AML, Adult, MDS, Refractory Myelodysplastic Syndromes, Relapsed/Refractory AML
Conditions
Keywords
NKG2D, CAR, Allogeneic, Natural killer, ACR, NKX101, IL15, Interleukin 15, NK cell, Cell Therapy, Immunotherapy, Adoptive cell therapy, r/r AML, Off-the-shelf
Brief summary
This is a single-arm, open-label, multi-center, Phase 1 study to determine safety and tolerability of an experimental therapy called NKX101 (allogeneic CAR NK cells targeting NKG2D ligands) in patients with relapsed/refractory AML or intermediate, high and very high risk relapsed/refractory MDS.
Detailed description
This is a dose-finding study of NKX101 and will be conducted in 2 parts: Part 1: dose finding with two dosing regimens, utilizing modified 3+3 enrollment schema. Part 2: dose expansion to further evaluate safety and tolerability, cellular kinetics, pharmacodynamics and anti-tumor response in expansion cohorts of patients with either AML or MDS.
Interventions
BIOLOGICALNKX101 - CAR NK cell therapy
NKX101 is an investigational allogeneic CAR NK product targeting NKG2D ligands on cancer cells. Part 2 will use the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of NKX101 as determined in Part 1.
Sponsors
Nkarta, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* General: * ECOG performance status ≤2 * Disease related: * For AML subjects: * Previously treated relapsed/refractory AML, including subjects with MRD+ disease * Received at most 3 lines of previous anti-leukemia therapy * For subjects with targetable fms-like tyrosine kinase 3 (FLT3)-mutated or isocitrate dehydrogenase (IDH)1/2 mutated disease, subjects must have received at least 1 prior respective targeted therapy and may receive up to 4 lines of prior therapy * White blood cell count of ≤25 × 10\^9/L * For groups receiving NKX101 after lymphodepletion with fludarabine/cyclophosphamide +/- decitabine: Disease localized to the bone marrow, as evidenced by ≤ 5% peripheral blasts and no evidence of extramedullary disease * For groups receiving NKX101 after lymphodepletion with fludarabine/ cyclophosphamide +/- decitabine, group receiving NKX101 after lymphodepletion with fludarabine/ara-C: Additional subjects with specifically high-risk genetic mutations may be enrolled. High risk genetic mutation per ELN 2022 should be evaluated as per local assay and discussed with the Sponsor prior to study entry * For groups receiving NKX101 after lymphodepletion with fludarabine/cyclophosphamide +/- decitabine, group receiving NKX101 after lymphodepletion with fludarabine/ara-C: Additional subjects who have relapsed following HCT may be enrolled. * For MDS subjects: * Intermediate-, high-, or very high-risk MDS * Previously treated relapsed/refractory MDS * Received at least 1 and at most 3 lines of previous standard anti-MDS therapy * For groups receiving NKX101 after lymphodepletion with fludarabine/ cyclophosphamide +/- decitabine: Additional subjects with specifically high-risk disease may be enrolled. High-risk genetic mutation should be evaluated as per local assay * For group receiving lymphodepletion with fludarabine/cyclophosphamide +/- decitabine and NKX101: Additional subjects who have relapsed following HCT may be enrolled. * Adequate Organ Function * Platelet count ≥30,000/uL (platelet transfusions acceptable) * Other: * Signed informed consent * Agree to use an effective barrier method of birth control
Exclusion criteria
* Disease related: * Acute promyelocytic leukemia with t(15;17) (q22;q12); or abnormal promyelocytic leukemia/retinoic acid receptor alpha (APML-RARA) and AML arising from chronic myelomonocytic leukemia (CMML) * Evidence of leukemic meningitis or known active central nervous system disease * Peripheral leukocytosis with ≥ 20,000 blasts/μL or other evidence of rapidly progressive disease that would preclude subject from completing at least 1 cycle of treatment * Use of any anti-AML/MDS chemotherapeutic or targeted small molecule drug within protocol specified window prior to the first dose of NKX101 * Presence of residual non-hematologic toxicity from prior therapies that has not resolved to ≤ Grade 1 * Any hematopoietic cell transplantation within 16 weeks * Other comorbid conditions and concomitant medications prohibited as per study protocol * Other: * Pregnant or lactating female
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | 30 days after last dose of NKX101 | 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. |
| Response rate to NKX101 (for Part 2) | 28 days from first dose of NKX101 | Responses will be assessed per modified ELN criteria and will include complete and partial remission with and without varying degrees of hematologic recovery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of NKX101 half-life | 28 days from first dose of NKX101 | Time required for 50% reduction from maximum amount of circulating NKX101 |
| NKX101 duration of persistence | Followed up to 2 years after last dose of NKX101 | Testing NKX101 in peripheral blood every 3 months after dosing to determine persistence |
| Evaluation of host immune response against NKX101 | Followed up to 2 years after last dose of NKX101 | Serum samples will be measured for antibodies against NKX101 |
| Response rate to NKX101 | Primary assessment: 28 days after first dose of NKX101 followed up to 2 years after last dose of NKX101 | Time-to-first response, time-to-best response, duration of response, transfusion independent rate, bridge-to-transplant rate, event-free survival, progression-free survival (PFS), overall survival (OS) (for all subjects), and hematologic improvement rates (for subjects with myelodysplastic syndrome \[MDS\]) |
Countries
United States
Outcome results
None listed