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

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.

Time frame: 6 months post-tisagenlecleucel infusion

Population: Efficacy Analysis Set (EAS): all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline, i.e participants with complete or unknown response after bridging therapy were excluded from the efficacy analysis set.

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.

Time frame: 0 to 28 days

Population: CKAS: subjects in the FAS who provided at least 1 valid cellular kinetic concentration for tisagenlecleucel. Certain PK parameters were not estimable for all subjects due to insufficient samples.

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.

Time frame: 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

Population: CKAS: subjects in the FAS who provided at least 1 valid cellular kinetic concentration for tisagenlecleucel. Certain PK parameters were not estimable for all subjects due to insufficient samples.

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.

Time frame: 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

Population: Cellular kinetic analysis set (CKAS): subjects in the FAS who provided at least 1 valid cellular kinetic concentration for tisagenlecleucel. Certain PK parameters were not estimable for all subjects due to insufficient samples.

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.

Time frame: 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

Population: CKAS: subjects in the FAS who provided at least 1 valid cellular kinetic concentration for tisagenlecleucel. Certain PK parameters were not estimable for all subjects due to insufficient samples.

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.

Time frame: 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

Population: CKAS: subjects in the FAS who provided at least 1 valid cellular kinetic concentration for tisagenlecleucel. Certain PK parameters were not estimable for all subjects due to insufficient samples.

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.

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Population: EAS: all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline. Only participants with best response of CR/PR post-infusion were included in the DOR analysis.

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).

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Population: EAS: all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline, i.e participants with complete or unknown response after bridging therapy were excluded from the efficacy analysis set.

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).

Time frame: Until disease progression or through study completion, up to 4 years

Population: Safety set: All participants who received an infusion of tisagenlecleucel

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.

Time frame: Through study completion, up to 4 years

Population: Safety set: All participants who received an infusion of tisagenlecleucel

Overall survival (OS) is defined as the time from date of first tisagenlecleucel infusion to the date of death due to any cause.

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Population: EAS: all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline, i.e participants with complete or unknown response after bridging therapy were excluded from the efficacy analysis set.

These participants proceeded to transplant any time post-tisagenlecleucel therapy until end of study (EOS).

Time frame: Through study completion, up to 4 years

Population: Safety set: All participants who received an infusion of tisagenlecleucel

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.

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Population: EAS: all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline, i.e participants with complete or unknown response after bridging therapy were excluded from the efficacy analysis set.

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.

Time frame: Post-infusion Day 28, Month 3, Month 6, Month 9, Month 12, Month 18, Month 24, and then annually until Month 48

Population: EAS: all subjects with aggressive r/r B-cell NHL who received an infusion of tisagenlecleucel and had measurable disease at baseline. Only participants with best response of CR/PR post-infusion were included in the RFS analysis.

On-treatment deaths were collected during the post-infusion period starting at the day of first infusion until the end of the study, up to 48 months. All deaths is the sum of pre-infusion and post-infusion deaths.

Time frame: Pre-treatment deaths: from enrollment to pre-infusion; On-treatment deaths: post-infusion up to 48 months

Population: Clinical Database Population: All infused and non-infused participants who met the criteria to be enrolled in the study