A Non-Interventional Study (NIS) PASS to characterize secondary malignancies of T-cell origin following tisagenlecleucel therapy (CCTL019B2402)

Study type

• Study topic:
  Disease /health condition

  Other
• Study topic, other:
  Non Interventional Study
• Study type:
  Non-interventional study
• Scope of the study:
  Safety study (incl. comparative)
• Data collection methods:
  Primary data collection

Non-interventional study

• Non-interventional study design:
  Other
• Non-interventional study design, other:
  All CAR-T products using a lenti-viral vector in EU have wording in their SmPC stating that in the event of secondary malignancy the company should be contacted for sample collection and testing. ; This NIS PASS protocol CCTL019B2402 aims to provide a procedural framework to facilitate collection of existing participant samples (tumor and/or blood) for testing to address the potential risk for secondary malignancy of T-cell origin.

Study drug and medical condition

• Study drug International non-proprietary name (INN) or common name:
  TISAGENLECLEUCEL
• Anatomical Therapeutic Chemical (ATC) code:
  (L01XL04) tisagenlecleucel

  tisagenlecleucel

Population studied

• Short description of the study population:
  Cohort 1 includes participants who received tisagenlecleucel in Novartis CTL019 interventional clinical trials, and discontinued from the interventional clinical trial.; Cohort 2 includes participants who received tisagenlecleucel in the post-marketing/commercial setting, including patients who received OOS (Out Of Specification) product, or patients enrolled into a MAP (Managed Access Program) or IIT (Investigated Initiated Trial).;
• Age groups:
  • Paediatric Population (< 18 years)
  • Adult and elderly population (≥18 years)
• Special population of interest:
  Other
• Special population of interest, other:
  Patients that used of tisagenlecleucel treatment in CTL019 clinical trial setting but who are no longer followed, or post-marketing/commercial tisagenlecleucel setting and confirmed diagnosis of secondary malignancy of T-cell origin
• Estimated number of subjects:
  30

Study design details

• Study design:
  Once participants are enrolled, existing participant samples will be collected and tested for muCAR19 transgene and RCL by qPCR. Other existing testing samples may occur for cases that test positive for muCAR19qPCR/VCN in the tumor sample. As this is an NIS, there is no study drug given.
• Main study objective:
  The study aims to provide an adequate procedural framework and process guidance to support and facilitate collection of existing participant samples for testing to address the risk for secondary malignancy of T-cell origin. Formal testing of existing tumor tissue, bone marrow aspirate/biopsy and/or blood or DNA from blood or bone marrow aspirate, using samples where the malignant T cells are documented, will assess a potential role of tisagenlecleucel in the development/oncogenesis of secondary malignancies of T-cell origin.
• Setting:
  • Test specific participant samples using qPCR for muCAR19 transgene/Vector Copy Number (VCN) to determine whether the tumor is positive for the muCAR19 transgene with sufficiently positive VCN (≥0.1 viral copies/cell). In cases where there is insufficient DNA to perform qPCR, or when the tumor tissue contains bone (such as bone marrow biopsy), IHC will be performed when feasible. The presence of bone in the sample precludes isolation of DNA of appropriate quality to perform qPCR. In cases where muCAR19 transgene copies are not detectable per qPCR, and/or IHC for muCAR19 is negative, no further testing is performed.; • A percentage of muCAR19 qPCR and VCN positive tumors tested in the total number of patients enrolled in the study will be calculated and reported at the 5 and 10 year interim CSR.; • To estimate the average vector copy number (VCN) and replication competent lentivirus (RCL) among confirmed secondary primary malignancy tumors from patients exposed to tisagenlecleucel.; • To determine whether there is any evidence for a contribution from tisagenlecleucel in the oncogenesis of the secondary malignancy of T-cell origin.; • For any case where VCN value in the tumor tissue is sufficiently positive with a muCAR19-positive tumor, or positive muCAR19 IHC, perform Lentiviral Integration Site Analysis (LISA).; • Determine whether LISA demonstrates any evidence for insertional oncogenesis.;
• Data analysis plan:
  This study provides a procedural framework to ensure case summaries and testing performed with results reviewed as outlined, on existing/archived samples from the participants. The percentage of secondary malignancy of T cell origin muCAR19 transgene positive cases will be determined. For the cases of positive muCAR19 transgene or muCAR19 IHC, LISA will analyze for insertional oncogenesis. This information, combined with additional testing will be used to evaluate a potential causal contribution of tisagenlecleucel in the oncogenesis of secondary malignancy of T-cell origin. A descriptive analysis for each participant will be provided. Therefore, no statistical endpoint is being evaluated, and no hypothesis testing is being conducted.