NKX101, Intravenous Allogeneic CAR NK Cells, in Adults With AML or MDS

Sponsor

Nkarta Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04623944

Collaborator

(none)

Enrollment

Locations

Arm

213.3

Anticipated Duration (Months)

12.9

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Relapsed/Refractory AML AML, Adult MDS Refractory Myelodysplastic Syndromes	Biological: NKX101 - CAR NK cell therapy	Phase 1

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

90 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 Study of NKX101, an Activating Chimeric Receptor Natural Killer Cell Therapy, in Subjects With Hematological Malignancies or Dysplasias

Actual Study Start Date :

Sep 21, 2020

Anticipated Primary Completion Date :

Jul 1, 2023

Anticipated Study Completion Date :

Jul 1, 2038

Arms and Interventions

Arm	Intervention/Treatment
Experimental: NKX101 - CAR NK cell therapy All subjects in Part 1 will receive fludarabine/cyclophosphamide lymphodepletion followed by 3 or 2 (Regimen A or B, respectively) weekly doses of NKX101. Subjects in Part 2 will receive either fludarabine/cyclophosphamide lymphodepletion or, if an AML combination arm is opened, fludarabine/cytarabine (ara-C), followed by 3 or 2 weekly doses of NKX101 depending on specific expansion cohort. Regimen A will have 3 doses of NKX101 on Day 0, 7, and 14 of a 28-day cycle. Regimen B will have 2 doses of NKX101 on Day 0 and 7 of a 28-day cycle. Part 1 and 2: either haplo-matched related donor derived or unrelated off-the-shelf donor derived NKX101 will be used.	Biological: NKX101 - CAR NK cell therapy NKX101 is an investigational allogeneic CAR NK product targeting NKG2D ligands on cancer cells. The starting dose of NKX101 in Part 1/Regimen A is 1 × 10^8 NK cells (2 × 10^6/kg for patients < 50 kg) administered as 3 weekly doses. The starting dose of NKX101 in Part 1/Regimen B is 1.5 × 10^8 NK cells (3 × 10^6/kg for patients < 50 kg) administered as 2 weekly doses. Part 2 will use the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of NKX101 as determined in Part 1. Other Names: Cyclophosphamide Fludarabine Cytarabine (ara-C)

Arm

Intervention/Treatment

Experimental: NKX101 - CAR NK cell therapy

All subjects in Part 1 will receive fludarabine/cyclophosphamide lymphodepletion followed by 3 or 2 (Regimen A or B, respectively) weekly doses of NKX101. Subjects in Part 2 will receive either fludarabine/cyclophosphamide lymphodepletion or, if an AML combination arm is opened, fludarabine/cytarabine (ara-C), followed by 3 or 2 weekly doses of NKX101 depending on specific expansion cohort. Regimen A will have 3 doses of NKX101 on Day 0, 7, and 14 of a 28-day cycle. Regimen B will have 2 doses of NKX101 on Day 0 and 7 of a 28-day cycle. Part 1 and 2: either haplo-matched related donor derived or unrelated off-the-shelf donor derived NKX101 will be used.

Biological: NKX101 - CAR NK cell therapy

NKX101 is an investigational allogeneic CAR NK product targeting NKG2D ligands on cancer cells. The starting dose of NKX101 in Part 1/Regimen A is 1 × 10^8 NK cells (2 × 10^6/kg for patients < 50 kg) administered as 3 weekly doses. The starting dose of NKX101 in Part 1/Regimen B is 1.5 × 10^8 NK cells (3 × 10^6/kg for patients < 50 kg) administered as 2 weekly doses. Part 2 will use the maximum tolerated dose (MTD) or recommended Phase 2 dose (RP2D) of NKX101 as determined in Part 1.

Other Names:

Cyclophosphamide

Fludarabine

Cytarabine (ara-C)

Outcome Measures

Primary Outcome Measures

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.
Proportion of subjects experiencing dose-limiting toxicities of NKX101 [28 days from first dose of NKX101]
DLTs are defined as adverse events attributable to NKX101 treatment that occur during Cycle 1 and meet protocol-specified criteria
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 Outcome Measures

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])

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

General:
ECOG performance status ≤2
Haplo-matched related subjects require a suitable haplo-matched related donor, who is able and willing to undergo leukapheresis
Disease related:
For AML subjects:
Previously treated relapsed/refractory AML, including subjects with MRD+ disease
Received at least 1 and at most 2 lines of previous standard anti-leukemia therapy
For subjects with 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 3 lines of prior therapy
White blood cell count of ≤25 × 10^9/L
For MDS subjects:
Intermediate-, high-, or very high-risk MDS
Previously treated relapsed/refractory MDS
Received at least 1 and at most 2 lines of previous standard anti-MDS therapy
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)
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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
2	Winship Cancer Institute, Emory University	Atlanta	Georgia	United States	30322
3	University of Chicago Medical Center	Chicago	Illinois	United States	60637
4	The Cleveland Clinic - Taussig Cancer Institute	Cleveland	Ohio	United States	44195
5	Sarah Cannon at TriStar Bone Marrow Transplant Center	Nashville	Tennessee	United States	37203
6	MD Anderson Cancer Center, University of Texas	Houston	Texas	United States	77030
7	Methodist Healthcare System of San Antonio	San Antonio	Texas	United States	78229