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Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

3. november 2020 opdateret af: University of Milano Bicocca

Allogeneic Haematopoietic Stem Cell Transplantation From a Matched Donor in Patients With Chronic Myeloid Leukemia Failing to Gain Normal Hemopoiesis Under TKIs Therapy

Patients newly diagnosed with chronic phase chronic myeloid leukemia undergo treatment with TK inhibitors (TKI). A possible cause of TK failure is represented by the insufficient recovery of normal Ph- hematopoiesis during TKI treatment, with consequent severe cytopenias that limit TKI adequate administration. Although rare, this event happens in a proportion of 4-5% of CML patients. Our hypothesis is to circumvent this peculiar condition by providing a normal hematopoiesis from a HLA-matched donor (Human Leukocyte Antigen). The transplant procedure is therefore intended in providing a sustained hematopoiesis that will allow an early treatment with an adequate dosing of TKI. The transplant procedure planned in our study is built on all available evidences to provide the lowest incidence of acute and chronic GvHD (Graft-versus-host disease). Therefore, a bone marrow will be the preferential source and a GvHD prophylaxis based on Anti-thrombocyte globulin (ATG) and Cyclosporine/Methotrexate will be used according to standard current experience in the field of family and unrelated donors. The pre-transplant TKI will be continued until aplasia will develop, in order to decrease the tumor load as much as possible.The use of TKIs shortly after transplant carries the risk of inhibiting the newly transplanted hematopoietic cells, as Kit, an important kinase in normal bone marrow cells, is frequently blocked by Abl inhibitors. The use of bosutinib as post-transplant therapy is justified by the lack of Kit inhibition that distinguishes bosutinib from all other TKIs, and which could allow a minimal inhibitory activity against the transplanted normal bone marrow.

Studieoversigt

Status

Afsluttet

Betingelser

Intervention / Behandling

Undersøgelsestype

Interventionel

Tilmelding (Faktiske)

2

Fase

  • Fase 2

Kontakter og lokationer

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

Studiesteder

  • Italien
    • Italy/MB
      • Monza, Italy/MB, Italien, 20900
        • ASST-Monza
    • MI
      • Milano, MI, Italien, 20132
        • Ospedale San Raffaele

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 til 70 år (Voksen, Ældre voksen)

Tager imod sunde frivillige

Ingen

Køn, der er berettiget til at studere

Alle

Beskrivelse

Inclusion Criteria:

  1. Chronic Myeloid Leukaemia -CML- in chronic phase (CP)
  2. Failure to achieve at least a Major Cytogenetic Response (MCyR) after a minimum of 18 months of TKIs treatment
  3. Inability to tolerate 3 months of uninterrupted full dose TKIs therapy due to hematological toxicity
  4. A minimum of three treatment interruptions due to hematological toxicity Availability of a HLA-identical related donor (Matched Related Donor, MRD)
  5. Availability of unrelated donor (Matched Unrelated Donor, MUD) satisfying the criteria of a 10/10 antigen match at (Human Leukocyte Antigen) HLA-A, -B, -C and - DRB1, -DQB1 at high resolution typing, or 9/10 with a permissive - DP disparity according to Fleischhauer model (Crocchiolo et al, Blood 2009)
  6. Target graft size (bone marrow):
  7. bone marrow: > 3 x 106 CD34+ cells/kg BW recipient or > 3 x 108 nucleated cells/kg BW
  8. Karnofsky Index > 80 %
  9. Age ≥18 and ≤70 years
  10. Adequate contraception in female patients of child-bearing potential
  11. Written informed consent

Exclusion Criteria:

  1. Secondary malignancies
  2. A hematopoietic cell transplantation-specific comorbidity index (Sorror et al Appendix C) > 4
  3. Known and manifested malignant involvement of the Central Nervous System (CNS)
  4. Active infectious disease
  5. Active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis B virus (HCV) infection
  6. Impaired liver function (Bilirubin > upper normal limit; Transaminases > 3.0 x upper normal limit)
  7. Impaired renal function (Creatinine-clearance < 60 ml/min; Serum Creatinine > 1.5 x upper normal limit).
  8. Pleural effusion or ascites > 1.0 L
  9. Pregnancy or lactation
  10. Known hypersensitivity to Busilvex and/or fludarabine 11 Non-co-operative behaviour or non-compliance 12 Psychiatric diseases or conditions that might impair the ability to give informed consent

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: Bosutinib and Bone Marrow Transplant
Subjects will receive 400mg of bosutinib from day at least -45 to day -15 to assess the sensitivity of patient Chronic Myeloid Leukemia (CML) to this TKI. Patients will be transplanted with the aim to transplant > 3 x 106 CD34+ cells/kg Body Weight (BW) recipient from bone marrow or > 3 x 108 nucleated cells/kg BW recipient from bone marrow. Then, subjects will receive 400mg of bosutinib once daily from day +30 after transplant.
Medicin: Bosutinib
Subjects will receive 400mg of bosutinib once daily from day +30 after transplant, by mouth with food, preferably in the morning. Bosutinib will also be administered from day at least -45 to day -15 to assess the sensitivity of patient CML to this TKI.
Andre navne:
  • SKI-606
  • Bosulif
Procedure: Bone Marrow Transplant

Samples of the unrelated stem cell graft shall be characterised with respect to the number of CD34 positive cells per kg body weight of the recipient.

The number of transplanted CD34 positive cells per kg body weight (BW) of the recipient shall be recorded in the Case Report Form (CRF). If the transplant was cryopreserved the number of viable CD34 positive cells has to be determined after thawing and documented.

The goal is to transplant > 3 x 106 CD34+ cells/kg BW recipient from bone marrow or > 3 x 108 nucleated cells/kg BW recipient from bone marrow

Medicin: Bone Marrow cells

Hvad måler undersøgelsen?

Primære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Efficacy as assessed by the percentage of patients with Complete Cytogenetic Response (CCyR)
Tidsramme: 12 months
The percentage of patients with Complete Cytogenetic Response (CCyR) will be calculated as the complement to the percentage of failures on the total number of patients treated, where failure includes the following events: no engraftment, death within 12 months, no CCyR at 12 months.
12 months

Sekundære resultatmål

Resultatmål
Foranstaltningsbeskrivelse
Tidsramme
Samlet overlevelse
Tidsramme: 12 måneder
12 måneder
Percentage of patients with engraftment
Tidsramme: 12 months
12 months
percentage of patients with complete chimerism (95%)
Tidsramme: Day +28, +56 and +100
Day +28, +56 and +100
Evaluation of Major Cytogenetic Response (MCyR)
Tidsramme: 12 months
Major Cytogenetic Response (MCyR) is < 36% Ph+ metaphases
12 months
Evaluation of molecular responses
Tidsramme: 12 months

Molecular response is defined

  • Complete: if there is undetectable BCR-ABL transcript
  • Major: if ratio BCR/ABL <= 0.1% on International Scale
12 months
Relapse incidence (RI)
Tidsramme: 12 months
12 months
Incidence of non-relapse mortality (NRM)
Tidsramme: Within day +28 and +360
Within day +28 and +360
Incidence and severity of acute and chronic graft vs. host disease (GvHD)
Tidsramme: 12 months
12 months
Quality of Life (QoL)
Tidsramme: 12 months
Evaluation of QoL with EQ-5D-5L (Italian - Version 2) and FACT-Leu (Italian -Version 4)
12 months
Overall Survival (OS)
Tidsramme: 36 months
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
36 months
Progression Free Survival (PFS)
Tidsramme: 36 months
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
36 months
Relapse Incidence (RI)
Tidsramme: 36 months
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
36 months
Chronic Graft-versus-host Disease (cGvHD)
Tidsramme: 36 months
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
36 months

Samarbejdspartnere og efterforskere

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

Sponsor

University of Milano Bicocca

Samarbejdspartnere

IRCCS San Raffaele

Efterforskere

  • Ledende efterforsker: CARLO GAMBACORTI-PASSERINI, MD, University of Milano Bicocca

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.

Generelle publikationer

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)

1. november 2015

Primær færdiggørelse (Faktiske)

29. november 2018

Studieafslutning (Faktiske)

1. februar 2020

Datoer for studieregistrering

Først indsendt

9. december 2015

Først indsendt, der opfyldte QC-kriterier

22. december 2015

Først opslået (Skøn)

23. december 2015

Opdateringer af undersøgelsesjournaler

Sidste opdatering sendt (Faktiske)

5. november 2020

Sidste opdatering indsendt, der opfyldte kvalitetskontrolkriterier

3. november 2020

Sidst verificeret

1. november 2020

Mere information

Begreber relateret til denne undersøgelse

Yderligere relevante MeSH-vilkår

Andre undersøgelses-id-numre

  • alloCML

Disse oplysninger blev hentet direkte fra webstedet clinicaltrials.gov uden ændringer. Hvis du har nogen anmodninger om at ændre, fjerne eller opdatere dine undersøgelsesoplysninger, bedes du kontakte register@clinicaltrials.gov. Så snart en ændring er implementeret på clinicaltrials.gov, vil denne også blive opdateret automatisk på vores hjemmeside .

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