Safety and Efficacy of Expanded, Universal Donor Natural Killer Cells for Relapsed/Refractory AML

Acute Myeloid Leukemia Clinical Trial

— KARMA  

Official title:

Killer Cells Against Relapsed/Refractory Myeloid Acute Leukemia (KARMA): A Clinical Trial Evaluating the Safety and Efficacy of Expanded, Universal Donor Natural Killer Cells for Treatment of Young Adults With Relapsed/Refractory Acute Myeloid Leukemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05503134
• Other study ID #: KARMA
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: February 14, 2022
• Est. completion date: February 2027

Study information

• Verified date: September 2023
• Source: Nationwide Children's Hospital
• Contact: Melinda C Triplet
• Phone: 6147226039
• Email: Melinda.Triplet[@]nationwidechildrens.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a phase I/II dose escalation study designed to determine the safety and estimate the efficacy of UD-NK cells combined with FLA chemotherapy in patients age 18-24.99 with relapsed or refractory acute myeloid leukemia.

PRIMARY OBJECTIVE:

I. To determine the safety and recommended phase II dose of adoptive NK cell therapy using UD-NK cells in pediatric and young adult patients with relapsed/refractory AML.

SECONDARY OBJECTIVES:

I. To estimate the efficacy of UD- NK cells with FLA chemotherapy in pediatric and young adult patients with relapsed/refractory AML.

EXPLORATORY OBJECTIVES:

I. To determine the immunophenotype and function of UD-NK cells

II. To characterize in vivo expansion of UD-NK cells

III. To determine the persistence of UD-NK cells

Six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.

Description:

The treatment plan consists of Fludarabine/Cytarabine chemotherapy followed by six doses of universal donor mbIL-21 expanded NK cells (UD-NK) given thrice weekly for two weeks. Days may vary and NK cells can be given from days 0 to 21. Patients may receive up to 2 cycles of fludarabine/cytarabine (FLA) + NK cells (up to 12 NK cell infusions) if they do not achieve CR after cycle 1 or if necessary to bridge to transplant.

In this study the first NK cell infusion is referred as day zero (D0), treatment plan activities prior or after D0 are denominated as day minus (D-) or day plus (D+).

FLA will be give as follows: Fludarabine 30 mg/m2/day (day -6 to day -2) and Cytarabine 2000 mg/ m2/day (days -6 to day -2)

Six doses of UD-NK cells will be given thrice weekly for two weeks beginning day 0. NK cell administration schedule may vary and doses may be given from day 0 to 21. A minimum of 2 days between NK cell doses is required. Patients must meet eligibility criteria for NK cell infusion as described in the protocol.

Patients will be eligible to receive a second cycle of chemotherapy for the following reasons:

1. 500/uL AND platelets >50,000/uL prior to beginning cycle 2

5. Prior treatment related toxicities must have resolved to ≤ Grade 2

NK Cell Dose Levels:

1. Dose level 1: 1.00x10^7 NK cell/kg (±20%) each dose for 6 doses per cycle

2. Dose level 2: 3.00x10^7 NK cell/kg (±20%) each dose for 6 doses per cycle

3. Dose level 3: 1.00x10^8 NK cell/kg (±20%) each dose for 6 doses per cycle

The NK dose will be calculated based on actual body weight. Dose escalation will proceed according to the study design outlined in Section 9.1 to determine the MTD. Once a patient is enrolled at a dose level, the dose will remain at the enrolled dose level for all subsequent NK cell infusions.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 20
• Est. completion date: February 2027
• Est. primary completion date: February 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Year to 24 Years

Eligibility

Inclusion Criteria:

• Patients with relapsed or primary refractory AML, including:

• Patients with relapsed AML (Any patient in first or subsequent relapse are eligible. Patients with relapse after HSCT are eligible)

• Primary refractory AML defined as failure to achieve a complete response after 2 cycles of induction chemotherapy, including persistent MRD positivity

• Patients with isolated CNS or extramedullary disease are eligible Note: a response monitoring plan must be developed a priori for subjects with extramedullary disease

• Patient age 1-24.99 years old

• Negative serum test to rule out pregnancy within 2 weeks prior to enrollment in females of childbearing potential

o Sexually active males and females of childbearing potential must agree to use a form of contraception considered effective and medically acceptable by the Investigator for 6 months after the last dose of chemotherapy and/or NK cell infusion

• Negative serology for human immunodeficiency virus (HIV)

• Both males and females and members of all races and ethnic groups are eligible

• Organ function requirements:

• Renal function: Creatinine = 2 mg/dl OR creatinine clearance > 60 ml/min/1.73m2.

• Liver function: Total bilirubin = 2 mg/dl (unless Gilbert's syndrome), AST and ALT = 5 times the upper limit of normal (unless related to leukemic involvement). Upper limit of normal should be determined by the institutional defined normal laboratory range.

• Cardiac function: left ventricular ejection fraction = 40% or shortening fraction =20%. May be eligible after cardiology clearance if qualitatively normal function or repeat measures are normal.

• CNS: Patients with seizure disorder may be eligible if seizures well controlled

• All prior treatment related non-hematologic toxicities must have resolved to = Grade 2 prior to enrollment unless granted approval by study PI and/or Co-Is.

• All patients and/or their legal guardians must be able to understand and willing to sign a written informed consent document

Exclusion Criteria:

• AML directed therapies in the 2 weeks prior to beginning treatment on this protocol (except for hydroxyurea)

o Note: There is no waiting period required for patients having received intrathecal cytarabine, methotrexate and/or hydrocortisone

• Patients on immunosuppressive therapy

o Patients must be off of all systemic immunosuppressive therapy for at least 2 weeks prior to enrollment with no evidence of recurrent GVHD

• Patients with a history of donor lymphocyte infusion or cellular therapy within the last 30 days are not eligible for this study

• Allogeneic SCT < 3 months prior to study enrollment

• Any comorbidities that in the opinion of the investigator will preclude receiving study therapy

• Performance status: Karnofsky or Lansky Performance Scale (PS) < 50

• Uncontrolled infection, defined as an infection which has not resolved or does not show evidence of significant resolution after initiating appropriate therapy

o Asymptomatic viremia such as CMV, HPV, BK virus, HCV, etc. is NOT considered as an exclusion criterion

• Uncontrolled arrhythmias or uncontrolled symptomatic cardiac disease

• History of autoimmune disease

• Active GVHD at the time of enrollment

• Patients with a history of adoptive cell therapy are excluded unless at least 30 days from infusion and with evidence of recovery of normal hematopoiesis (ANC = 500/µL, platelet count = 50,000/µL).

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Biological:
• Universal Donor Natural Killer Cells
Six doses of UD-NK cells will be given thrice weekly for two weeks for up to 2 cycles of treatment

Locations

Country	Name	City	State
United States	Nationwide Children's Hospital	Columbus	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Nationwide Children's Hospital

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Immunophenotype of UD-NK cells	Immunophenotyping by flow cytometry and CyTOF.	Weekly samples from day 0 to day +28 after the first NK cell infusion for each cycle (each cycle is 28 days)
Other	Function of UD-NK Cells	Cytokine secretion and cytotoxicity of UD-NK cells cultured with patient leukemia samples	Day 0 of the first cycle
Other	Expansion/persistence of UD-NK cells after infusion	Peripheral blood will be obtained before therapy, during the NK cell treatment period, and after NK cell treatment to evaluate for UD-NK cell expansion and persistence. UD-NK cells will be identified by chimerism assay. Chimerism may be determined by flow cytometry using haplotype-specific antibodies, short tandem repeat polymorphisms, or when there is a sex-mismatch between the donor and the recipient, assays based on determining the frequency of sex-chromosomes may be used.	Weekly samples from day 0 to day +28 after the first NK cell infusion for each cycle (each cycle is 28 days)
Primary	Incidence and severity of adverse events		Up to 56 days after the first NK cell infusion
Primary	Rate of dose limiting toxicities		Up to 56 days after the first NK cell infusion
Secondary	Minimal Residual Disease (MRD) negative response rate by flow cytometry		At the end of Cycle 1 and Cycle 2 (each cycle is 28 days)
Secondary	CR rate after first cycle		At the end of Cycle 1 (each cycle is 28 days)
Secondary	Relapse free survival and overall survival		1 year
Secondary	Median time to neutrophil and platelet count recovery		1 year
Secondary	Median duration of remission for patients who do not go onto transplant		1 year
Secondary	Incidence of infectious complications		1 year
Secondary	Percentage of patients receiving this regimen who are rendered transplant-eligible		1 year