Chronic Myeloid Leukemia MedDRA version: 21.0 Level: LLT Classification code 10009700 Term: CML System Organ Class: 100000004864
Conditions
Interventions
Trade Name: bosulif
Product Name: Bosulif
Pharmaceutical Form: Tablet
INN or Proposed INN: Bosutinib
Current Sponsor code: Bosutinib
Other descriptive name: BOSUTINIB MONOHYDRATE
Concentration unit: m
Sponsors
Erasmus MC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML at either time of initial CML diagnosis or at time of study screening: -Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases. -Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I-FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted. -Qualitative RT-PCR should be performed on RNA extracted from freshly collected bone marrow or peripheral blood cells. It identifies the transcript type, either e14a2 or 13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCR-ABL protein weight (P210, rarely P230 or P190). 2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI). • The 2013 European LeukemiaNet guidelines will be used to define suboptimal response and failure to prior TKI therapy. Details are provided in appendices 3 and 4. -Intolerance to prior TKI therapy will be determined by the treating investigator, but generally applies to patients who are unable to receive standard or reduced doses of a TKI due to significant drug-related toxicity and/or when the drug-related toxicity is not responding to appropriate medical management. Patients who enroll as a result of intolerance to prior TKI therapy may have any level of response to their prior therapy and still be eligible. 3. Age =1 and 16 years of age (appendix 5). 5. Adequate bone marrow function: -For second-line and third-line CP CML patients: -Absolute neutrophil count >1000/mm3 (>1.0 x109/L); -Platelets =75,000/mm3 (=75 x109/L) without any platelet transfusions during the preceding 7 days. -For fourth-line CP and all for all AP/BP CML patients: -Absolute neutrophil count >500/mm3 (>0.5 x109/L); -Platelets =50,000/mm3 (=50 x109/L) without any platelet transfusions during the preceding 7 days. 6. Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) = 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR (see appendix 11). 7. Adequate liver function, including: • AST/ALT =2.5 x upper limit normal (ULN) or =5 x ULN if attributable to disease involvement of the liver; • Total bilirubin =1.5 x ULN unless the patient has documented Gilbert syndrome. 8. Recovered to Grade 0-1, or to baseline, from any acute toxicities of prior chemotherapy, immunotherapy, radiotherapy, differentiation therapy, or biologic therapy, with the exception of alopecia 9. Able to reliably swallow whole capsules, whole tablets, or drug substance (from capsule contents) added to a suitable foodstuff. 10. Serum/urine pregnancy test (for all girls = age of menarche) negative at screening. 11. Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A patie
Exclusion criteria
Exclusion criteria: 1. Diagnosis of primary Ph+ acute lymphoblastic leukemia. 2. In patients with AP/BC CML: leptomeningeal leukemia, defined as positive cytology on lumbar puncture (including both CNS2 and CNS3 status), or clinical symptoms or signs present. This assessment is not required for inclusion of CP CML patients. 3. Extramedullary disease only. 4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. This exclusion criterion is based on whether there is a known history of these mutations at the time of study entry. If these mutations become evident during the study the patient will go off study). 5. Any prior treatment with a TKI within 7 days prior to study entry, or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to study entry. 6. Prior growth factors or biologic agents within 7 days prior to study entry. 7. Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7 days prior and/or concomitant to bosutinib treatment 8. Use of proton pump inhibitors within 7 days prior and/or concomitant to bosutinib treatment. 9. Prior radiotherapy within 3 months prior to study entry. 10. Allogeneic stem cell transplantation within 3 months prior to study entry. 11. Donor lymphocyte infusion (DLI) within 1 month prior to study entry. 12. Hereditary bone marrow failure disorder. 13. Graft-versus-host disease (GVHD) within 60 days prior to study entry. 14. Major surgery within 14 days prior to study entry (recovery from any previous surgery should be complete before day 1). 15. History of clinically significant or uncontrolled cardiac disease, including: • History of or active congestive heart failure; • Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); • Diagnosed or suspected congenital or acquired prolonged QT syndrome; • History of prolonged QTc. 16. Prolonged QTc (>450 msec, average of triplicate ECGs). 17. Need for medications known to prolong the QT interval. 18. Pregnant and/or nursing women 19. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval. 20. Left ventricular ejection fraction <50% or shortening fraction <28%. 21. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug. 22. Evidence of serious active or uncontrolled bacterial, fungal or viral infection. 23. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness. 24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study. For phase 2 ND patients: 1. Diagnosis of primary Ph+ ALL 2. EMD only. 3. Documented prior history of T315I or V299L BCR-ABL1 mutations 4. Any prior treatment with a TKI or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) 5. Prior growth factors or biologi
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary Objective phase 1: - To determine the Recommended Phase 2 Dose (RP2D) of bosutinib for R/I (RP2DR/I) and ND chronic phase (RP2DND) pediatric patients with CML, based on the pharmacokinetic, safety and tolerability profile of bosutinib observed at various dose levels in pediatric patients with CML who are resistant or intolerant to prior TKI therapy. Primary Objectives phase 2: - To assess the PK of bosutinib at the RP2DND and RP2DR/I in pediatric patients with ND or R/I Ph + CML. - To assess the population PK of bosutinib. - To assess the pooled safety and tolerability profile (based on AEs) of bosutinib in pediatric patients with ND and R/I Ph+ CML. ;Secondary Objective: Secondary Objectives phase 1: - To evaluate the overall safety profile during the first cycle of therapy (28 days) - To evaluate the safety and tolerability profile during the prolonged exposure to bosutinib - To preliminary evaluate the anti-leukemic activity in pediatric patients with Philadelphia chromosome positive CML following resistance or intolerance to one or more TKIs Secondary Objectives phase 2: -To describe the clinical efficacy of bosutinib in pediatric patients with newly diagnosed Ph+ CML in chronic phase; -To describe the clinical efficacy of bosutinib in pediatric patients with Ph + CML in any phase of disease following resistance or intolerance to one or more TKIs -To assess other safety parameters of bosutinib -To assess the relationship between the PK of bosutinib and key safety and efficacy metrics Exploratory: -Evaluate effects on growth bone metabolism; -Assess changes in GI symptoms during therapy -Assess palatability of bosutinib ;Primary end point(s): PHASE 1: Primary endpoints - Incidence and severity of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment. - PK parameters of bosutinib: Maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from t | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Phase 1: - AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy; -Laboratory abnormalities as characterized by type, frequency, severity and timing; -PK parameters of bosutinib: t1/2, tmax, CL/F, Vss/F will be assessed if possible; -Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR, defined as CCyR plus PCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecularly undetectable disease (definitions in appendix 2). Phase 2: -Overall cumulative disease response by the line of therapy: complete hematologic response (CHR), major cytogenetic response (MCyR, defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]), CCyR, major molecular response (MMR) and deep molecular response. - Time to and duration of the respective responses by line of therapy. - Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2). - Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy . - Laboratory abnormalities as characterized by type, frequency, severity and timing (pooled across ND and R/I CML and by line of therapy). - ECG and performance status abnormalities - Relationships between PK parameters of bosutinib ;Timepoint(s) of evaluation of this end point: 3-5 years | — |
Countries
Australia, Czech Republic, Denmark, France, Germany, Ireland, Israel, Italy, Netherlands, Spain, Switzerland, United States
Contacts
Public ContactProf. Dr. CM Zwaan
Erasmus MC
Outcome results
None listed