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Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

Primary Purpose

Leukemia, Myelogenous, Chronic

Status
Completed
Phase
Phase 2
Locations
Italy
Study Type
Interventional
Intervention
Bosutinib
Bone Marrow Transplant
Bone Marrow cells
Sponsored by
University of Milano Bicocca
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Leukemia

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • ASST-Monza
  • Ospedale San Raffaele

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Bosutinib and Bone Marrow Transplant

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Overall Survival
Percentage of patients with engraftment
percentage of patients with complete chimerism (95%)
Evaluation of Major Cytogenetic Response (MCyR)
Major Cytogenetic Response (MCyR) is < 36% Ph+ metaphases
Evaluation of molecular responses
Molecular response is defined Complete: if there is undetectable BCR-ABL transcript Major: if ratio BCR/ABL <= 0.1% on International Scale
Relapse incidence (RI)
Incidence of non-relapse mortality (NRM)
Incidence and severity of acute and chronic graft vs. host disease (GvHD)
Quality of Life (QoL)
Evaluation of QoL with EQ-5D-5L (Italian - Version 2) and FACT-Leu (Italian -Version 4)
Overall Survival (OS)
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Progression Free Survival (PFS)
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Relapse Incidence (RI)
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Chronic Graft-versus-host Disease (cGvHD)
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)

Full Information

First Posted
December 9, 2015
Last Updated
November 3, 2020
Sponsor
University of Milano Bicocca
Collaborators
IRCCS San Raffaele
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1. Study Identification

Unique Protocol Identification Number
NCT02638467
Brief Title
Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy
Official Title
Allogeneic Haematopoietic Stem Cell Transplantation From a Matched Donor in Patients With Chronic Myeloid Leukemia Failing to Gain Normal Hemopoiesis Under TKIs Therapy
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
November 2015 (Actual)
Primary Completion Date
November 29, 2018 (Actual)
Study Completion Date
February 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Milano Bicocca
Collaborators
IRCCS San Raffaele

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Leukemia, Myelogenous, Chronic, BCR-ABL Positive

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Bosutinib and Bone Marrow Transplant
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Bosutinib
Other Intervention Name(s)
Bosulif, SKI-606
Intervention Description
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.
Intervention Type
Procedure
Intervention Name(s)
Bone Marrow Transplant
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Bone Marrow cells
Primary Outcome Measure Information:
Title
Efficacy as assessed by the percentage of patients with Complete Cytogenetic Response (CCyR)
Description
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.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Overall Survival
Time Frame
12 months
Title
Percentage of patients with engraftment
Time Frame
12 months
Title
percentage of patients with complete chimerism (95%)
Time Frame
Day +28, +56 and +100
Title
Evaluation of Major Cytogenetic Response (MCyR)
Description
Major Cytogenetic Response (MCyR) is < 36% Ph+ metaphases
Time Frame
12 months
Title
Evaluation of molecular responses
Description
Molecular response is defined Complete: if there is undetectable BCR-ABL transcript Major: if ratio BCR/ABL <= 0.1% on International Scale
Time Frame
12 months
Title
Relapse incidence (RI)
Time Frame
12 months
Title
Incidence of non-relapse mortality (NRM)
Time Frame
Within day +28 and +360
Title
Incidence and severity of acute and chronic graft vs. host disease (GvHD)
Time Frame
12 months
Title
Quality of Life (QoL)
Description
Evaluation of QoL with EQ-5D-5L (Italian - Version 2) and FACT-Leu (Italian -Version 4)
Time Frame
12 months
Title
Overall Survival (OS)
Description
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Time Frame
36 months
Title
Progression Free Survival (PFS)
Description
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Time Frame
36 months
Title
Relapse Incidence (RI)
Description
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Time Frame
36 months
Title
Chronic Graft-versus-host Disease (cGvHD)
Description
2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses)
Time Frame
36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 Exclusion Criteria: 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlo Gambacorti-Passerini, MD
Organizational Affiliation
University of Milano Bicocca
Official's Role
Principal Investigator
Facility Information:
Facility Name
ASST-Monza
City
Monza
State/Province
Italy/MB
ZIP/Postal Code
20900
Country
Italy
Facility Name
Ospedale San Raffaele
City
Milano
State/Province
MI
ZIP/Postal Code
20132
Country
Italy

12. IPD Sharing Statement

Citations:
PubMed Identifier
14748660
Citation
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.
Results Reference
background
PubMed Identifier
6316147
Citation
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.
Results Reference
background
Links:
URL
http://www.cancer.org
Description
Cancer Facts and Figures. 2006, American Cancer Society

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Allogeneic Stem Cell Transplantation in Chronic Myeloid Leukemia Failing TKIs Therapy

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