Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients

A Phase II, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02445248

Acronym

JULIET

Enrollment

115

Registered

2015-05-15

Start date

2015-07-29

Completion date

2022-12-22

Last updated

2024-04-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Diffuse Large B-cell Lymphoma (DLBCL)

Keywords

Diffuse large B-cell lymphoma, DLBCL, Relapsed/refractory, CTL019, CART19, CART, CAR T cells, Chimeric antigen receptor

Brief summary

This is a multi-center, phase II study to determine the efficacy and safety of CTL019 in adult patients with relapsed or refractory DLBCL.

Detailed description

This was a single arm, open-label, multi-center, Phase II study conducted to determine the efficacy and safety of tisagenlecleucel in adult patients with r/r DLBCL. The study consisted of the following sequential periods: Screening, Pre-Treatment, Treatment and Primary follow-up, Secondary follow-up, Survival follow-up. Patients were enrolled in 2 cohorts to receive one tisagenlecleucel infusion as follows: * Main Cohort (patients treated with tisagenlecleucel manufactured at the Novartis manufacturing facility in Morris Plains, US, referred to as US manufacturing facility) and * Cohort A (patients treated with tisagenlecleucel manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany, referred to as EU manufacturing facility). The study enrolled adult patients ≥ 18 years with histologically confirmed relapsed or refractory (r/r) DLBCL after ≥ 2 lines of chemotherapy, with a life expectancy of ≥ 12 weeks and not eligible or not consenting to stem cell transplantation (SCT). Patients had measurable disease at time of enrollment, adequate organ function and zero or one Eastern Cooperative Oncology Group performance status at screening. For each patient, the apheresis product of non-mobilized cells was received and accepted by the manufacturing site.

Interventions

BIOLOGICALTisagenlecleucel

The target dose of CTL019 transduced cells for adult patients consisted of a single infusion of 5 x 10\^8 viable CTL019 transduced cells, which was administered via intravenous infusion. The acceptable dose range was 1 - 5x10\^8 viable CTL019 transduced cells.

DRUGLymphodepleting chemotherapy

Prior to CTL019 cell infusion, an additional lymphodepleting chemotherapy cycle was planned. The use of any additional bridging therapy prior to the recommended lymphodepleting chemotherapy was at the discretion of the investigator and dependent on the patient's disease burden. Lymphodepleting chemotherapy was started 14 to 5 days before CTL019 infusion (D1) to allow for at least 48 hours from last dose of lymphodepleting chemotherapy to CTL019 infusion. The lymphodepleting regimen was: Fludarabine (25 mg/m\^2 intravenously \[i.v.\] daily for 3 doses) and cyclophosphamide (250 mg/m\^2 i.v. daily for 3 doses starting with the first dose of fludarabine).

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

Inclusion criteria

* Written informed consent must be obtained prior to any screening procedures * Histologically confirmed DLBCL at last relapse(by central pathology review before enrolment. .- Relapsed or refractory disease after ≥2 lines of chemotherapy including rituximab and anthracycline and either having failed autologous Hematopoietic stem cell transplantation (ASCT), or being ineligible for or not consenting to ASCT * Measurable disease at time of enrollment * Life expectancy ≥12 weeks * Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening * Adequate organ function: * Renal function defined as: * A serum creatinine of ≤1.5 x Upper Limit of Normal ULN OR * Estimated Glomerular Filtration Rate (eGFR) ≥ 60 mL/min/1.73 m\^2 * Liver function defined as: * Alanine Aminotransferase (ALT) ≤ 5 times the Upper Limit of Normal (ULN) for age * Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert-Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN * Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation \> 91% on room air * Hemodynamically stable and Left Ventricle Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multigated Radionuclide Angiography (MUGA) * Adequate bone marrow reserve without transfusions defined as: * Absolute neutrophil count (ANC) \> 1.000/mm\^3 * Absolute lymphocyte count (ALC) ≥ 300/mm\^3 and absolute number of CD3+ T cells \> 150/mm\^3 * Platelets ≥ 50.000//mm\^3 * Hemoglobin \> 8.0 g/dl * Must have an apheresis product of non-mobilized cells accepted for manufacturing * Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests

Exclusion criteria

* Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy * Treatment with any prior gene therapy product * Active Central Nervous System (CNS) involvement by malignancy * Prior allogeneic HSCT * Eligible for and consenting to HSCT * Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion * Investigational medicinal product within the last 30 days prior to screening * The following medications are excluded: * Steroids: Therapeutic doses of steroids must be stopped \>72 hours prior to leukapheresis and \>72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: \< 12 mg/m\^2/day hydrocortisone or equivalent * Immunosuppression: Any other immunosuppressive medication must be stopped ≥2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators) * Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion * Short acting drugs used to treat leukemia or lymphoma (e.g. tyrosine kinase inhibitors, and hydroxyurea) must be stopped \> 72 hour prior to leukapheresis and \> 72 hours prior to CTL019 infusion * Other cytotoxic drugs, including low dose daily or weekly maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion * Fludarabine may be associated with prolonged lymphopenia. This should be taken into consideration when evaluating the optimal timing for leukapheresis collection. * Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respected antibody, whichever is longer * CNS disease prophylaxis must be stopped \> 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate) * Prior radiation therapy within 2 weeks of infusion * Active replication of or prior infection with hepatitis B or active hepatitis C( HCV RNA positive ) * HIV positive patients * Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion) * Unstable angina and/or myocardial infarction within 6 months prior to screening * Previous or concurrent malignancy with the following exceptions: * Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry) * In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study * A primary malignancy which has been completely resected and in complete remission for ≥ 5 years * Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before lymphodepletion * Intolerance to the excipients of the CTL019 cell product * Cardiac arrhythmia not controlled with medical management * Prior treatment with any adoptive T cell therapy * Patients with T-cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly, Richter's transformation, and Burkitt lymphoma * Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain Barre Syndrome, Amyptrophic Lateral Sclerosis)

Design outcomes

Primary

Measure	Time frame	Description
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort	60 months	ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first. Response was assessed according to Evaluation Criteria in diffuse large B cell lymphoma studies (based on Cheson Response criteria and the Lugano Classification (2014))

Secondary

Measure	Time frame	Description
Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)	up to approx. 3.3 months	TTR is the time between date of CTL019 infusion until first documented response (CR or PR).
Duration of Overall Response (DOR) Per IRC	up to approx. 60.1 months	DOR is the time from achievement of CR or PR, whichever occurs first, to relapse or death due to diffuse large B-cell lymphoma (DLBCL).
Event Free Survival (EFS) Per Independent Review Committee	up to approx. 61 months	EFS is the time from date of CTL019 infusion to the date of first documented disease progression or relapse, new treatment for lymphoma or death due to any cause.
Progression Free Survival (PFS) Per Independent Review Committee	up to approx. 61 months	PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.
Overall Survival (OS) Per Independent Review Committee	60 months	OS is the time from date of CTL019 infusion to the date of death due to any cause.
Pharmacokinetics (Pk): Cmax	60 months	Cmax is the maximum (peak) observed in peripheral blood or other body fluid drug concentration after single dose administration. Cmax, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. The reported Cmax is the summary of maximum level observed based on the data from each patient and based on all the data that's been collected for up to 60 months in a patient.
Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients	5 years	ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first.
Pharmacokinetics (Pk): AUC0-28d and AUC0-84d	0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d	The AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood. AUC0-28d and AUC0-84d, based on the transgene level data by qPCR, were summarized by Month 3 response, per Independent Review Committee assessment.
Pharmacokinetics (Pk): T1/2	60 months	T1/2 is the half-life associated with the disposition phase slopes (alpha, beta, gamma etc.) of a semi logarithmic concentration-time curve in peripheral blood. T1/2, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame of 60 months reflects the maximum duration up to which the transgene levels were collected to measure the half life.
Pharmacokinetics (Pk): Clast	60 months	Clast is the last observed quantifiable concentration in peripheral blood. Clast, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame reflects maximum duration of 60 months up to which the transgene levels were collected.
Pharmacokinetics (Pk): Tlast	60 months	Tlast is the time of last observed quantifiable concentration in peripheral blood. Tlast, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. This time frame reflects maximum duration of 60 months up to which the transgene levels were collected.
Incidence of Immunogenicity to CTL019	pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years	This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by complete response (CR), partial response (PR), Stable disease (SD), progressive disease (SD), Unknown for all participants who received with tisagenlecleucel.
Pharmacokinetics (Pk): Tmax	60 months	Tmax is the time to reach maximum (peak) peripheral blood or other body fluid drug concentration after single dose administration (days). Tmax, based on the transgene level data by qPCR, was summarized by Month 3 response, per Independent Review Committee assessment. The time frame of 60 months refers to the duration for which the data were reviewed to identify the time of Cmax for this measure.

Countries

Australia, Austria, Canada, France, Germany, Italy, Japan, Netherlands, Norway, United States

Participant flow

Recruitment details

115 participants were infused in this study: 99 in the Main Cohort and 16 in Cohort A.

Pre-assignment details

After informed consent/assent was obtained, and prior to infusion, participants underwent a routine lymphodepleting therapy, 14 to 5 days before CTL019 infusion. There were 27 centers across 10 countries for this trial.

Participants by arm

Arm	Count
Tisagenlecleucel - Main Cohort Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel manufactured at the Novartis manufacturing facility in Morris Plains, US.	99
Tisagenlecleucel Cohort A Adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who received tisagenlecleucel manufactured at the Fraunhofer Institut für Zelltherapie, Leipzig, Germany.	16
Total	115

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	1	0
Overall Study	Death	45	12
Overall Study	Lost to Follow-up	1	0
Overall Study	Physician Decision	5	0
Overall Study	Progressive disease	13	1
Overall Study	Subject decision	8	0

Baseline characteristics

Characteristic	Tisagenlecleucel Cohort A	Total	Tisagenlecleucel - Main Cohort
Age, Continuous	51.1 years STANDARD_DEVIATION 12.98	53.8 years STANDARD_DEVIATION 13.07	54.3 years STANDARD_DEVIATION 13.09
ECOG performance status ECOG status of 0	11 Participants	65 Participants	54 Participants
ECOG performance status ECOG status of 1	5 Participants	50 Participants	45 Participants
Race/Ethnicity, Customized Asian	0 Participants	10 Participants	10 Participants
Race/Ethnicity, Customized Black	0 Participants	4 Participants	4 Participants
Race/Ethnicity, Customized Other	1 Participants	3 Participants	2 Participants
Race/Ethnicity, Customized White	15 Participants	98 Participants	83 Participants
Sex: Female, Male Female	8 Participants	44 Participants	36 Participants
Sex: Female, Male Male	8 Participants	71 Participants	63 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	76 / 115
other Total, other adverse events	113 / 115
serious Total, serious adverse events	84 / 115

Outcome results

Primary

Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort

ORR, which includes complete response (CR) and partial response (PR) in the Main cohort as determined by IRC assessment. ORR is the percentage of participants with a best overall disease response of CR or PR, where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until progressive disease or start of new anticancer therapy (including ASCT), whichever comes first. Response was assessed according to Evaluation Criteria in diffuse large B cell lymphoma studies (based on Cheson Response criteria and the Lugano Classification (2014))

Time frame: 60 months

Population: Full Analysis Set (FAS): Comprised of all patients in the Main cohort who received infusion of tisagenlecleucel.

Arm	Measure	Value (NUMBER)
Tisagenlecleucel - Main Cohort	Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Main Cohort	54.5 Percentage of participants

Secondary

Duration of Overall Response (DOR) Per IRC

DOR is the time from achievement of CR or PR, whichever occurs first, to relapse or death due to diffuse large B-cell lymphoma (DLBCL).

Time frame: up to approx. 60.1 months

Population: Full Analysis Set (FAS): Comprised all patients who received infusion of tisagenlecleucel and who achieved a completer response (CR) or a partial response (PR).

Arm	Measure	Value (MEDIAN)
Tisagenlecleucel - Main Cohort	Duration of Overall Response (DOR) Per IRC	NA Months
Tisagenlecleucel - All Patients	Duration of Overall Response (DOR) Per IRC	NA Months
Tisagenlecleucel - All Patients	Duration of Overall Response (DOR) Per IRC	NA Months

Secondary

Event Free Survival (EFS) Per Independent Review Committee

EFS is the time from date of CTL019 infusion to the date of first documented disease progression or relapse, new treatment for lymphoma or death due to any cause.

Time frame: up to approx. 61 months

Population: Full Analysis Set (FAS): Comprised all patients who received infusion of tisagenlecleucel.

Arm	Measure	Value (MEDIAN)
Tisagenlecleucel - Main Cohort	Event Free Survival (EFS) Per Independent Review Committee	2.8 Months
Tisagenlecleucel - All Patients	Event Free Survival (EFS) Per Independent Review Committee	2.1 Months
Tisagenlecleucel - All Patients	Event Free Survival (EFS) Per Independent Review Committee	2.8 Months

Secondary

Incidence of Immunogenicity to CTL019

This is defined as the percentage of participants who tested positive for anti-mCAR19 antibodies at any time post-baseline, reported by complete response (CR), partial response (PR), Stable disease (SD), progressive disease (SD), Unknown for all participants who received with tisagenlecleucel.

Time frame: pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years

Population: Full Analysis Set (FAS): Comprised all patients who received infusion of tisagenlecleucel.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Tisagenlecleucel - Main Cohort	Incidence of Immunogenicity to CTL019	Complete response	36 Participants
Tisagenlecleucel - Main Cohort	Incidence of Immunogenicity to CTL019	Partial response	6 Participants
Tisagenlecleucel - Main Cohort	Incidence of Immunogenicity to CTL019	Stable disease	1 Participants
Tisagenlecleucel - Main Cohort	Incidence of Immunogenicity to CTL019	Progressive disease	50 Participants
Tisagenlecleucel - Main Cohort	Incidence of Immunogenicity to CTL019	Unknown	14 Participants
Tisagenlecleucel - Main Cohort	Incidence of Immunogenicity to CTL019	All Participants	107 Participants

Secondary

Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients

Time frame: 5 years

Population: Full Analysis Set (FAS): Comprised all patients who received infusion of tisagenlecleucel.

Arm	Measure	Value (NUMBER)
Tisagenlecleucel - Main Cohort	Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients	43.8 Percentage of participants
Tisagenlecleucel - All Patients	Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients	53.0 Percentage of participants

Secondary

Overall Survival (OS) Per Independent Review Committee

OS is the time from date of CTL019 infusion to the date of death due to any cause.

Time frame: 60 months

Population: Full Analysis Set (FAS): Comprised all patients who received infusion of tisagenlecleucel.

Arm	Measure	Value (MEDIAN)
Tisagenlecleucel - Main Cohort	Overall Survival (OS) Per Independent Review Committee	12.5 Months
Tisagenlecleucel - All Patients	Overall Survival (OS) Per Independent Review Committee	5.9 Months
Tisagenlecleucel - All Patients	Overall Survival (OS) Per Independent Review Committee	11.1 Months

Secondary

Pharmacokinetics (Pk): AUC0-28d and AUC0-84d

The AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood. AUC0-28d and AUC0-84d, based on the transgene level data by qPCR, were summarized by Month 3 response, per Independent Review Committee assessment.

Time frame: 0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d