- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01898793
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
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.
Study Overview
Status
Conditions
Detailed Description
Amendment 16: Based on the data indicating that ALT-803/IL-15 result in more modulation of the NK cells in vivo, the investigators performed a lead in cohort with ALT-803 replacing IL-2 at a dose of 10 mcg/kg SQ administered q5 days starting on the date of NK cell infusion. The first two patients treated in the ALT-803 lead in cohort experienced a set of symptoms consistent with cytokine release syndrome (CRS) including fevers, elevated markers of inflammation between days 10-14 after ML NK cell infusion.
Based on the evidence of increased CD8 T cell activation, the in vitro data indicating that ALT-803 promoted recipient CD8 T cell expansion and killing of donor ML NK cells, and the lack of clinical responses using ALT-803, the lead in cohort was closed, and a decision was made to return to rhIL-2 support, mimicking the cytokine support utilized in the phase 2 portion of the trial.
PLEASE NOTE: THE PEDIATRIC PORTION OF THE STUDY IS CLOSED TO FURTHER ENROLLMENT.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
-
-
Missouri
-
Saint Louis, Missouri, United States, 63110
- Washington University School of Medicine
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
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.
- Negative for hepatitis, HTLV, and HIV on donor viral screen
- Not pregnant
- Voluntary written consent to participate in this study
- 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 IULN
- Creatinine within normal institutional limits OR creatinine clearance ≥ 50 mL/min/1.73 m2 by Cockcroft-Gault Formula (adults) or Schwartz formula (pediatric cohort)
- 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 infusion of the CIML NK cells. 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 throughout the DLT evaluation period.
- Ability to understand and willingness to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).
Exclusion Criteria:
- 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.
Study Plan
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 |
Intervention / Treatment |
---|---|
Experimental: Lead-in Cohort & Phase II (ALT-803): Maximum NK cell/number kg
|
Other Names:
Other Names:
Other Names:
-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
|
Experimental: Pediatric Cohort: Maximum NK cell/number kg
|
Other Names:
Other Names:
Other Names:
Other Names:
-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
|
Experimental: Phase II (IL-2): Maximum NK cell/number kg
The 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.
|
Other Names:
Other Names:
Other Names:
Other Names:
-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
|
Experimental: Phase I Dose Level 1: 0.5 x 10^6/kg CIML NK cells
|
Other Names:
Other Names:
Other Names:
Other Names:
-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
|
Experimental: Phase I Dose Level 2: 1.0 x 10^6/kg CIML NK cells
|
Other Names:
Other Names:
Other Names:
Other Names:
-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
|
Experimental: Phase I Dose Level 3: Maximum NK cell/number kg
|
Other Names:
Other Names:
Other Names:
Other Names:
-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
|
No Intervention: Donors
-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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Maximal Tolerated or Tested Dose (MT/TD) of CIML-NK Cells (Phase I)
Time Frame: 35 days
|
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)
Time Frame: Up to 3 years
|
|
Up to 3 years
|
Safety of CIML NK Cells as Measured by the Number of Participants With Treatment Related Adverse Events (Pediatric Cohort)
Time Frame: Through Day 100
|
|
Through Day 100
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Response Assessed According to IWG Criteria (Phase 1, Phase II, and Pediatric)
Time Frame: 35 days
|
35 days
|
|
Duration of Remission (DOR) (Phase I, Phase II, and Pediatric)
Time Frame: Up to 3 years
|
DOR is defined only for patients who achieve a complete remission (CR), complete remission with incomplete blood count recovery (CRi), marrow complete response (mCR), or partial remission (PR), and is measured from the first date of attaining CR or PR until the date of disease progression or death.
|
Up to 3 years
|
Time to Progression (Phase I, Phase II, and Pediatric)
Time Frame: Up to 3 years
|
TTP is defined as the time from date of first dose of fludarabine until evidence of disease progression.
|
Up to 3 years
|
Disease Free Survival (DFS) (Phase I, Phase II, and Pediatric)
Time Frame: Up to 3 years
|
DFS is defined as the time from the day CR, mCR, or CRi is documented until disease progression or death.
|
Up to 3 years
|
Overall Survival (OS) (Phase I, Phase II, and Pediatric)
Time Frame: Up to 3 years
|
OS is defined from the date of first dose of fludarabine on this study until death.
|
Up to 3 years
|
Toxicity as Measured by the Number of Participants With Treatment Related Adverse Events (Phase I and Phase II)
Time Frame: Through Day 100
|
|
Through Day 100
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Amanda Cashen, M.D., Washington University School of Medicine
Publications and helpful links
General Publications
- 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.
- Romee 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.
- Ni 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.
- Berrien-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.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myeloid, Acute
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Anti-Infective Agents
- Peripheral Nervous System Agents
- Antiviral Agents
- Anti-HIV Agents
- Anti-Retroviral Agents
- Analgesics
- Sensory System Agents
- Analgesics, Non-Narcotic
- Antirheumatic Agents
- Antimetabolites, Antineoplastic
- Antimetabolites
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Aldesleukin
- Cyclophosphamide
- Fludarabine
- Fludarabine phosphate
- Interleukin-2
Other Study ID Numbers
- 201401085
- 5F32CA200253-02 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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.
Clinical Trials on Leukemia, Myeloid, Acute
-
University of PennsylvaniaActive, not recruitingAcute Myeloid Leukemia, in Relapse | Acute Myeloid Leukemia, Refractory | Acute Myeloid Leukemia, PediatricUnited States
-
Terrence J Bradley, MDImago BioSciences, Inc., a subsidiary of Merck & Co., Inc., (Rahway, New...RecruitingAcute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Acute Myeloid Leukemia, in RelapseUnited States
-
Bhavana BhatnagarCTI BioPharmaCompletedRecurrent Adult Acute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Untreated Adult Acute Myeloid Leukemia | Therapy-Related Acute Myeloid LeukemiaUnited States
-
Washington University School of MedicineWithdrawnRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
-
C. Babis AndreadisGateway for Cancer Research; AVEO Pharmaceuticals, Inc.TerminatedAcute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
-
National Cancer Institute (NCI)RecruitingAcute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Recurrent Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI)RecruitingAcute Myeloid Leukemia | Recurrent Adult Acute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Refractory Acute Myeloid LeukemiaUnited States
-
City of Hope Medical CenterNational Cancer Institute (NCI)Active, not recruitingAcute Myeloid Leukemia | Secondary Acute Myeloid Leukemia | Untreated Adult Acute Myeloid Leukemia | Recurrent Acute Myeloid Leukemia | Refractory Acute Myeloid Leukemia | Therapy-Related Acute Myeloid LeukemiaUnited States
-
Massachusetts General HospitalExelixisCompletedRefractory Acute Myeloid Leukemia | Relapsed Acute Myeloid LeukemiaUnited States
-
Jacqueline Garcia, MDEli Lilly and CompanyCompletedCombination Merestinib and LY2874455 for Patients With Relapsed or Refractory Acute Myeloid LeukemiaRelapsed Adult Acute Myeloid Leukemia | Refractory Adult Acute Myeloid LeukemiaUnited States
Clinical Trials on Cyclophosphamide
-
Children's Hospital Los AngelesLucile Packard Children's HospitalTerminatedMetabolic Diseases | Stem Cell Transplantation | Chronic Granulomatous Disease | Bone Marrow Transplantation | Thalassemia | Wiskott-Aldrich Syndrome | Genetic Diseases | Peripheral Blood Stem Cell Transplantation | Pediatrics | Diamond-Blackfan Anemia | Allogeneic Transplantation | Combined Immune Deficiency | X-linked Lymphoproliferative Disease
-
Medical College of WisconsinNational Cancer Institute (NCI); National Heart, Lung, and Blood Institute... and other collaboratorsCompletedAnemia, AplasticUnited States
-
Columbia UniversityUnknownSevere Combined Immunodeficiency | Fanconi Anemia | Bone Marrow Failure | OsteopetrosisUnited States
-
National Cancer Institute, NaplesImmatics Biotechnologies GmbH; CureVac; European Commission -FP7-Health-2013-Innovation-1CompletedHepatocellular CarcinomaBelgium, Germany, Italy, Spain, United Kingdom
-
Mahidol UniversityTerminatedRenal Insufficiency | InfectionThailand
-
Centre Oscar LambretCompleted
-
Eisai Inc.CompletedBreast Cancer | Ovarian Cancer | Prostate Cancer | Colon Cancer | Renal CancerUnited States
-
Baylor Research InstituteCompletedMalignant Melanoma Stage IVUnited States
-
University of Turin, ItalyUnknown
-
Merck KGaA, Darmstadt, GermanyCompleted