Study Stopped
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Cytokine-induced Memory-like NK Cells in Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
A Phase 1/2 Study of Cytokine-Induced Memory-Like NK Cells in Patients With AML or MDS
2 other identifiers
interventional
89
1 country
1
Brief Summary
This phase I/2 trial studies the side effects and best dose of activated natural killer cells in treating patients with relapsed or refractory acute myeloid leukemia and myelodysplastic syndromes. Giving chemotherapy before a donor natural killer cell infusion helps stop the growth of cancer cells and stops the patient's immune system from rejecting the donor's natural killer cells. Modified natural killer cells may help the body build an immune response to kill cancer cells. Aldesleukin (interleukin-2) may stimulate the white blood cells (including natural killer cells) to kill leukemia cells. In the phase II and pediatric portion of the study, the investigators intend to use maximal tolerated or tested (MT/TD) CIML NK cell dose as determined from the phase I part of this study. The phase II portion of the study also replaces IL-2 with ALT-803. The rationale for this change is to support the donor derived NK cells in vivo after adoptive transfer. With amendment 16, the decision was made to return to the use of rhIL-2 support instead of ALT-803.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_1
Started Aug 2014
Longer than P75 for phase_1
1 active site
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
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Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
July 9, 2013
CompletedFirst Posted
Study publicly available on registry
July 12, 2013
CompletedStudy Start
First participant enrolled
August 11, 2014
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 28, 2021
CompletedStudy Completion
Last participant's last visit for all outcomes
April 4, 2022
CompletedResults Posted
Study results publicly available
February 1, 2023
CompletedJanuary 17, 2024
December 1, 2023
7.4 years
July 9, 2013
December 7, 2022
December 20, 2023
Conditions
Outcome Measures
Primary Outcomes (3)
Maximal Tolerated or Tested Dose (MT/TD) of CIML-NK Cells (Phase I)
Defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity (DLT) or the maximum dose if less than or equal to 1 patient suffers a DLT at the maximum dose.
35 days
Complete Remission Rate (CR/CRi) in Participants With Relapsed or Refractory AML Following CIML NK Therapy (Phase II)
* Complete remission rate (CR): Morphologically leukemia free state (i.e. bone marrow with \<5% blasts by morphologic criteria and no blasts with Auer rods, no evidence of extramedullary leukemia) and absolute neutrophil count ≥1000 /μL and platelets ≥100,000 /μL. Patient must be independent of transfusions * Complete Remission with Incomplete Blood Count Recovery (CRi): All of the above criteria for CR must be met, except that absolute neutrophils \<1000 /μL or platelets \<100,000 /μL in the blood.
Up to 3 years
Safety of CIML NK Cells as Measured by the Number of Participants With Treatment Related Adverse Events (Pediatric Cohort)
* Graded using the National Cancer (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Related indicates possibly, probably, or definitely related to study treatment. * Adverse events will be collected from Day 0 to Day +35; however, bone marrow suppression (ANC \< 500/uL/µL) and AEs of GVHD involving the liver, skin, or GI tract will be recorded to Day 100.
Through Day 100
Secondary Outcomes (6)
Response Assessed According to IWG Criteria (Phase 1, Phase II, and Pediatric)
35 days
Duration of Remission (DOR) (Phase I, Phase II, and Pediatric)
Up to 3 years
Time to Progression (Phase I, Phase II, and Pediatric)
Up to 3 years
Disease Free Survival (DFS) (Phase I, Phase II, and Pediatric)
Up to 3 years
Overall Survival (OS) (Phase I, Phase II, and Pediatric)
Up to 3 years
- +1 more secondary outcomes
Study Arms (7)
Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cells
EXPERIMENTAL* Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. * Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. * CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. * Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses)
Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cells
EXPERIMENTAL* Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. * Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. * CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. * Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses)
Phase I Dose Level 3: Maximum NK cell/number kg
EXPERIMENTAL* Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. * Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors over 5 hours on day -1. * CIML NK Cells: Patients undergo CIML NK cell infusion over 15-60 minutes on day 0. * Interleukin-2: Patients receive aldesleukin SC every other day for 2 weeks starting on day 1 (total of 7 doses)
Phase II (IL-2): Maximum NK cell/number kg
EXPERIMENTALThe recipient will begin a lymphodepleting preparative regimen of fludarabine and cyclophosphamide on Day -6. The haploidentical donor identified by HLA matching of the immediate family members will undergo non-mobilized large volume (20-L) leukapheresis on Day -1, and the NK cell product will be infused into the recipient on Day 0. Subcutaneous IL-2 will begin approximately 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses.
Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
EXPERIMENTAL* Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. * Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors on Day -1. * CIML NK Cells: Patients undergo CIML NK cell infusion on Day 0. * Subcutaneous ALT-803 will begin approximately 4 hours after the infusion and will continue for a total of 2 doses (Days 0 and 5).
Pediatric Cohort: Maximum NK cell/number kg
EXPERIMENTAL* Lymphodepleting Preparative Regimen: Patients receive fludarabine phosphate IV over 1 hour on days -6 to -2 and cyclophosphamide IV over 2 hours on days -5 and -4. * Donor Leukapheresis: Peripheral blood cells are collected from haploidentical related donors on Day -1 * CIML NK Cells: Patients undergo CIML NK cell infusion on Day 0 * Subcutaneous IL-2 will begin approximately 2-4 hours after infusion and will continue every other day through Day 12 for a total of 7 doses
Donors
NO INTERVENTION-The haploidentical donor identified by HLA matching of the immediate family members (parents, siblings, and children) will undergo non-mobilized leukapheresis on Day -1. Peripheral blood mononuclear cells (PBMCs) will be collected using standard collection techniques.
Interventions
-Screening, Day 0 prior to CIML NK infusion, Day 1, Day 3, Day 7, Day 8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 60, Day 100, 6 months, 9 months, 12 months, and at disease relapse
-Screening, Day 8, Day 14, Day 28, Between Day 42 and 60, Day 100, at disease relapse
Eligibility Criteria
You may qualify if:
- Diagnosis requirement for phase I patients:
- Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR.
- OR High-risk AML (by ELN criteria; See Appendix C) in complete remission (CR) and has either refused hematopoietic stem cell transplantation OR is currently not eligible for hematopoietic stem cell transplantation OR for whom hematopoietic stem cell transplantation is being reserved for later relapse. This is inclusive of patients with minimal residual disease evidenced by cytogenetics, molecular testing, and/or flow cytometry.
- OR Myelodysplastic syndrome (MDS) with excess blasts (\>5%) and progressive disease at any time after initiation of DNA hypomethylator treatment during the past 2 years, OR failure to achieve complete or partial response or hematological improvement (see section 12.4) after at least six cycles of azacytidine or four cycles of decitabine administered during the past 2 years, OR intolerance to azacytidine or decitabine. MDS patients with isolated 5q- abnormalities that meet these criteria after lenalidomide therapy and DNA hypomethylator therapy are also eligible.
- Diagnosis requirement for phase II patients:
- \*Refractory AML without CR after induction therapy (primary induction failure) or relapsed AML after obtaining a CR. Favorable-risk core binding factor (CBF) mutated AML and acute promyelocytic leukemia (APL) will be excluded.
- Diagnosis requirement for pediatric cohort patients:
- \*Refractory AML without complete remission (CR) after induction therapy (primary induction failure) or relapsed AML after obtaining a CR.
- Age requirement for phase I and phase II patients: At least 18 years of age.
- Age requirement for pediatric cohort: 2-17 years of age.
- Available HLA-haploidentical donor that meets the following criteria:
- Related donor (parent, sibling, offspring, or offspring of sibling)
- At least 18 years of age
- HLA-haploidentical donor/recipient match by at least Class I serologic typing at the A\&B locus.
- In general good health, and medically able to tolerate leukapheresis required for harvesting the NK cells for this study.
- +14 more criteria
You may not qualify if:
- Relapsed after allogeneic transplantation.
- Isolated extramedullary relapse (phase II only).
- More than one course of salvage chemotherapy for primary induction failure or AML relapsing after CR1 (phase II only).
- 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.
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- Washington University School of Medicinelead
- American Society of Clinical Oncologycollaborator
- American Society of Hematologycollaborator
- Gabrielle's Angel Foundationcollaborator
- The Leukemia and Lymphoma Societycollaborator
- National Cancer Institute (NCI)collaborator
- ImmunityBio, Inc.collaborator
Study Sites (1)
Washington University School of Medicine
St Louis, Missouri, 63110, United States
Related Publications (4)
Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM. Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A. 2009 Feb 10;106(6):1915-9. doi: 10.1073/pnas.0813192106. Epub 2009 Jan 30.
PMID: 19181844BACKGROUNDRomee R, Schneider SE, Leong JW, Chase JM, Keppel CR, Sullivan RP, Cooper MA, Fehniger TA. Cytokine activation induces human memory-like NK cells. Blood. 2012 Dec 6;120(24):4751-60. doi: 10.1182/blood-2012-04-419283. Epub 2012 Sep 14.
PMID: 22983442BACKGROUNDNi J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18-preactivated NK cells against established tumors. J Exp Med. 2012 Dec 17;209(13):2351-65. doi: 10.1084/jem.20120944. Epub 2012 Dec 3.
PMID: 23209317BACKGROUNDBerrien-Elliott MM, Becker-Hapak M, Cashen AF, Jacobs M, Wong P, Foster M, McClain E, Desai S, Pence P, Cooley S, Brunstein C, Gao F, Abboud CN, Uy GL, Westervelt P, Jacoby MA, Pusic I, Stockerl-Goldstein KE, Schroeder MA, DiPersio JF, Soon-Shiong P, Miller JS, Fehniger TA. Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy. Blood. 2022 Feb 24;139(8):1177-1183. doi: 10.1182/blood.2021011532.
PMID: 34797911DERIVED
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Results Point of Contact
- Title
- Amanda Cashen, M.D.
- Organization
- Washington University School of Medicine
Study Officials
- PRINCIPAL INVESTIGATOR
Amanda Cashen, M.D.
Washington University School of Medicine
Publication Agreements
- PI is Sponsor Employee
- Yes
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NON RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SEQUENTIAL
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
July 9, 2013
First Posted
July 12, 2013
Study Start
August 11, 2014
Primary Completion
December 28, 2021
Study Completion
April 4, 2022
Last Updated
January 17, 2024
Results First Posted
February 1, 2023
Record last verified: 2023-12
Data Sharing
- IPD Sharing
- Will not share