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Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

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ClinicalTrials.gov Identifier: NCT02750254
Recruitment Status : Active, not recruiting
First Posted : April 25, 2016
Last Update Posted : March 14, 2019
Sponsor:
Information provided by (Responsible Party):
Washington University School of Medicine

Brief Summary:
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with hematologic malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and acute lymphoblastic leukemia (ALL); however, human leukocyte antigen (HLA)-matched donor availability continues to be a major hurdle. Historically, HLA haploidentical donor hematopoietic cell transplantation (haplo-HCT) was associated with high incidences of graft rejection and excessive non-relapse mortality (NRM), but recent advances utilizing post-transplant cyclophosphamide (PT-Cy) have revolutionized haplo-HCT and the outcomes are now comparable to allo-HCT using more traditional HLA matched related and unrelated donors. However, graft-versus-host disease (GvHD) continues to be a problem and is associated with significant morbidity and mortality in allo-HCT patients including those who receive haplo-HCT on PT-Cy platform. The aim of this early phase study is to investigate the safety and overall efficacy of azacitidine in reducing the incidence and severity of GvHD when added to PT-Cy based haplo-HCT platform for patients with AML, ALL, or advanced MDS.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome Acute Lymphocytic Leukemia Drug: Fludarabine Radiation: Fractionated total body irradiation Drug: Busulfan Drug: Cyclophosphamide Radiation: Single dose total body irradiation Drug: Melphalan Drug: Granulocyte-colony stimulating factor Procedure: Stem cell transplant Drug: Azacitidine Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 5 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation
Actual Study Start Date : June 27, 2016
Actual Primary Completion Date : May 24, 2017
Estimated Study Completion Date : October 14, 2020


Arm Intervention/treatment
Experimental: Arm 1: Azacitidine
  • Treating physician must choose from one of these conditioning regimens (will be given per standard of care)

    • fludarabine and fractionated total body irradiation (Flu/FrTBI)
    • fludarabine and busulfan (Flu/Bu4)
    • fludarabine, cyclophosphamide, and single dose total body irradiation (Flu/Cy/sdTBI)
    • fludarabine and melphalan (Flu/Mel)
    • reduced-intensity fludarabine and busulfan (Flu/Bu2)
  • G-CSF from Day -5 through Day -1 per standard of care
  • On Day 0, the allograft will be infused per standard of care.
  • Azacitidine will be administered on Day +1 and +2 post-stem cell transfusion days
  • Cyclophosphamide on Days +3 and +4 post-transplant
Drug: Fludarabine
Other Names:
  • Fludara
  • 2-Fluoro-ara-A Monophosphate
  • 2-Fluoro-ara AMP
  • FAMP

Radiation: Fractionated total body irradiation
Drug: Busulfan
Other Names:
  • Myerlan
  • Busulphan

Drug: Cyclophosphamide
Other Names:
  • Cytoxan
  • CPM
  • CTX
  • CYT

Radiation: Single dose total body irradiation
Drug: Melphalan
Other Names:
  • Alkeran
  • Phenylalanine mustard

Drug: Granulocyte-colony stimulating factor
Other Names:
  • G-CSF
  • Plerixafor
  • Mozobil
  • Neupogen
  • Filgrastim

Procedure: Stem cell transplant
Drug: Azacitidine
Other Names:
  • Vidaza
  • Ladakamycin




Primary Outcome Measures :
  1. Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events [ Time Frame: Up to Day 35 ]
    The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting.

  2. Maximum tolerated dose of azacitidine (Phase I only) [ Time Frame: Estimated to be 3-4 months (completion of all Phase I patients through Day 35) ]
  3. Grade II-IV acute GvHD rate of azacitidine (Phase II only) [ Time Frame: Up to Day 100 ]

Secondary Outcome Measures :
  1. Event-free survival (EFS) [ Time Frame: Up to 48 months ]
    EFS is defined as the time from date of first dose of the preparative regimen until failure to engraft, treatment failure, disease progression/relapse, or death from any cause (whichever occurs first).

  2. Overall survival (OS) [ Time Frame: Up to 48 months ]
    OS is defined as the time from the date of Day 0 until death from any cause.

  3. Disease-free survival (DFS) [ Time Frame: Up to 48 months ]
  4. Non-relapse mortality (NRM) [ Time Frame: Up to Day 100 ]
    NRM is defined as death that results from a transplant procedure-related complication (e.g. infection, organ failure, hemorrhage, GvHD) rather than from relapse of the underlying disease prior to Day +100 visit.

  5. Time to neutrophil engraftment [ Time Frame: Up to 12 months ]
    Time to neutrophil engraftment is measured by determining the first of 3 consecutive measurements of neutrophil count ≥ 500/ul following conditioning regimen-induced nadir.

  6. Time to platelet engraftment [ Time Frame: Up to 12 months ]
    Time to platelet engraftment is measured by determining the first of 3 consecutive measurements of platelet count ≥ 20,000/ul without platelet transfusion support for 7 days.

  7. Rate of acute GvHD [ Time Frame: Up to Day 100 ]
    Incidence and severity of acute GvHD will be assessed based on the modified Glucksberg criteria and Seattle criteria. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).

  8. Rate of chronic GvHD [ Time Frame: Day 100 through Day 365 ]
    Incidence and severity of chronic GvHD will be assessed based on the NIH consensus criteria and global severity scoring system. Attempts should be made to confirm the diagnosis pathologically by biopsy of target organ(s).



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

Inclusion Criteria:

  • Diagnosis of acute leukemia (AML/ALL) or advanced MDS (INT-2 or high risk) in complete remission (CR/CRc/CRi) documented by bone marrow biopsy done within 30 days prior to the initiation of conditioning regimen.
  • Available HLA-haploidentical donor that meets the following criteria:

    • Immediate family member (sibling, offspring, or parent)
    • At least 18 years of age
    • HLA-haploidentical donor/recipient match by class I serologic typing at the A&B locus.
    • In the treating physician's opinion, is in general good health, and medically able to tolerate leukapheresis required for harvesting HSC
    • No active hepatitis (B, C), HTLV, and HIV infections
    • Not pregnant
  • Karnofsky performance status ≥ 70 %
  • Adequate organ function as defined below:

    • Total bilirubin ≤ 2.5 mg/dl (unless the patient has a history of Gilbert's syndrome)
    • AST(SGOT) and ALT(SGPT) ≤ 3.0 x IULN
    • Creatinine ≤ 2.0 x IULN OR estimated creatinine clearance ≥ 30 mL/min/1.73 m^2 by Cockcroft-Gault Formula
    • Oxygen saturation ≥ 90% on room air
    • LVEF ≥ 40%
    • FEV1 and FVC ≥ 50% predicted, corrected DLCO ≥ 40% predicted
  • At least 18 years of age at the time of study registration
  • Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable)

Exclusion Criteria:

  • Recipients with donor sensitive antibodies (DSA), defined by 2000 or higher MFI against one or more class I or II antigens
  • Known HIV or active Hepatitis B or C infection
  • Underwent a previous related or unrelated allogeneic transplant
  • Known hypersensitivity to one or more of the study agents
  • Currently receiving or has received any investigational drugs within the 14 days prior to the first dose of the conditioning regimen.
  • Pregnant and/or breastfeeding
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or unstable cardiac arrhythmias.
  • Presence of a readily available 6/6 matched sibling donor who is a candidate for donation

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): NCT02750254


Locations
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United States, Missouri
Washington University School of Medicine
Saint Louis, Missouri, United States, 63110
Sponsors and Collaborators
Washington University School of Medicine
Investigators
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Principal Investigator: Mark Schroeder, M.D. Washington University School of Medicine

Additional Information:
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Responsible Party: Washington University School of Medicine
ClinicalTrials.gov Identifier: NCT02750254     History of Changes
Other Study ID Numbers: 201604081
First Posted: April 25, 2016    Key Record Dates
Last Update Posted: March 14, 2019
Last Verified: March 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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Leukemia
Leukemia, Myeloid, Acute
Preleukemia
Leukemia, Lymphoid
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Myelodysplastic Syndromes
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Melphalan
Busulfan
Fludarabine
Fludarabine phosphate
Azacitidine
Sargramostim
Lenograstim
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents