Study of Tisagenlecleucel in Chinese Adult Patients With Relapsed or Refractory Diffuse Large B-cell Non-Hodgkin Lymphoma (DLBCL)

• ClinicalTrials.gov Identifier: NCT04456023
• Recruitment Status: Withdrawn
• First Posted: July 2, 2020
• Last Update Posted: March 2, 2022
• Sponsor: Novartis Pharmaceuticals
• Information provided by (Responsible Party): Novartis ( Novartis Pharmaceuticals )

Tracking Information

• First Submitted Date: June 29, 2020
• First Posted Date: July 2, 2020
• Last Update Posted Date: March 2, 2022
• Estimated Study Start Date: January 31, 2022
• Estimated Primary Completion Date: October 31, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 7, 2021)

Overall Response Rate (ORR) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]

Complete Response (CR) and Partial Response (PR) according to the Lugano classification as determined by the Investigator.

Original Primary Outcome Measures (submitted: June 29, 2020)

Overall Response Rate (ORR) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]

Overall Response Rate (ORR) is defined as the percentage of participants with best overall 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. The overall response assessment is based on the amended Lugano classification assessed by the investigator.

Current Secondary Outcome Measures (submitted: January 7, 2021)

• Duration of Response (DOR) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Time from CR or PR, whichever occurs first, to relapse or death due to DLBCL.
• Time to response (TTR) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Time from tisagenlecleucel infusion to CR or PR, whichever occurs first.
• Progression-Free Survival (PFS) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Time from tisagenlecleucel infusion to the first documented disease progression or death due to any cause.
• Event free survival (EFS) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Time from tisagenlecleucel infusion to the first documented disease progression or relapse, new treatment for lymphoma or death due to any cause.
• Overall Survival (OS) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Time from tisagenlecleucel infusion to death due to any cause.
• Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Deaths [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Analysis of absolute and relative frequencies for treatment emergent AE, SAE and Deaths by primary System Organ Class (SOC) through the monitoring of relevant clinical and laboratory safety parameters.
• Tisagenlecleucel immunogenicity (humoral) [ Time Frame: Up to Month 60 ]
  The humoral immunogenicity assay will be evaluated to measure the antibody titers specific to the tisagenlecleucel molecule prior to and following infusion.
• Tisagenlecleucel immunogenicity (cellular) [ Time Frame: Up to Month 60 ]
  The cellular immunogenicity assay will be evaluated to assess the presence of T lymphocytes activated by the tisagenlecleucel protein.
• In vivo cellular PK profile of tisagenelecleucel [ Time Frame: Up to Month 60 ]
  qPCR and flow cytometry to measure tisagenlecleucel transgene concentration in blood, bone marrow and other matrices/tissues.
• Concentration of Tocilizumab PK in tocilizumab treated subjects during CRS [ Time Frame: Up to Day 7 after tocilizumab infusion ]
  Concentration of Tocilizumab
• Serum cytokines (IL-10, interferon gamma, IL-6, CRP and ferritin) [ Time Frame: Up to Month 60 ]
  Concentration of soluble factors (IL-10, interferon gamma, IL-6, CRP and ferritin) will be listed and summarized by participant and time point.

Original Secondary Outcome Measures (submitted: June 29, 2020)

• Duration of Response (DOR) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Duration of response (DOR) applies only to subjects whose best overall disease response was CR or PR. It is defined as the time from the date of first documented disease response (CR or PR) to the date of first documented progression or death due to Diffuse Large B Cell Lymphoma (DLBCL). If a subject has not had an event, duration of overall response is censored at the date of the last adequate assessment.
• Time to response (TTR) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Time to response (TTR) is defined as the time from the date of tisagenlecleucel infusion to the date of first documented disease response (CR or PR), whichever occurs first.
• Progression-Free Survival (PFS) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Progression-Free Survival (PFS) is defined as the time from tisagenlecleucel infusion to the first documented disease progression or death due to any cause. If a subject has not had an event, progression-free survival is censored at the date of the last adequate assessment.
• Event free survival (EFS) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Event free survival (EFS) is defined as the time from tisagenlecleucel infusion to the first documented disease progression or relapse, new treatment for lymphoma (excluding hematopoietic stem cell transplantation (HSCT)) or death due to any cause.
• Overall Survival (OS) [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Overall survival (OS) is defined as the time from tisagenlecleucel infusion to death due to any cause. If a death has not been observed by the date of analysis cutoff, OS will be censored at the date of last contact.
• Number of Participants with On-Treatments Adverse Events, Serious Adverse Events, and Deaths [ Time Frame: From first dosing (single administration, Day 1) up to End of Study Visit (EOS), an average of 60 Months ]
  Analysis of absolute and relative frequencies for treatment emergent Adverse Event (AE), Serious Adverse Event (SAE) and Deaths by primary System Organ Class (SOC) to demonstrate that single intravenous (i.v.) infusion of tisagenlecleucel is safe through the monitoring of relevant clinical and laboratory safety parameters.
• Tisagenlecleucel immunogenicity (humoral) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Day 28, Months 3, 6 and 12 ]
  The humoral immunogenicity assay will be evaluated to measure the antibody titers specific to the tisagenlecleucel molecule prior to and following infusion. Data will be further fractionated to determine proportion of subjects who make transient versus sustained antibody responses.
• Tisagenlecleucel immunogenicity (cellular) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Day 28, Months 3, 6 and 12 ]
  The cellular immunogenicity assay will be evaluated to assess the presence of T lymphocytes activated by the tisagenlecleucel protein.
• Pharmacokinetic of Tisagenlecleucel: Area Under the Curve from time zero to day 28 (AUC0-28d) and/or DAY 84 (AUC0-84d) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 ]
  Area Under the Curve from time zero to day 28 (AUC0-28d) and/or DAY 84 (AUC0-84d) will be calculated from plasma concentration-time data using non-compartmental methods.
• Pharmacokinetic of Tisagenlecleucel: Maximum Observed Plasma Concentration (Cmax) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 ]
  Cmax is the observed maximum plasma concentration following drug administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
• Pharmacokinetic of Tisagenlecleucel: Time to reach the maximum concentration after drug administration (Tmax) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 ]
  Tmax is the time to reach maximum plasma concentration after single dose administration. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
• Pharmacokinetic of Tisagenlecleucel: Terminal elimination half-life (T^1/2) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 ]
  T^1/2 is the elimination half-life associated with the terminal slope of a semi logarithmic concentration-time curve. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
• Pharmacokinetic of Tisagenlecleucel: last observed quantifiable concentration in peripheral blood (Clast) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 30, 36, 42, 48, 54 and 60 ]
  Clast is the last observed quantifiable concentration in peripheral blood. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
• Pharmacokinetic of Tisagenlecleucel: time of last observed quantifiable concentration in peripheral blood (Tlast) [ Time Frame: Week -12 to Day -1 (Enrollment/Bridging chemotherapy), Days 4, 7, 11, 14 and 28, Months 3, 6, 9, 12, 18, 24, 30, 36, 40, 48, 54 and 60 ]
  Tlast is the time of last observed quantifiable concentration in peripheral blood. PK parameters are calculated from plasma concentration-time data using non-compartmental methods.
• Concentration of Tocilizumab PK in tocilizumab treated subjects during CRS [ Time Frame: up to Day 7 after tocilizumab infusion ]
  The concentration of Tocilizumab PK will be characterized by CRS grade and the impact of tocilizumab administration on cellular kinetics will be investigated.
• Serum Cytokine Levels [ Time Frame: From first dosing (single administration, Day 1) up to Month 3 ]
  The concentrations of soluble factors in blood and its correlation with CRS grade, neurologic toxicity and other clinical response (e.g., CR rate, MRD negativity rate, ORR, etc.) will be evaluated.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Tisagenlecleucel in Chinese Adult Patients With Relapsed or Refractory Diffuse Large B-cell Non-Hodgkin Lymphoma (DLBCL)
• Official Title: A Phase II, Single-arm, Multicenter Trial to Evaluate the Efficacy and Safety of Tisagenlecleucel in Chinese Adult Patients With Relapsed or Refractory Diffuse Large B-cell Non-Hodgkin Lymphoma (DLBCL)
• Brief Summary: This is a multi-center, phase II study to evaluate the efficacy and safety of CTL019 in Chinese adult patients with relapsed or refractory DLBCL.
• Detailed Description: Disease assessments will be performed at screening, after bridging, 1, 3, 6, 9 and 12 months after tisagenlecleucel infusion, and every 6 months in the second year, and annually up to 60 months after infusion. Efficacy will be assessed until progression; safety will be assessed throughout the study. A long term follow-up up to 15 years after CTL019 infusion will continue under a separate protocol (CCTL019A2205B)(NCT02445222).
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Diffuse Large B-Cell Lymphoma (DLBCL)

Intervention

Biological: Tisagenlecleucel

A single intravenous (i.v.) infusion of 0.6 - 6.0×10^8 CAR positive viable T cells.

Other Name: CTL019

Study Arms

Experimental: Tisagenlecleucel

All patients eligible for treatment with tisagenlecleucel will receive a single dose of tisagenlecleucel.

Intervention: Biological: Tisagenlecleucel

• Publications *: Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Recruitment Information

• Recruitment Status: Withdrawn
• Actual Enrollment (submitted: February 25, 2022): 0
• Original Estimated Enrollment (submitted: June 29, 2020): 30
• Estimated Study Completion Date: September 27, 2027
• Estimated Primary Completion Date: October 31, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study
2. Patients must be ≥18 years of age at the time of ICF signature
3. Histologically confirmed DLBCL at last relapse (including DLBCL transformed from follicular lymphoma and double-triple hit lymphoma)
4. Relapsed or refractory disease after at least 2 lines of systemic therapy, including anti-CD20 antibody and an anthracycline, or having failed or being ineligible for autologous HSCT
5. ECOG performance status that is either 0 or 1 at screening

6. Measurable disease at time of enrollment:

   • Nodal lesions greater than 15 mm in the long axis, regardless of the length of the short axis or
   • Extra nodal lesion (outside lymph node or nodal mass, but including liver and spleen) at least 10 mm in long and short axis
7. Adequate organ function
8. Must have a leukapheresis material of non-mobilized cells available for manufacturing

Exclusion Criteria:

1. Prior treatment with anti-CD19 therapy, adoptive T cell therapy, or any prior gene therapy product
2. Primary mediastinal large B-cell lymphoma, EBV+ DLBCL, Richter's transformation, Burkitt lymphoma, primary DLBCL of CNS, T cell / histiocyte rich large B-cell lymphoma, primary cutaneous DLBCL.
3. Eligible for and consenting to autologous HSCT
4. Prior allogeneic SCT
5. Active CNS involvement by disease under study, except if the CNS involvement has been effectively treated (i.e. patient is asymptomatic) and local treatment was greater than 4 weeks before enrollment
6. Active neurological autoimmune or inflammatory disorders (e.g. Guillain-Barre syndrome)
7. Investigational medicinal product within the last 30 days or five half-lives (whichever is longer) prior to screening

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided

Administrative Information

• NCT Number: NCT04456023
• Other Study ID Numbers: CCTL019C2203
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes

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

• URL: https://www.clinicalstudydatarequest.com

• Current Responsible Party: Novartis ( Novartis Pharmaceuticals )
• Original Responsible Party: Same as current
• Current Study Sponsor: Novartis Pharmaceuticals
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Novartis Pharmaceuticals; Novartis Pharmaceuticals

• PRS Account: Novartis
• Verification Date: February 2022