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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT02638467
Other study ID # alloCML
Secondary ID
Status Completed
Phase Phase 2
First received
Last updated
Start date November 2015
Est. completion date February 2020

Study information

Verified date November 2020
Source University of Milano Bicocca
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Recruitment information / eligibility

Status Completed
Enrollment 2
Est. completion date February 2020
Est. primary completion date November 29, 2018
Accepts healthy volunteers No
Gender All
Age group 18 Years to 70 Years
Eligibility 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

Study Design


Related Conditions & MeSH terms


Intervention

Drug:
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.
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
Drug:
Bone Marrow cells


Locations

Country Name City State
Italy Ospedale San Raffaele Milano MI
Italy ASST-Monza Monza Italy/MB

Sponsors (2)

Lead Sponsor Collaborator
University of Milano Bicocca IRCCS San Raffaele

Country where clinical trial is conducted

Italy, 

References & Publications (2)

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. — View 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. Review. — View Citation

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Overall Survival 12 months
Secondary Percentage of patients with engraftment 12 months
Secondary percentage of patients with complete chimerism (95%) Day +28, +56 and +100
Secondary Evaluation of Major Cytogenetic Response (MCyR) Major Cytogenetic Response (MCyR) is < 36% Ph+ metaphases 12 months
Secondary 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
12 months
Secondary Relapse incidence (RI) 12 months
Secondary Incidence of non-relapse mortality (NRM) Within day +28 and +360
Secondary Incidence and severity of acute and chronic graft vs. host disease (GvHD) 12 months
Secondary Quality of Life (QoL) Evaluation of QoL with EQ-5D-5L (Italian - Version 2) and FACT-Leu (Italian -Version 4) 12 months
Secondary Overall Survival (OS) 2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses) 36 months
Secondary 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) 36 months
Secondary Relapse Incidence (RI) 2 years after transplantation of the last patient included (this is intended to allow evaluations of all expected major molecular responses) 36 months
Secondary 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) 36 months
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