments to the date of first documented disease progression or death due to any cause.	Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
Secondary	Progression Free Survival (PFS)	Progression free survival (PFS) is defined as the time from the date of first tisagenlecleucel infusion to the date of first documented disease progression as determined by local investigator assessments or death due to any cause.; Progression is defined using the International non-Hodgkin Lymphoma Response Criteria. For a PET-based response, progressive disease is defined as a 4 or 5 on the 5 point scale with increased uptake compared to the nadir or new FDG-avid foci consistent with lymphoma. For a CT/MRI based response progressive disease is defined as a 25% increase in the SPD (sum of the products of two largest perpendicular diameters) of index lesions, or unequivocal progression in either non-index lesions or the spleen. Any new disease attributable to lymphoma would also constitute progressive disease.	Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
Secondary	Overall Survival (OS)	Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.	Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48
Secondary	Cellular Kinetics Parameter: Cmax	The maximum (peak) transgene level (copies/µg) observed in peripheral blood or other body fluid after single dose administration as measured by qPCR. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.	Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
Secondary	Cellular Kinetics Parameter: Tmax	The time to reach maximum (peak) transgene level (days) in peripheral blood or other body fluid after single dose administration. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.	Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
Secondary	Cellular Kinetics Parameter: AUC0-28d	Area Under the Concentration-time Curve (AUCs) from the time course of transgene levels in peripheral blood following tisagenlecleucel infusion (days*copies/µg), from day of infusion to day 28. D28 refers to the timepoint for definition of responder populations. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.	0 to 28 days
Secondary	Cellular Kinetics Parameter: Clast	The last observed quantifiable transgene level in peripheral blood. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.	Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
Secondary	Cellular Kinetics Parameter: Tlast	The time of last observed quantifiable transgene level in peripheral blood. Pharmacokinetics of tisagenlecleucel were based on chimeric antigen receptor (CAR) transgene levels in peripheral blood as detected by qPCR, unless otherwise noted.	Post-infusion day 4, day 7, day 11, day 14, day 21, day 28, month 3, month 6, month 9, month 12, month 18, month 24, and then annually until Month 48
Secondary	Levels of Pre-existing and Treatment Induced Humoral Immunogenicity and Cellular Immunogenicity Against Tisagenlecleucel Cellular Kinetics, Safety and Efficacy	The humoral immunogenicity assay measures the antibody titers specific to tisagenlecleucel prior to and following infusion by flow cytometry. A subject was only defined as positive for tisagenlecleucel treatment-induced or -boosted anti-mCAR19 antibodies when the anti-mCAR19 antibody median fluorescence intensity at any time post-infusion was at least 2.28-fold higher (for samples analyzed on or prior to 05-May-2021) or 2.38-fold higher (for samples analyzed on or after 06-May-2021) than pre-infusion levels for participants whose baseline status was positive (boosted) or if the baseline status was negative but any post-baseline interpretation was positive (induced).	Until disease progression or through study completion, up to 4 years
Secondary	Percentage of Participants Who Proceeded to Stem Cell Transplant (SCT) After Tisagenlecleucel Infusion	These participants proceeded to transplant any time post-tisagenlecleucel therapy until end of study (EOS).	Through study completion, up to 4 years
Secondary	Maximum Positive Predictive Value (PPV)	Retrospective assessment of potential cytokine release syndrome (CRS) predictive models considering also data from other CTL019 trials. The Positive Predictive Value (PVV) is the percentage of participants who actually had severe CRS out of all the cases where the prediction model predicts that severe CRS will occur. The maximum PPV is the highest value attained across all potential CRS predictive models.	Through study completion, up to 4 years

External Links

•   Patient Lay Trial Summary