Study of Tisagenlecleucel in Combination With Ibrutinib in r/r Diffuse Large B-cell Lymphoma Patients

Study Overview
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Brief Summary
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A multi-center, open-label, phase Ib study to evaluate the safety and tolerability of the administration of tisagenlecleucel in combination with ibrutinib in patients with r/r DLBCL who have received two or more lines of systemic therapy, including an anti-CD20 and anthracycline based chemotherapy, and who have progressed after or are not candidates for ASCT.

Official Title
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A Phase Ib, Multicenter Study to Determine the Safety and Tolerability of Tisagenlecleucel in Combination With Ibrutinib in Adult Patients With Relapsed and/or Refractory Diffuse Large B-cell Lymphoma

Conditions
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Diffuse Large B-cell Lymphoma

Intervention / Treatment
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* Biological: Tisagenlecleucel
* Drug: Ibrutinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed DLBCL as per the local histopathological assessment. Relapsed or refractory disease having received 2 or more lines of systemic therapy, including anti-CD20 and anthracycline based chemotherapy, and either having progressed after (or relapsed after) ASCT, or being ineligible for or not consenting to ASCT. Measurable disease at time of enrollment. Eastern Cooperative Oncology Group (ECOG) performance status that is either 0 or 1 at screening. Adequate renal, liver, and bone marrow, organ function, and minimum level of pulmonary reserve. Exclusion Criteria: Patients with Richter's transformation, Burkitt's lymphoma, and primary DLBCL of the CNS. Prior anti-CD19 directed therapy. Prior gene therapy. Prior adoptive T cell therapy. Prior ibrutinib therapy within the 30 days prior to screening. Patients with active CNS involvement are excluded, except if the CNS involvement has been effectively treated and provided that local treatment was > 4 weeks before enrollment. Prior allogeneic HSCT . Significant cardiac abnormality including history of myocardial infarction within 6 months prior to screening as detailed in the study protocol. Other eligibility criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Parallel Assignment
Interventional Model Description: The study will enroll patients into two arms in parallel: Arm 1: Patients will start ibrutinib treatment before leukapheresis. Arm 2: Patients will start ibrutinib treatment after leukapheresis. Approximately 3-6 patients will be enrolled into each of the two arms in parallel. An early safety review will be performed after these patients have received sufficient ibrutinib treatment and tisagenlecleucel infusion, and have completed at least 21 days of follow up. Additional patients (up to 20 total) will be enrolled into both arms to further characterize the safety, tolerability and preliminary efficacy of ibrutinib in combination with tisagenlecleucel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ibrutinib (before leukapheresis) + Tisagenlecleucel<br>Patients will start ibrutinib treatment before leukapheresis | Biological: Tisagenlecleucel<br>* Infusion<br>Drug: Ibrutinib<br>* Oral (tablets or capsules)<br>|
| Experimental: Ibrutinib (after leukapheresis) + Tisagenlecleucel<br>Patients will start ibrutinib treatment after leukapheresis. | Biological: Tisagenlecleucel<br>* Infusion<br>Drug: Ibrutinib<br>* Oral (tablets or capsules)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events (AEs) and serious adverse events (SAEs) | Month 24 is planned study end | 24 months | 
| Severity of adverse events (AEs) and serious adverse events (SAEs) | Month 24 is planned study end | 24 months | 
| Ibrutinib dose modification following tisagenlecleucel infusion | Month 24 is planned study end | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate | 3-months post tisagenlecleucel infusion, assessed by local investigator according to Lugano criteria | Month 3 | 
| Response Rate | 6-month post tisagenlecleucel infusion, assessed by local investigator according to Lugano criteria | Month 6 | 
| Overall Response Rate |  | 24 months | 
| Duration of Response |  | 24 months | 
| Progression Free Survival (PFS) |  | 24 months | 
| Overall Survival (OS) |  | 24 months | 
| Tisagenlecleucel transgene concentrations | qPCR will be used to measure tisagenlecleucel transgene concentrations in available tissue, such as peripheral blood, bone marrow, tumor/lymph node tissue, and/or CSF. | 24 months | 
| Cellular kinetics of Tisagenlecleucel (Cmax) | Cmax cellular kinetics parameter (via qPCR) for tisagenlecleucel in the presence of ibrutinib | 24 months | 
| Cellular kinetics of Tisagenlecleucel (Tmax) | Tmax cellular kinetics parameter (via qPCR) for tisagenlecleucel in the presence of ibrutinib | 24 months | 
| Cellular kinetics of Tisagenlecleucel (AUC) | AUC cellular kinetics parameter (via qPCR) for tisagenlecleucel in the presence of ibrutinib | 24 months | 
| Cellular kinetics of Tisagenlecleucel (Clast) | Clast cellular kinetics parameter (via qPCR) for tisagenlecleucel in the presence of ibrutinib | 24 month | 
| Cellular kinetics of Tisagenlecleucel (Tlast) | Tlast cellular kinetics parameter (via qPCR) for tisagenlecleucel in the presence of ibrutinib | 24 month | 
| Anti-drug antibody (ADA) response to Tisagenlecleucel (humoral immunogenicity) | Pre-existing and treatment related immunogenicity (humoral) of tisagenlecleucel will be characterized by flow cytometry | 24 months | 
| Anti- tisagenlecleucel t-cell response (cellular immunogenicity) | Pre-existing and treatment related immunogenicity (cellular) of tisagenlecleucel will be characterized IFN-g staining and flow cytometry | 24 months | 
| Characterize cellular kinetic parameters in the presence of ADA and/or anti-tisagenlecleucel t-cell response |  | 24 months | 
| Characterize efficacy of tisagenlecleucel in the presence of ADA and/or anti-tisagenlecleucel t-cell response |  | 24 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Diffuse Large B-cell lymphoma, DLBCL, r/r Diffuse Large B-cell Lymphoma, relapsed/refractory DLBCL, CTL019, Tisagenlecleucel, Ibrutinib