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Cytokine Induced Memory-like NK Cell Adoptive Therapy After Haploidentical Donor Hematopoietic Cell Transplantation

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ClinicalTrials.gov Identifier: NCT02782546
Recruitment Status : Recruiting
First Posted : May 25, 2016
Last Update Posted : June 11, 2019
Sponsor:
Collaborators:
National Institutes of Health (NIH)
The V Foundation for Cancer Research
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:

This is a standard phase 2 study powered to demonstrate improvement in the 100 day leukemia free survival to 30% from <10% expected with the use of reduced intensity haplo-HCT in this extremely high-risk patient cohort (based on the institutional experience using non-myeloablative / reduced intensity conditioning in a similar patient cohort).

A formal safety evaluation will be done after every 6th patient enrolled and the trial will be stopped if noted to have unusually higher engraftment failure (acute GVHD rates (>60% any grades or >30% grade III/IV or ≥ 50% severe cGVHD) or engraftment failure rates (≥15%).


Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Drug: Fludarabine Drug: Cyclophosphamide Radiation: Single dose total body irradiation Procedure: Graft cell infusion Drug: Tacrolimus Drug: Mycophenolate mofetil Drug: G-CSF Procedure: CIML NK cell infusion Drug: ALT-803 Procedure: Leukapheresis Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Cytokine Induced Memory-like NK Cell Adoptive Therapy After Haploidentical Donor Hematopoietic Cell Transplantation
Actual Study Start Date : January 30, 2017
Estimated Primary Completion Date : November 30, 2020
Estimated Study Completion Date : February 28, 2022


Arm Intervention/treatment
Experimental: Recipient
  • Standard of care reduced intensity preparative regimen consisting of fludarabine, cyclophosphamide, and single dose total body irradiation (TBI) on Day -1
  • Graft cell infusion on Day 0
  • Post-transplant cyclophosphamide on Days +3 and +4
  • GvHD prophylaxis with tacrolimus and mycophenolate mofetil (MMF) will start on Day +5. MMF will continue till Day +35 and tacrolimus till Day +180 in the absence of GvHD
  • G-CSF will start on Day +7 and will continue until neutrophil engraftment as per institutional guidelines
  • The cytokine-induced memory like natural killer (CIML NK) cells will be infused on Day +7 without a filter or pump, slowly by gravity over at least 15 minutes.
  • ALT-803 will start approximately 4 hours after the CIML NK cell infusion. ALT-803 will be administered subcutaneously at a dose of 10 mcg/kg subcutaneously from Day +7 (on the day of CIML NK cell infusion), Day +12, Day +17, and Day +22 for a total of 4 doses.
Drug: Fludarabine
-Standard of care
Other Names:
  • Fludara
  • 2-Fluoro-ara-A Monophosphate
  • 2-Fluoro-ara AMP
  • FAMP

Drug: Cyclophosphamide
-Standard of care
Other Names:
  • Cytoxan
  • Neosar
  • CPM
  • CTX
  • CYT

Radiation: Single dose total body irradiation
-Standard of care
Other Name: TBI

Procedure: Graft cell infusion
-Day 0
Other Name: HCT

Drug: Tacrolimus
-GVHD prophylaxis
Other Name: Prograf

Drug: Mycophenolate mofetil
-GVHD prophylaxis
Other Names:
  • CellCept
  • Myfortic

Drug: G-CSF
-Continue until neutrophil engraftment as per institutional guidelines
Other Name: Granulocyte-colony stimulating factor

Procedure: CIML NK cell infusion
-Day +7

Drug: ALT-803
-Start approximately 4 hours after CIML NK cell infusion

Experimental: Donor
  • Donors will receive subcutaneous G-CSF from Day -4 till Day 0 and undergo 20L apheresis per institutional guidelines.
  • Two consecutive days for collection are allowed in case of the target CD34+ cell dose being less than the target 4 x106/kg-bw from the first day of collection.
  • On Day +6 (one day before the planned CIML NK cell infusion), peripheral blood mononuclear cells will be collected by a single standard 20-L apheresis over 4-5 hours from the same haploidentical related donor that provided the HCT graft.
Procedure: Leukapheresis
-Day +6




Primary Outcome Measures :
  1. Leukemia free survival rate (LFS) [ Time Frame: 1 year post transplantation ]
    -LFS is defined as the time from achievement of CR to the time of relapse, death in remission, or last follow-up.


Secondary Outcome Measures :
  1. Leukemia free survival rate (LFS) [ Time Frame: 3 months post transplantation ]
    -LFS is defined as the time from achievement of CR to the time of relapse, death in remission, or last follow-up.

  2. Rate of overall survival (OS) [ Time Frame: 1 year post transplantation ]
    -OS is defined as the time from the date of Day 0 until death from any cause.

  3. Incidence of relapse in patients who are found to be CR (complete remission) [ Time Frame: Day 28 post transplantation ]
    -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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Recipient Inclusion Criteria:

  • Refractory AML without complete remission (CR) after 2 or more cycles of induction therapy (primary induction failure), or AML relapsed after obtaining a CR and failed one or more cycles of re-induction therapy. Standard dose 10-day decitabine (20 mg/m2 daily IV x 10 days) or 7-day azacitidine (75-100 mg/m2 daily SC/IV x 7 days) will be considered as one cycle of induction therapy.
  • At least 18 years of age
  • Deemed to be not otherwise eligible for a non-myeloablative hematopoietic cell transplant by the treating physician.
  • Available HLA-haploidentical donor that meets the criteria in the protocol
  • 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 performance status > 60 %
  • 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 > 60 mL/min/1.73 m2 by Cockcroft-Gault Formula
    • Oxygen saturation ≥90% on room air and adjusted DLCO of at least 40%
    • Ejection fraction ≥40%
  • Able to be off of corticosteroids (10 mg or less of prednisone or equivalent doses of other systemic steroids are allowed) and any other immune suppressive medications beginning on Day -3
  • 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).

Recipient Exclusion Criteria:

  • Relapsed after allogeneic transplantation.
  • Circulating blast count >30,000/uL by morphology or flow cytometry (cyto-reductive therapies including leukapheresis or hydroxyurea are allowed).
  • Uncontrolled bacterial or viral infections, or known HIV, Hepatitis B or C infection.
  • Presence of donor specific antibodies (DSA) with Mean Fluorescence Intensity (MFI) of >5000 as assessed by the single antigen bead assay, < 6 weeks prior to starting transplant conditioning
  • 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 day of transplant conditioning
  • Pregnant and/or breastfeeding

Donor Inclusion Criteria:

  • Related donor (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.
  • Ability to understand and willingness to sign an IRB approved written informed consent document

Donor Exclusion Criteria:

  • Positive for hepatitis, HTLV, or HIV infection
  • Pregnant and/or breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02782546


Contacts
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Contact: Amanda Cashen, M.D. (314) 454-8323 acashen@wustl.edu

Locations
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United States, Missouri
Washington University School of Medicine Recruiting
Saint Louis, Missouri, United States, 63110
Contact: Amanda Cashen, M.D.    314-454-8323    acashen@wustl.edu   
Principal Investigator: Amanda Cashen, M.D.         
Sub-Investigator: Todd Fehniger, M.D., Ph.D.         
Sub-Investigator: John DiPersio, M.D., Ph.D.         
Sub-Investigator: Peter Westervelt, M.D., Ph.D.         
Sub-Investigator: Geoffrey Uy, M.D.         
Sub-Investigator: Ravi Vij, M.D.         
Sub-Investigator: Camille Abboud, M.D.         
Sub-Investigator: Meagan Jacoby, M.D., Ph.D.         
Sub-Investigator: Iskra Pusic, M.D.         
Sub-Investigator: Armin Ghobadi, M.D.         
Sub-Investigator: Mark Schroeder, M.D.         
Sub-Investigator: Keith Stockerl-Goldstein, M.D.         
Sponsors and Collaborators
Washington University School of Medicine
National Institutes of Health (NIH)
The V Foundation for Cancer Research
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Amanda Cashen, M.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02782546     History of Changes
Other Study ID Numbers: 201610088
1P50CA171963-01A1 ( U.S. NIH Grant/Contract )
2P50CA171963-06 ( U.S. NIH Grant/Contract )
First Posted: May 25, 2016    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Mycophenolic Acid
Cyclophosphamide
Fludarabine
Fludarabine phosphate
Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Calcineurin Inhibitors
Enzyme Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Antibiotics, Antineoplastic
Antibiotics, Antitubercular
Antitubercular Agents
Anti-Bacterial Agents
Anti-Infective Agents