Study of Efficacy and Safety of CTL019 in Adult DLBCL Patients

Diffuse Large B-cell Lymphoma (DLBCL) Clinical Trial

— JULIET  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02445248
• Other study ID #: CCTL019C2201
• Secondary ID: 2014-003060-20
• Status: Completed
• Phase: Phase 2
• Start date: July 29, 2015
• Est. completion date: December 22, 2022

Study information

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

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 115
• Est. completion date: December 22, 2022
• Est. primary completion date: December 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Diffuse Large B-cell Lymphoma (DLBCL)
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse

Intervention

Biological:
• Tisagenlecleucel
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.

Drug:
• Lymphodepleting 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).

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Camperdown
Australia	Novartis Investigative Site	Melbourne	Victoria
Austria	Novartis Investigative Site	Vienna
Canada	Novartis Investigative Site	Hamilton	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
France	Novartis Investigative Site	Pierre Benite
Germany	Novartis Investigative Site	Koeln	Nordrhein-Westfalen
Germany	Novartis Investigative Site	Wuerzburg
Italy	Novartis Investigative Site	Milano	MI
Japan	Novartis Investigative Site	Chuo ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Sapporo city	Hokkaido
Netherlands	Novartis Investigative Site	Amsterdam
Norway	Novartis Investigative Site	Oslo
United States	Uni of Michigan Health System SC CTL019	Ann Arbor	Michigan
United States	Emory University School of Medicine/Winship Cancer Institute SC CTL019	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center SC-2	Baltimore	Maryland
United States	University of Chicago Medical Center Hematology and Oncology SC - CTL019B2207J	Chicago	Illinois
United States	The Ohio State University James Cancer Hospital &	Columbus	Ohio
United States	MD Anderson Cancer Center SC	Houston	Texas
United States	University of Minnesota	Minneapolis	Minnesota
United States	Weill Cornell Medical College	New York	New York
United States	University of Pennsylvania Perelman School of Medicine	Philadelphia	Pennsylvania
United States	Oregon Health Sciences University Oregon Health & Sci Uni	Portland	Oregon
United States	UCSF Medical Center .	San Francisco	California
United States	University of Kansas Cancer Center SC - CTL019C2201	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
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))	60 months
Secondary	Overall Response Rate (ORR) Per Independent Review Committee (IRC) in Cohort A & in All Patients	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.	5 years
Secondary	Time to Response (TTR) as Assessed by Independent Review Committee (Main Cohort & All Patients)	TTR is the time between date of CTL019 infusion until first documented response (CR or PR).	up to approx. 3.3 months
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).	up to approx. 60.1 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.	up to approx. 61 months
Secondary	Progression Free Survival (PFS) Per Independent Review Committee	PFS is the time from date of CTL019 infusion to the date of first documented disease progression or death due to any cause.	up to approx. 61 months
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.	60 months
Secondary	Pharmacokinetics (Pk): Cmax	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.	60 months
Secondary	Pharmacokinetics (Pk): Tmax	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.	60 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.	0 - 28 days after infusion for AUC0-28d, 0 - 84 days after infusion for AUC0-84d
Secondary	Pharmacokinetics (Pk): T1/2	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.	60 months
Secondary	Pharmacokinetics (Pk): Clast	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.	60 months
Secondary	Pharmacokinetics (Pk): Tlast	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.	60 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.	pre-infusion and at any time point post-baseline, up to duration of the study, up to 5 years