Study of IMPT-314 in R/R Aggressive B-cell NHL

Study Overview
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Brief Summary
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This is a Phase 1/2, multi-center, open-label study evaluating the safety and efficacy of IMPT-314, a bispecific chimeric antigen receptor (CAR) targeting cluster of differentiation (CD)19 and CD20 in participants with aggressive B-cell NHL. Two cohorts of participants will be enrolled: 1) CAR T naïve and 2) CAR T experienced. Up to approximately 60 patients (15 per dose level per cohort) will be enrolled in dose finding Phase 1 part of the study, which will determine the recommended phase 2 dose. Phase 2 will enroll up to approximately 40 additional participants (20 per cohort) to evaluate further the safety and efficacy of IMPT-314. IMPT-314 treatment consists of a single infusion of CAR-transduced autologous T cells administered intravenously after a conditioning chemotherapy regimen consisting of fludarabine and cyclophosphamide, administered over 3 days. Individual participants will remain in the active post-treatment period for approximately 2 years. Participants will continue in long-term follow-up for 15 years from treatment.

Official Title
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A Phase 1/2 Multi-center Study Evaluating the Safety and Efficacy of IMPT-314, a CD19/20 Bispecific Chimeric Antigen Receptor (CAR) T Cell Therapy in Participants With Relapsed or Refractory Aggressive B-Cell Non-Hodgkin Lymphoma

Conditions
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Relapsed Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: IMPT-314


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older Willing and able to provide written informed consent Histologically confirmed aggressive NHL, including the following types defined by the World Health Organization (WHO) 2017: DLBCL not otherwise specified (NOS) DLBCL arising from follicular lymphoma Primary mediastinal (thymic) large B-cell lymphoma High-grade large B-cell lymphoma with or without MYC and BCL2 and/or BCL6 rearrangement Received at least 2 prior lines of therapy. Prior therapy must have included: Anti-CD20 monoclonal antibody An anthracycline containing chemotherapy regimen Participants with TFL must have received at least one of their prior lines of therapy after transformation to DLBCL Relapsed or refractory disease, defined by the following: Disease progression after last regimen (including salvage therapy after autologous stem cell transplantation [ASCT]), or Refractory disease is defined failure to achieve a PR or CR to the last regimen At least 1 measurable lesion (the Lugano classification). Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Absolute neutrophil count (ANC) ≥ 1000/uL Other protocol-defined criteria apply. Exclusion Criteria: History of malignancy other than non-melanoma skin cancer or carcinoma in situ (e.g., cervix, bladder, breast) unless disease-free for at least 3 years. Participants who have received therapy for a prior malignancy within the prior 3 years, e.g., in the adjuvant setting, are not excluded Active central nervous system (CNS) involvement by malignancy on magnetic resonance imaging (MRI) or by lumbar puncture. Participants with prior evidence of brain metastasis successfully treated at least 8 weeks prior to enrollment will not be excluded for participation if they are deemed under control at the time of study enrollment History of cardiac lymphoma involvement Ongoing or impending oncologic emergency (e.g., tumor mass effect, tumor lysis syndrome) Received the following therapies in the specified time frame prior to enrollment/leukapheresis Any systemic therapy within 2 weeks Any systemic inhibitory/stimulatory immune checkpoint molecule therapy within 3 half-lives prior to enrollment (e.g., ipilimumab, nivolumab, pembrolizumab, atezolizumab, OX40 agonists, 4- 1BB agonists) Bendamustine or fludarabine within 12 weeks Alemtuzumab or antithymocyte globuline (ATG) within 6 months Received radiation therapy within 3 weeks prior to enrollment Experiencing toxicities due to prior therapy (stable and recovered to grade ≤ 1 or non- clinically significant toxicities such as alopecia are allowed) History of allogeneic stem cell transplantation Receipt of autologous stem cell transplantation within 6 weeks prior to enrollment History of prior genetically modified T cell therapy other than a product targeting CD19 with an FMC63-based CAR (e.g., axicabtagene ciloleucel (axi-cel, YESCARTA®), tisagenlecleucel (tisa-cel, KYMRIAH®), or lisocabtagene maraleucel (liso-cel, BREYANZI®) Primary immunodeficiency History of autoimmune disease (e.g., Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years Other protocol-defined criteria 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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose finding Phase I followed by a Phase II part. Two Phase I dose levels and one Phase II dose level. Two cohorts in each phase.
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose Level I CAR T experienced cohort<br>Phase I 3+3 design Dose level 1: 1×10e8 (± 20%) IMPT-314 cells Single dose/infusion during 28 day window | Drug: IMPT-314<br>* CAR T-cell therapy<br>|
| Experimental: Phase I Dose Level II CAR T experienced cohort<br>Phase I 3+3 design Dose level 2: 3×10e8 (± 20%) IMPT-314 cells Single dose/infusion during 28 day window | Drug: IMPT-314<br>* CAR T-cell therapy<br>|
| Experimental: Phase II CAR T experienced cohort<br>Single dose determined during Phase I. | Drug: IMPT-314<br>* CAR T-cell therapy<br>|
| Experimental: Phase I Dose Level I CAR T naïve cohort<br>Phase I 3+3 design Dose level 1: 1×10e8 (± 20%) IMPT-314 cells Single dose/infusion during 28 day window | Drug: IMPT-314<br>* CAR T-cell therapy<br>|
| Experimental: Phase I Dose Level II CAR T naïve cohort<br>Phase I 3+3 design Dose level 2: 3×10e8 (± 20%) IMPT-314 cells Single dose/infusion during 28 day window | Drug: IMPT-314<br>* CAR T-cell therapy<br>|
| Experimental: Phase II CAR T naïve cohort<br>Single dose determined during Phase I. | Drug: IMPT-314<br>* CAR T-cell therapy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Incidence of DLTs and other treatment-emergent adverse events (TEAEs) |  | Baseline to Month 24 | 
| Phase I: Investigator-assessed complete response (CR) rate |  | Baseline to Month 24 | 
| Phase I: Proportion of enrolled participants who receive the target dose |  | Baseline to Month 24 | 
| Phase II: Complete response based on investigator assessment per the Lugano classification |  | Baseline to Month 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I and II: Proportion of enrolled participants who receive the target dose of IMPT-314 |  | Baseline to Month 24 | 
| Phase I and II: Overall response rate (ORR) |  | Baseline to Month 24 | 
| Phase I and II: Duration of response (DOR) |  | Baseline to Month 24 | 
| Phase I and II: Duration of complete response (DOCR) |  | Baseline to Month 24 | 
| Phase I and II: Median progression free survival (PFS) |  | Baseline to Month 24 | 
| Phase I and II: Median overall survival (OS) |  | Baseline to Month 24 | 
| Phase I and II: Cmax from time 0 to Day 28 (AUC0-28) |  | Baseline to Day 28 | 
| Phase I and II: Area under the curve from time 0 to Day 28 (AUC0-28) |  | Baseline to Day 28 | 
| Phase I and II: Persistence of IMPT-314 (Concentration of IMPT-314 cells in peripheral blood). |  | Baseline to Day 28 | 
| Phase II: Incidence of TEAEs |  | Baseline to Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR T-cell, Non-Hodgkin Lymphoma, CD19/20, CD19, CD20, NHL, Diffuse Large B-cell lymphoma, DLBCL, Transformed follicular lymphoma, TFL, Primary mediastinal B-cell lymphoma, PMBCL, High-grade B-cell lymphoma, HGBL