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

NCT04893915 | Withdrawn Phase 2 DMC FDA Drug

• 1 other identifier: 202106075
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

Relapsed Acute Myeloid Leukemia; Refractory Acute Myeloid Leukemia; Myelodysplastic Syndromes

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (13)

• Overall survival (OS) of recipients

  Through completion of follow-up (estimated to be 12 months)

• Event free survival (EFS) of recipients

  Through completion of follow-up (estimated to be 12 months)

• Duration of overall response (DOR) of recipients

  Through 12 month follow-up

• Duration of complete response (DoCR) of recipients

  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)

Study Arms (3)

Lead In Cohort Recipient: Cytokine-induced memory-like NK cells

EXPERIMENTAL

* 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; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Interleukin-2

Phase II Recipient: Cytokine-induced memory-like NK cells

EXPERIMENTAL

* 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; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Interleukin-2

Donor

EXPERIMENTAL

* 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

Interventions

Cytokine-induced memory-like NK cells BIOLOGICAL

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.

Lead In Cohort Recipient: Cytokine-induced memory-like NK cells; Phase II Recipient: Cytokine-induced memory-like NK cells

Fludarabine DRUG

-Lymphodepleting regimen

Lead In Cohort Recipient: Cytokine-induced memory-like NK cells; Phase II Recipient: Cytokine-induced memory-like NK cells

Cyclophosphamide DRUG

-Lymphodepleting regimen

Lead In Cohort Recipient: Cytokine-induced memory-like NK cells; Phase II Recipient: Cytokine-induced memory-like NK cells

Donor Leukapheresis PROCEDURE

-Apheresis will be performed via peripheral IVs or central line, as determined by the apheresis team.

Donor

Interleukin-2 DRUG

-IL-2 will start approximately 2-4 hours after the NK cell infusions.

Also known as: IL-2

Lead In Cohort Recipient: Cytokine-induced memory-like NK cells; Phase II Recipient: Cytokine-induced memory-like NK cells

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Washington University School of Medicine: lead
• Wugen, Inc.: collaborator

Related Links

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

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

fludarabine; Cyclophosphamide; Interleukin-2

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Bone Marrow Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Interleukins; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Lymphokines; Proteins; Biological Factors

Study Officials

• Amanda Cashen, M.D.

  Washington University School of Medicine

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2021
• First Posted: May 20, 2021
• Study Start: June 30, 2022
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: March 11, 2022

Record last verified: 2022-02

Data Sharing

• IPD Sharing: Will not share