Cytokine-induced Memory-like NK Cells in Relapsed/Refractory AML and MDS

February 23, 2022 updated by: Washington University School of Medicine

A Phase 2 Study of Cytokine-induced Memory-like NK Cells in Relapsed/Refractory AML and MDS

Patients with relapsed/refractory acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) will receive lymphodepleting chemotherapy (Flu/Cy) and two infusions of cytokine-induced memory-like NK cells at the previously defined maximum tolerated dose (MTD), fourteen days apart. Low dose rhIL-2 will be administered to patients for in vivo expansion following cell infusion. Patients will be assessed for anti-leukemic efficacy and safety. Re-infusion of patients who relapsed after clinical response will be considered.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Refractory AML without CR after induction therapy (primary induction failure); relapsed AML after obtaining a CR; progressive AML after non-intensive therapy (e.g., HMA + venetoclax or targeted therapy); Intermediate risk to very-high-risk MDS by IPSS-R that is relapsed or refractory after prior therapy with an HMA-containing regimen
  • At least 18 years of age.

  • Available allogeneic donor that meets the following criteria:

    • Able and willing to undergo multiple rounds of leukapheresis
    • At least 18 years of age
    • In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study.
    • Negative for hepatitis, HTLV, and HIV on donor viral screen
    • Not pregnant
    • Voluntary written consent to participate in this study
    • All HLA-match/mismatch statuses will be included, with preference for unmatched donors all else being equal
  • Patients with known CNS involvement with AML are eligible provided that they have been treated and CSF is clear for at least 2 weeks prior to enrollment into the study. CNS therapy (chemotherapy or radiation) should continue as medically indicated during the study treatment.
  • Karnofsky/Lansky performance status > 50 %

  • Adequate organ function as defined below:

    • Total bilirubin < 2 mg/dL
    • AST(SGOT)/ALT(SGPT) < 3.0 x ULN
    • Creatinine within normal institutional limits OR creatinine clearance ≥ 40 mL/min by Cockcroft-Gault Formula
    • Oxygen saturation ≥90% on room air
    • Ejection fraction ≥35%
  • Able to be off corticosteroids and any other immune suppressive medications beginning on Day -3 and continuing until 30 days after the last infusion of the NK cell product. However, use of low-level corticosteroids is permitted if deemed medically necessary. Low-level corticosteroid use is defined as 10mg or less of prednisone (or equivalent for other steroids) per day.
  • Women of childbearing potential must have a negative pregnancy test within 28 days prior to study registration. Female and male patients (along with their female partners) must agree to use two forms of acceptable contraception, including one barrier method, during participation in the study and until 30 days after the last NK cell product infusion.
  • Ability to understand and willingness to sign an IRB approved written informed consent document

Exclusion Criteria:

  • Relapsed after allogeneic transplantation.
  • Circulating blast count >30,000/µL by morphology or flow cytometry (cytoreductive therapies including leukapheresis or hydroxyurea are allowed).
  • Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.
  • Uncontrolled angina, severe uncontrolled ventricular arrhythmias, or EKG suggestive of acute ischemia or active conduction system abnormalities.
  • New progressive pulmonary infiltrates on screening chest x-ray or chest CT scan that have not been evaluated with bronchoscopy. Infiltrates attributed to infection must be stable/ improving after 1 week of appropriate therapy (4 weeks for presumed or proven fungal infections).
  • Known hypersensitivity to one or more of the study agents.
  • Received any investigational drugs within the 14 days prior to the first dose of fludarabine.
  • Pregnant and/or breastfeeding.
  • Any condition that, in the opinion of the investigator, would prevent the participant from consenting to or participating in the study

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Lead In Cohort Recipient: Cytokine-induced memory-like NK cells
  • Fludarabine and cyclophosphamide beginning on Day -6.
  • NK cell product will be infused on Day 0.
  • IL-2 will begin 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses.
  • NK cell product will be infused into the recipient on Day +14.
  • IL-2 will begin 2-4 hours after infusion and will continue every other day through Day 26 for an additional 7 doses, and a total of 14 doses, to a maximum of two vials of rhIL-2 per IL-2 course.
  • In the Lead-in Cohort, three patients will receive NK cell product on Day 0 and Day +14, receiving the maximum NK cells generated, capped at 20x10^6/kg.
  • Patients that have an initial response but then subsequently relapse or progress will be able to receive a third dose of NK cell product with or without lymphodepleting chemotherapy depending on the interval duration between the second dose and relapse, after approval by the study PI. The third dose should be administered not less than 45 days from Day 0.
Biological: Cytokine-induced memory-like NK cells
Cell product processing is performed at the Siteman Cancer Center Biological Therapy Core or another FACT-accredited cellular therapy production facility that can manufacture the product per the IND CMC.
Drug: Fludarabine
-Lymphodepleting regimen
Drug: Cyclophosphamide
-Lymphodepleting regimen
Drug: Interleukin-2
-IL-2 will start approximately 2-4 hours after the NK cell infusions.
Other Names:
  • IL-2
Experimental: Phase II Recipient: Cytokine-induced memory-like NK cells
  • Fludarabine and cyclophosphamide beginning on Day -6.
  • NK cell product will be infused on Day 0.
  • IL-2 will begin 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses.
  • NK cell product will be infused into the recipient on Day +14.
  • IL-2 will begin 2-4 hours after infusion and will continue every other day through Day 26 for an additional 7 doses, and a total of 14 doses, to a maximum of two vials of rhIL-2 per IL-2 course.
  • Will receive the NK cell product on Day 0 and Day +14, receiving the maximum NK cells generated, capped at 20x10^6/kg.
  • Patients that have an initial response but then subsequently relapse or progress will be able to receive a third dose of NK cell product with or without lymphodepleting chemotherapy depending on the interval duration between the second dose and relapse, after approval by the study PI. The third dose should be administered not less than 45 days from Day 0.
Biological: Cytokine-induced memory-like NK cells
Cell product processing is performed at the Siteman Cancer Center Biological Therapy Core or another FACT-accredited cellular therapy production facility that can manufacture the product per the IND CMC.
Drug: Fludarabine
-Lymphodepleting regimen
Drug: Cyclophosphamide
-Lymphodepleting regimen
Drug: Interleukin-2
-IL-2 will start approximately 2-4 hours after the NK cell infusions.
Other Names:
  • IL-2
Experimental: Donor
  • The allogeneic donor will undergo non-mobilized large volume (20-L) leukapheresis on Day -1.
  • On Day +13 the allogeneic donor will again undergo non-mobilized large volume (20-L) leukapheresis
Procedure: Donor Leukapheresis
-Apheresis will be performed via peripheral IVs or central line, as determined by the apheresis team.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Overall response rate (ORR) of recipients
Time Frame: Through 12 month follow-up
  • Defined as the proportion of patients achieving complete remission (CR), complete remission with partial hematologic recovery (CRh), and complete remission with incomplete blood count recovery (CRi).
  • Response will be assessed according to the criteria from the International Working Group Response Criteria
Through 12 month follow-up

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Overall survival (OS) of recipients
Time Frame: Through completion of follow-up (estimated to be 12 months)
-Defined as time from first dose of lymphodepleting chemotherapy (LDC) until death from any cause
Through completion of follow-up (estimated to be 12 months)
Event free survival (EFS) of recipients
Time Frame: Through completion of follow-up (estimated to be 12 months)
-Defined as time from first dose of lymphodepleting chemotherapy (LDC) until treatment failure, relapse from complete response, or death
Through completion of follow-up (estimated to be 12 months)
Duration of overall response (DOR) of recipients
Time Frame: Through 12 month follow-up
-Defined as duration for first occurrence of documented ORR until disease progression or death
Through 12 month follow-up
Duration of complete response (DoCR) of recipients
Time Frame: Through 12 month follow-up
-Defined as duration from documented complete remission until disease progression or death
Through 12 month follow-up
Proportion of recipients that receive multiple doses of NK cell product
Time Frame: Through Day +14 of all recipients enrolled (estimated to be 19 months)
Through Day +14 of all recipients enrolled (estimated to be 19 months)
Number of dose-limiting toxicities (DLTs) that recipients experience in the safety lead-in cohort
Time Frame: Through Day 28
Through Day 28
Mortality rate of recipients
Time Frame: Day +30
Day +30
Mortality rate of recipients
Time Frame: Day +100
Day +100
Number of adverse events experienced by recipients
Time Frame: Through Day +100
  • Incidence, nature, and severity of adverse events
  • Adverse events will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC < 500/µL) and adverse events of graft-versus-host disease (GVHD) involving the liver, skin, or gastrointestinal tract will be recorded until Day +100.
Through Day +100
Proportion of recipients with prolonged cytopenia
Time Frame: At 8 weeks
At 8 weeks
Change in quality of life experienced by recipients as measured by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30)
Time Frame: Day 0, Day +28, Day +100, 6 months, 9 months, and 12 months
Day 0, Day +28, Day +100, 6 months, 9 months, and 12 months
Overall response rate (ORR) of recipients compared across subgroups
Time Frame: Through 12 month follow-up
  • Subgroups will be defined by degree of HLA-match from allogeneic donor
  • Defined as the proportion of patients achieving complete remission (CR), complete remission with partial hematologic recovery (CRh), and complete remission with incomplete blood count recovery (CRi).
  • Response will be assessed according to the criteria from the International Working Group Response Criteria
Through 12 month follow-up
Number of adverse events experienced by recipients compared across subgroups
Time Frame: Through Day +100
  • Subgroups will be defined by degree of HLA-match from allogeneic donor
  • Incidence, nature, and severity of adverse events
  • Adverse events will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC < 500/µL) and adverse events of graft-versus-host disease (GVHD) involving the liver, skin, or gastrointestinal tract will be recorded until Day +100.
Through Day +100

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Washington University School of Medicine

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Wugen, Inc.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 30, 2022

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2024

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 14, 2021

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 14, 2021

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 20, 2021

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
March 11, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
February 23, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
February 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 202106075

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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