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Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

16. oktober 2020 opdateret af: Washington University School of Medicine

A Phase I/II Study of Azacitidine in Haploidentical Donor Hematopoietic Cell Transplantation

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.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

5

Fase

  • Fase 1

Kontakter og lokationer

Dette afsnit indeholder kontaktoplysninger for dem, der udfører undersøgelsen, og oplysninger om, hvor denne undersøgelse udføres.

Studiesteder

  • Forenede Stater
    • Missouri
      • Saint Louis, Missouri, Forenede Stater, 63110
        • Washington University School of Medicine

Deltagelseskriterier

Forskere leder efter personer, der passer til en bestemt beskrivelse, kaldet berettigelseskriterier. Nogle eksempler på disse kriterier er en persons generelle helbredstilstand eller tidligere behandlinger.

Berettigelseskriterier

Aldre berettiget til at studere

18 år og ældre (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

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

Studieplan

Dette afsnit indeholder detaljer om studieplanen, herunder hvordan undersøgelsen er designet, og hvad undersøgelsen måler.

Hvordan er undersøgelsen tilrettelagt?

Design detaljer

  • Primært formål: Behandling
  • Tildeling: N/A
  • Interventionel model: Enkelt gruppeopgave
  • Maskning: Ingen (Åben etiket)

Våben og indgreb

Deltagergruppe / Arm
Intervention / Behandling
Eksperimentel: 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
Medicin: Cyclofosfamid
Andre navne:
  • Cytoxan
  • CPM
  • CTX
  • CYT
Medicin: Fludarabin
Andre navne:
  • Fludara
  • 2-Fluoro-ara-A monofosfat
  • 2-fluor-ara AMP
  • FAMP
Procedure: Stamcelletransplantation
Medicin: Melphalan
Andre navne:
  • Phenylalanin sennep
  • Alkeran
Medicin: Busulfan
Andre navne:
  • Busulfan
  • Myerlan
Medicin: Azacitidin
Andre navne:
  • Ladakamycin
  • Vidaza
Stråling: Fraktioneret total kropsbestråling
Stråling: Single dose total body irradiation
Medicin: Granulocyte-colony stimulating factor
Andre navne:
  • Filgrastim
  • G-CSF
  • Neupogen
  • Mozobil
  • Plerixafor

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Safety of azacitidine (Phase I only) as measured by frequency and grade of adverse events
Tidsramme: 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.
Up to Day 35
Maximum tolerated dose of azacitidine (Phase I only)
Tidsramme: Estimated to be 3-4 months (completion of all Phase I patients through Day 35)
Estimated to be 3-4 months (completion of all Phase I patients through Day 35)
Grade II-IV acute GvHD rate of azacitidine (Phase II only)
Tidsramme: Up to Day 100
Up to Day 100

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Event-free survival (EFS)
Tidsramme: 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).
Up to 48 months
Overall survival (OS)
Tidsramme: Up to 48 months
OS is defined as the time from the date of Day 0 until death from any cause.
Up to 48 months
Disease-free survival (DFS)
Tidsramme: Up to 48 months
Up to 48 months
Non-relapse mortality (NRM)
Tidsramme: 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.
Up to Day 100
Time to neutrophil engraftment
Tidsramme: 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.
Up to 12 months
Time to platelet engraftment
Tidsramme: 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.
Up to 12 months
Rate of acute GvHD
Tidsramme: 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).
Up to Day 100
Rate of chronic GvHD
Tidsramme: 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).
Day 100 through Day 365

Samarbejdspartnere og efterforskere

Det er her, du vil finde personer og organisationer, der er involveret i denne undersøgelse.

Sponsor

Washington University School of Medicine

Publikationer og nyttige links

Den person, der er ansvarlig for at indtaste oplysninger om undersøgelsen, leverer frivilligt disse publikationer. Disse kan handle om alt relateret til undersøgelsen.

Hjælpsomme links

Datoer for undersøgelser

Disse datoer sporer fremskridtene for indsendelser af undersøgelsesrekord og resumeresultater til ClinicalTrials.gov. Studieregistreringer og rapporterede resultater gennemgås af National Library of Medicine (NLM) for at sikre, at de opfylder specifikke kvalitetskontrolstandarder, før de offentliggøres på den offentlige hjemmeside.

Studer store datoer

Studiestart (Faktiske)

27. juni 2016

Primær færdiggørelse (Faktiske)

24. maj 2017

Studieafslutning (Faktiske)

14. oktober 2020

Datoer for studieregistrering

Først indsendt

18. april 2016

Først indsendt, der opfyldte QC-kriterier

20. april 2016

Først opslået (Skøn)

25. april 2016

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

20. oktober 2020

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

16. oktober 2020

Sidst verificeret

1. oktober 2020

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • 201604081

Plan for individuelle deltagerdata (IPD)

Planlægger du at dele individuelle deltagerdata (IPD)?

INGEN

Lægemiddel- og udstyrsoplysninger, undersøgelsesdokumenter

Studerer et amerikansk FDA-reguleret lægemiddelprodukt

Ja

Studerer et amerikansk FDA-reguleret enhedsprodukt

Ingen

produkt fremstillet i og eksporteret fra U.S.A.

Ingen

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