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

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• Status: Withdrawn
• Conditions: Myelodysplastic Syndromes; Refractory Acute Myeloid Leukemia; Relapsed Acute Myeloid Leukemia
• Intervention / Treatment: Biological: Cytokine-induced memory-like NK cells; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Interleukin-2; Procedure: Donor Leukapheresis

• Study Type: Interventional
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR) of recipients	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

Outcome Measure	Measure Description	Time Frame
Overall survival (OS) of recipients	-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	-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	-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	-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		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		Through Day 28
Mortality rate of recipients		Day +30
Mortality rate of recipients		Day +100
Number of adverse events experienced by recipients	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		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)		Day 0, Day +28, Day +100, 6 months, 9 months, and 12 months
Overall response rate (ORR) of recipients compared across subgroups	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	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

• Sponsor: Washington University School of Medicine
• Collaborators: Wugen, Inc.

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Anticipated): June 30, 2022
• Primary Completion (Anticipated): December 31, 2024
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: May 14, 2021
• First Submitted That Met QC Criteria: May 14, 2021
• First Posted (Actual): May 20, 2021

Study Record Updates

• Last Update Posted (Actual): March 11, 2022
• Last Update Submitted That Met QC Criteria: February 23, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide; Fludarabine; Interleukin-2
• Other Study ID 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