NKX019, Intravenous Allogeneic Chimeric Antigen Receptor Natural Killer Cells (CAR NK), in Adults With B-cell Cancers

Study Overview
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Brief Summary
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This is a single arm, open-label, multi-center, Phase 1 study to determine the safety and tolerability of an experimental therapy called NKX019 (allogeneic CAR NK cells targeting CD19) in patients with relapsed/refractory non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) or B cell acute lymphoblastic leukemia (B-ALL)

Detailed Description
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This is a dose-finding study of NKX019 and will be conducted in 2 parts: Part 1: dose finding utilizing a 3+3 enrollment schema and safety lead-in to confirm dose for NKX019 in combination with rituximab expansion cohorts (as applicable) Part 2: dose expansion to further evaluate safety and tolerability, cellular kinetics, pharmacodynamics and anti-tumor response in expansion cohorts of patients with large B cell lymphoma (LBCL), mantle cell lymphoma (MCL), indolent lymphoma (IL), Waldenström macroglobulinemia (WM), CLL/ small lymphocytic lymphoma (SLL), and B-ALL.

Official Title
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A Phase 1 Study of NKX019, a CD19 Chimeric Antigen Receptor Natural Killer (CAR NK) Cell Therapy, in Subjects With B-cell Malignancies

Conditions
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Lymphoma, Non-Hodgkin, B-cell Acute Lymphoblastic Leukemia, Large B-cell Lymphoma, Mantle Cell Lymphoma, Indolent Lymphoma, Waldenstrom Macroglobulinemia, Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Aggressive Lymphoma, Large-cell Lymphoma

Intervention / Treatment
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* Biological: NKX019


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: General: Eastern Cooperative Oncology Group (ECOG) performance status ≤1 • Disease Related: Have a histologically or cytologically confirmed diagnosis of r/r B cell NHL or CLL or B-ALL as defined by WHO 2016 classification Subjects who received prior CD19/CD20-directed therapy must have disease that remains CD19+ and/or CD20+ respectively Have measurable disease Have received ≥2 lines of therapy except subjects with MCL, CAR T Naïve cohorts and WM, who must have received at least 1 prior line of therapy Have received a combination of an anti CD20 monoclonal antibody and cytotoxic chemotherapy for subjects with NHL Received: BTKi for subjects with MCL, CLL/SLL, WM, and other indications where a BTKi is approved Venetoclax for subjects with CLL/SLL Tyrosine kinase inhibitor for subjects with Philadelphia chromosome (Ph+) B-ALL Not responded or relapsed within 12 months of completion of their prior line of therapy, with the exception of a newly diagnosed Richter's transformation of CLL/SLL or other transformation of an indolent lymphoma, including from WM Subjects must not have evidence of rapidly progressive disease that would preclude subject from completing at least 1 cycle of treatment. Adequate organ function White blood cell count of ≤20 × 109/L Platelet count ≥30,000/uL Exclusion Criteria: • Disease related: Burkitt Lymphoma, primary central nervous system (CNS) lymphoma, Richter's transformation to Hodgkin lymphoma Subjects with WM who underwent plasmapheresis <35 days prior to the first dose of NKX019 Subjects with NHL with any evidence of active CNS malignancy Subjects with B-ALL who have extramedullary disease (EMD) Subjects with any prior cellular therapy except subjects enrolling in selected cohorts who must have received prior CAR T therapy, recent HCT, or complications from HCT Recent use of any cancer-directed therapy within protocol specified window prior to the first dose of NKX019 Residual toxicities ≥Grade 2 due to prior therapy Other comorbid conditions and concomitant medications prohibited as per study protocol Pregnant or lactating female

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NKX019 - CAR NK cell therapy<br>All subjects will receive fludarabine/cyclophosphamide lymphodepletion followed by 3 weekly doses of NKX019 on Day 0, 7, and 14 of a 28-day cycle. Combination cohorts (if opened) will additionally receive rituximab with each cycle. | Biological: NKX019<br>* NKX019 is an investigational allogeneic CAR NK product targeting CD19 on cells. The starting dose of NKX019 in Part 1 is 3 × 10^8 NK cells (6 × 10^6/kg for patients < 50 kg) administered as 3 weekly doses. Part 2 (dose expansion cohorts) will use the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of NKX019 as determined in Part 1.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Incidence, nature, and severity of treatment related adverse events will be evaluated. An adverse event is any unfavorable and unintended sign including clinically significant abnormal laboratory findings, symptom or disease. | 30 days after last dose of NKX019 | 
| Proportion of subjects experiencing dose-limiting toxicities of NKX019 | DLTs are defined as adverse events attributable to NKX019 treatment that occur during Cycle 1 and meet protocol-specified criteria | 28 days from first dose of NKX019 | 
| Objective response rate to NKX019 in Part 2 | Percentage of subjects with complete and partial response. Response to treatment will be assessed based on: Lugano classification with LYRIC refinement for subjects with NHL (except CLL/SLL and WM); 2018 iwCLL guidelines for subjects with CLL/SLL; Version 1.2020 NCCN for subjects with B-ALL; consensus criteria from the 6th International Workshop on Waldenström Macroglobulinemia for subjects with WM. | Primary assessment: 28 days after the first dose of NKX019 followed up to 2 years after the last dose of NKX019] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of NKX019 half-life | Time required for 50% reduction from maximum amount of circulating NKX019 | Time Frame: 28 days from first dose of NKX019 | 
| NKX019 duration of persistence | Testing NKX019 in peripheral blood every 3 months after dosing to determine persistence | Followed up to 2 years after last dose of NKX019 | 
| Evaluation of host immune response against NKX019 | Serum samples will be measured for antibodies against NKX019 | Followed up to 2 years after last dose of NKX019 | 
| Objective response rate to NKX019 in Part 1 | Percentage of subjects with complete and partial response. Response to treatment will be assessed based on: Lugano classification with LYRIC refinement for subjects with NHL (except CLL/SLL and WM); 2018 iwCLL guidelines for subjects with CLL/SLL; Version 1.2020 NCCN for subjects with B-ALL; consensus criteria from the 6th International Workshop on Waldenström Macroglobulinemia for subjects with WM. | Primary assessment: 28 days after first dose of NKX019 followed up to 2 years after last dose of NKX019 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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r/r CLL, CD19, CAR, Allogeneic, Natural killer, ACR, NKX019, IL15, Interleukin 15, NK cell, Cell Therapy, Immunotherapy, Adoptive cell therapy, r/r NHL, r/r B-ALL, r/r MCL, r/r IL, r/r WM, r/r SLL, Aggressive lymphoma, Indolent lymphoma, LCL