Chronic Myelogenous Leukaemia Clinical Trial
Official title:
Multicenter, Open-label Single Arm Phase II Study Testing the Tolerability and the Efficacy of Bosutinib step-in Dosing in Chronic Phase CML Patients Intolerant or Refractory to Previous Imatinib, Nilotinib or Dasatinib Therapy
Bosutinib is a 2nd generation tyrosine kinase inhibitor that has shown promising results from first up to fourth line treatment in patients with in chronic phase of chronic myelogenous leukaemia. Most patients discontinuing the treatment with Bosutinib do so because of side effects occuring early after starting the treatment. A step in dosing scheme could improve these early toxicities. The aim of this study therefore is to demonstrate that temporary lowering of the Bosutinib dose during early treatment may help to reduce or prevent side effects while preserving efficacy.
Objectives:
The objective of the BODO trial is to assess the tolerability and efficacy of a step-in
dosing concept of the dual SRC-ABL kinase inhibitor Bosutinib in CP-CML patients who either
developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as
1st line therapy.
Primary endpoint:
• Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) within the
first 6 months of treatment
Secondary endpoints:
- Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) at month 6, 12
and 24
- Efficacy parameters: CCyR, MMR, MR4 and MR4.5 rate at month 3, 6, 12, 18 and 24
- Patient-reported outcome measures (QoL)
- Progression-free survival (PFS)
- Overall survival (OS)
- The rate of emerging mutations during Bosutinib treatment
Exploratory endpoints linked to substudies:
Vascular biology substudy:
- Effects of previous therapy on the baseline vascular risk profile (i.e. Nilotinib- vs.
Dasatinib-pre-treatment)
- Biological and clinical surrogates for vascular alterations during Bosutinib therapy at
baseline, months 6, 12, and 24
Pharmacokinetic (PK), pharmacodynamic (PD) and immunology sub- study:
- Correlation of PK with response and toxicity
- Correlation of PK with PD (i.e. phosphoproteomic changes) in immune cell populations
- Correlation of PD changes in immune cell populations with response
- Evaluation of the effects of Bosutinib on frequency and phenotype of immune cells
- Evaluation whether Bosutinib-induced changes of immune cells correlate to response
Ultra-deep next-generation sequencing (UD-NGS) and telomere substudy:
- Documentation of subclone evolution or elimination during Bosutinib treatment
- Evaluation of telomere length in leukemic and non-leukemic cells as a prognostic
indicator for depth and kinetics of response to and tolerability of Bosutinib
;