NCT02638467

Brief Summary

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.

Trial Health

87
On Track

Trial Health Score

Automated assessment based on enrollment pace, timeline, and geographic reach

Enrollment
2

participants targeted

Target at below P25 for phase_2 leukemia

Timeline
Completed

Started Nov 2015

Geographic Reach
1 country

2 active sites

Status
completed

Health score is calculated from publicly available data and should be used for screening purposes only.

Trial Relationships

Click on a node to explore related trials.

Study Timeline

Key milestones and dates

Study Start

First participant enrolled

November 1, 2015

Completed
1 month until next milestone

First Submitted

Initial submission to the registry

December 9, 2015

Completed
14 days until next milestone

First Posted

Study publicly available on registry

December 23, 2015

Completed
2.9 years until next milestone

Primary Completion

Last participant's last visit for primary outcome

November 29, 2018

Completed
1.2 years until next milestone

Study Completion

Last participant's last visit for all outcomes

February 1, 2020

Completed
Last Updated

November 5, 2020

Status Verified

November 1, 2020

Enrollment Period

3.1 years

First QC Date

December 9, 2015

Last Update Submit

November 3, 2020

Conditions

LeukemiaMyelogenousChronicBCR-ABL Positive

Outcome Measures

Primary Outcomes (1)

  • Efficacy as assessed by the percentage of patients with Complete Cytogenetic Response (CCyR)

    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

Secondary Outcomes (13)

  • Overall Survival

    12 months

  • Percentage of patients with engraftment

    12 months

  • percentage of patients with complete chimerism (95%)

    Day +28, +56 and +100

  • Evaluation of Major Cytogenetic Response (MCyR)

    12 months

  • Evaluation of molecular responses

    12 months

  • +8 more secondary outcomes

Study Arms (1)

Bosutinib and Bone Marrow Transplant

EXPERIMENTAL

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.

Drug: BosutinibProcedure: Bone Marrow TransplantDrug: Bone Marrow cells

Interventions

BosutinibDRUG

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.

Also known as: Bosulif, SKI-606
Bosutinib and Bone Marrow Transplant
Bone Marrow TransplantPROCEDURE

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

Bosutinib and Bone Marrow Transplant
Bone Marrow cellsDRUG
Bosutinib and Bone Marrow Transplant

Eligibility Criteria

Age18 Years - 70 Years
Sexall
Healthy VolunteersNo
Age GroupsAdult (18-64), Older Adult (65+)

You may qualify if:

  • Chronic Myeloid Leukaemia -CML- in chronic phase (CP)
  • Failure to achieve at least a Major Cytogenetic Response (MCyR) after a minimum of 18 months of TKIs treatment
  • Inability to tolerate 3 months of uninterrupted full dose TKIs therapy due to hematological toxicity
  • A minimum of three treatment interruptions due to hematological toxicity Availability of a HLA-identical related donor (Matched Related Donor, MRD)
  • 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)
  • Target graft size (bone marrow):
  • bone marrow: \> 3 x 106 CD34+ cells/kg BW recipient or \> 3 x 108 nucleated cells/kg BW
  • Karnofsky Index \> 80 %
  • Age ≥18 and ≤70 years
  • Adequate contraception in female patients of child-bearing potential
  • Written informed consent

You may not qualify if:

  • Secondary malignancies
  • A hematopoietic cell transplantation-specific comorbidity index (Sorror et al Appendix C) \> 4
  • Known and manifested malignant involvement of the Central Nervous System (CNS)
  • Active infectious disease
  • Active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis B virus (HCV) infection
  • Impaired liver function (Bilirubin \> upper normal limit; Transaminases \> 3.0 x upper normal limit)
  • Impaired renal function (Creatinine-clearance \< 60 ml/min; Serum Creatinine \> 1.5 x upper normal limit).
  • Pleural effusion or ascites \> 1.0 L
  • Pregnancy or lactation
  • 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

Contact the study team to confirm eligibility.

Sponsors & Collaborators

Study Sites (2)

ASST-Monza

Monza, Italy/MB, 20900, Italy

Location

Ospedale San Raffaele

Milan, MI, 20132, Italy

Location

Related Publications (2)

  • Redaelli A, Bell C, Casagrande J, Stephens J, Botteman M, Laskin B, Pashos C. Clinical and epidemiologic burden of chronic myelogenous leukemia. Expert Rev Anticancer Ther. 2004 Feb;4(1):85-96. doi: 10.1586/14737140.4.1.85.

    PMID: 14748660BACKGROUND

  • Heisterkamp N, Stephenson JR, Groffen J, Hansen PF, de Klein A, Bartram CR, Grosveld G. Localization of the c-ab1 oncogene adjacent to a translocation break point in chronic myelocytic leukaemia. Nature. 1983 Nov 17-23;306(5940):239-42. doi: 10.1038/306239a0.

    PMID: 6316147BACKGROUND

Related Links

MeSH Terms

Conditions

LeukemiaBronchiolitis Obliterans Syndrome

Interventions

bosutinibBone Marrow TransplantationSLC25A33 protein, human

Condition Hierarchy (Ancestors)

Neoplasms by Histologic TypeNeoplasmsHematologic DiseasesHemic and Lymphatic DiseasesOrganizing PneumoniaBronchiolitis ObliteransBronchiolitisBronchitisBronchial DiseasesRespiratory Tract DiseasesLung Diseases, ObstructiveLung DiseasesGraft vs Host DiseaseImmune System Diseases

Intervention Hierarchy (Ancestors)

Tissue TransplantationCell- and Tissue-Based TherapyBiological TherapyTherapeuticsTransplantationSurgical Procedures, Operative

Study Officials

  • Carlo Gambacorti-Passerini, MD

    University of Milano Bicocca

    PRINCIPAL INVESTIGATOR

Study Design

Study Type
interventional
Phase
phase 2
Allocation
NA
Masking
NONE
Purpose
TREATMENT
Intervention Model
SINGLE GROUP
Sponsor Type
OTHER
Responsible Party
SPONSOR

Study Record Dates

First Submitted

December 9, 2015

First Posted

December 23, 2015

Study Start

November 1, 2015

Primary Completion

November 29, 2018

Study Completion

February 1, 2020

Last Updated

November 5, 2020

Record last verified: 2020-11

Locations

IT(2)