BOSUTINIB for Chronic myeloid leukemia

Inclusion criteria

• {"criterion_text":"- Phase 1 and Phase 2 (R/I patients): Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML at either time of initial CML diagnosis or at time of study screening: 1. Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases. 2. 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. 3. 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).\n- Phase 1 and Phase 2 (R/I patients): Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.\n- Phase 1 and Phase 2 (R/I patients): 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 patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.\n- Phase 1 and Phase 2 (R/I patients): Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations).\n- Phase 1 and Phase 2 (R/I patients): Patients (including legally acceptable representative for minors where applicable) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.\n- Phase 2 (Newly Diagnosed CML patients): Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML at either time of initial CML diagnosis or at time of study screening: 1. Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases. 2. 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. 3. 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 e13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCR- ABL protein weight (P210, rarely P230 or P190).\n- Phase 2 (Newly Diagnosed CML patients): Newly diagnosed CP Ph+ CML of ≤ 6 months (from initial diagnosis) without any previous TKI treatment (with the exception of hydroxyurea and/or anagrelide) for CML.\n- Phase 2 (Newly Diagnosed CML patients): Age ≥1 and <18 years at day of attaining the informed consent.\n- Phase 2 (Newly Diagnosed CML patients): Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age.\n- Phase 2 (Newly Diagnosed CML patients): Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR.\n- Phase 2 (Newly Diagnosed CML patients): Adequate liver function, including: 1. AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver; 2. Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.\n- Phase 1 and Phase 2 (R/I patients): 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): 1. The 2013 European LeukemiaNet guidelines will be used to define suboptimal response and failure to prior TKI therapy. 2. 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.\n- Phase 2 (Newly Diagnosed CML patients): Able to reliably swallow whole capsules, whole tablets; or drug added to a suitable foodstuff (from capsule contents, added to either apple sauce or yogurt); or tablets and/or capsules dissolved as an oral syringe drinking solution, or tablets dissolved and administered by NG tube when needed.\n- Phase 2 (Newly Diagnosed CML patients): Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.\n- Phase 2 (Newly Diagnosed CML patients): 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 patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.\n- Phase 2 (Newly Diagnosed CML patients): Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations).\n- Phase 2 (Newly Diagnosed CML patients): Patients (including legally acceptable representative for minors where applicable) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.\n- Phase 1 and Phase 2 (R/I patients): Age ≥1 and <18 years at day of attaining the informed consent.\n- Phase 1 and Phase 2 (R/I patients): Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age.\n- Phase 1 and Phase 2 (R/I patients): Adequate bone marrow function: 1. For second-line and third-line CP CML patients: a. Absolute neutrophil count >1000/mm3 (>1.0 x109/L); b. Platelets ≥75,000/mm3 (≥75 x109/L) without any platelet transfusions during the preceding 7 days. 2. For fourth-line CP and all for all AP/BP CML patients: a. Absolute neutrophil count >500/mm3 (>0.5 x109/L); b. Platelets ≥50,000/mm3 (≥50 x109/L) without any platelet transfusions during the preceding 7 days.\n- Phase 1 and Phase 2 (R/I patients): Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR.\n- Phase 1 and Phase 2 (R/I patients): Adequate liver function, including: 1. AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver; 2. Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.\n- Phase 1 and Phase 2 (R/I patients): 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.\n- Phase 1 and Phase 2 (R/I patients): Able to reliably swallow whole capsules, whole tablets; or drug added to a suitable foodstuff (from capsule contents, added to either apple sauce or yoghurt); or tablets and/or capsules dissolved in water as an oral syringe drinking solution, or tablets dissolved and administered by NG tube when needed."}

Exclusion criteria

• {"criterion_text":"- Phase 1 and Phase 2 (R/I patients): Diagnosis of primary Ph+ acute lymphoblastic leukemia.\n- Phase 1 and Phase 2 (R/I patients): Pregnant and/or nursing women.\n- Phase 1 and Phase 2 (R/I patients): Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.\n- Phase 1 and Phase 2 (R/I patients): In patients with AP/BP 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.\n- Phase 1 and Phase 2 (R/I patients): Left ventricular ejection fraction <50% or shortening fraction <28%.\n- Phase 1 and Phase 2 (R/I patients): Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.\n- Phase 1 and Phase 2 (R/I patients): Evidence of serious active or uncontrolled bacterial, fungal or viral infection.\n- Phase 1 and Phase 2 (R/I patients): Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.\n- Phase 1 and Phase 2 (R/I patients): 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.\n- Phase 2 (Newly Diagnosed CML patients): Diagnosis of primary Ph+ acute lymphoblastic leukemia.\n- Phase 2 (Newly Diagnosed CML patients): Extramedullary disease only.\n- Phase 1 and Phase 2 (R/I patients): Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment.\n- Phase 2 (Newly Diagnosed CML patients): 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).\n- Phase 2 (Newly Diagnosed CML patients): Any prior treatment with a TKI or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide).\n- Phase 2 (Newly Diagnosed CML patients): Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Extramedullary disease only.\n- Phase 2 (Newly Diagnosed CML patients): Use of strong or moderate CYP3A4 inhibitors and inducers within 7 days prior and/or concomitant to bosutinib treatment.\n- Phase 2 (Newly Diagnosed CML patients): Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment).\n- Phase 2 (Newly Diagnosed CML patients): Hereditary bone marrow failure disorder.\n- Phase 2 (Newly Diagnosed CML patients): Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).\n- Phase 2 (Newly Diagnosed CML patients): History of clinically significant or uncontrolled cardiac disease, including: 1. History of or active congestive heart failure; 2. Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); 3. Diagnosed or suspected congenital or acquired prolonged QT syndrome; 4 History of prolonged QTc.\n- Phase 2 (Newly Diagnosed CML patients): Prolonged QTc (>450 msec, average of triplicate ECGs).\n- Phase 1 and Phase 2 (R/I patients): Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment.\n- Phase 2 (Newly Diagnosed CML patients): Need for medications known to prolong the QT interval.\n- Phase 2 (Newly Diagnosed CML patients): Pregnant and/or nursing women.\n- Phase 2 (Newly Diagnosed CML patients): Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.\n- Phase 2 (Newly Diagnosed CML patients): Left ventricular ejection fraction <50% or shortening fraction <28%.\n- Phase 1 and Phase 2 (R/I patients): 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).\n- Phase 2 (Newly Diagnosed CML patients): Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.\n- Phase 2 (Newly Diagnosed CML patients): Evidence of serious active or uncontrolled bacterial, fungal or viral infection.\n- Phase 2 (Newly Diagnosed CML patients): Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.\n- Phase 2 (Newly Diagnosed CML patients): 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.\n- Phase 1 and Phase 2 (R/I patients): Any prior treatment with a TKI within 7 days prior to starting bosutinib treatment, or other anti- tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to start of bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Hereditary bone marrow failure disorder.\n- Phase 1 and Phase 2 (R/I patients): Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Use of strong or moderate CYP3A4 inhibitors and inducers within 7 days prior and/or concomitant to bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Prior radiotherapy within 3 months prior to bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Known hypersensitivity to the active substance or to any of the excipients\n- Phase 2 (Newly Diagnosed CML patients): Known hypersensitivity to the active substance or to any of the excipients\n- Phase 1 and Phase 2 (R/I patients): Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment.\n- Phase 1 and Phase 2 (R/I patients): Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).\n- Phase 1 and Phase 2 (R/I patients): History of clinically significant or uncontrolled cardiac disease, including: 1. History of or active congestive heart failure; 2. Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); 3. Diagnosed or suspected congenital or acquired prolonged QT syndrome; 4 History of prolonged QTc\n- Phase 1 and Phase 2 (R/I patients): Prolonged QTc (>450 msec, average of triplicate ECGs).\n- Phase 1 and Phase 2 (R/I patients): Need for medications known to prolong the QT interval."}

Primary endpoints

• {"endpoint_text":"- Phase 1: Incidence and severity of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.","definition_or_measurement_approach":"DLTs assessed during the first 28 days of treatment (safety assessment window)."}
• {"endpoint_text":"- Phase 1: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ), pre-dose concentration (Ctrough) and apparent clearance (CL/F).","definition_or_measurement_approach":"Standard PK sampling to derive Cmax, Tmax, AUCτ, Ctrough and CL/F from plasma concentrations."}
• {"endpoint_text":"- Phase 2: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy (pooled across ND and R/I CML patients and by line of therapy).","definition_or_measurement_approach":"Adverse events collected and graded per CTCAE v4.03; characterized by type, frequency, severity, timing, seriousness and relationship to study drug."}
• {"endpoint_text":"- Phase 2: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time zero the dosing interval (AUCτ), predose concentration (Ctrough) and apparent clearance CL/F.","definition_or_measurement_approach":"Phase 2 PK sampling to estimate Cmax, Tmax, AUCτ, Ctrough and CL/F."}
• {"endpoint_text":"- Phase 2: Population PK parameters of bosutinib including clearance and volume of distribution based on combined PK data from Phase 1 and Phase 2.","definition_or_measurement_approach":"Population PK modelling combining Phase 1 and Phase 2 PK data to estimate clearance and volume of distribution."}

Secondary endpoints

• {"endpoint_text":"- Phase 1: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;","definition_or_measurement_approach":"AEs collected and graded per CTCAE v4.03."}
• {"endpoint_text":"- Phase 1: Laboratory abnormalities as characterized by type, frequency, severity and timing;","definition_or_measurement_approach":"Laboratory tests monitored and abnormalities summarized by type, frequency, severity and timing."}
• {"endpoint_text":"- Phase 1: ECG and performance status abnormalities","definition_or_measurement_approach":"ECG and performance status assessments documented and summarized."}
• {"endpoint_text":"- Phase 1: Overall cumulative disease response: 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.","definition_or_measurement_approach":"Hematologic, cytogenetic and molecular response assessments per protocol definitions (CHR, MCyR, CCyR, MMR, deep molecular response)."}
• {"endpoint_text":"- 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.","definition_or_measurement_approach":"Response rates (CHR, MCyR, CCyR, MMR, deep molecular response) by line of therapy per protocol definitions."}
• {"endpoint_text":"- Phase 2: Time to and duration of the respective responses by line of therapy.","definition_or_measurement_approach":"Time-to-response and duration measured from treatment start to response and from response to relapse/last follow-up."}
• {"endpoint_text":"- Phase 2: Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy.","definition_or_measurement_approach":"EFS measured including time to transformation to accelerated or blast phase."}
• {"endpoint_text":"- Phase 2: Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy.","definition_or_measurement_approach":"OS measured from treatment start to death from any cause."}
• {"endpoint_text":"- Phase 2: Laboratory abnormalities as characterized by type, frequency, severity and timing (pooled across ND and R/I CML and by line of therapy).","definition_or_measurement_approach":"Laboratory abnormalities summarized by type, frequency, severity and timing pooled across groups."}
• {"endpoint_text":"- Phase 2: ECG and performance status abnormalities.","definition_or_measurement_approach":"ECG and performance status changes documented and summarized."}
• {"endpoint_text":"- Phase 2: Relationships between PK parameters of bosutinib and key safety and efficacy metrics.","definition_or_measurement_approach":"PK/PD and PK-safety analyses to assess associations between PK parameters and safety/efficacy outcomes."}

France

Earliest CTIS Part Ii Submission Date

16-01-2024

Latest Decision Or Authorization Date

03-09-2024

Processing Time Days

231

Number Of Sites

4

Number Of Participants

4

Italy

Earliest CTIS Part Ii Submission Date

16-01-2024

Latest Decision Or Authorization Date

27-09-2024

Processing Time Days

255

Number Of Sites

3

Number Of Participants

12

Germany

Earliest CTIS Part Ii Submission Date

16-01-2024

Latest Decision Or Authorization Date

21-08-2024

Processing Time Days

218

Number Of Sites

1

Number Of Participants

1

Netherlands

Earliest CTIS Part Ii Submission Date

16-01-2024

Latest Decision Or Authorization Date

08-05-2025

Processing Time Days

478

Number Of Sites

2

Number Of Participants

10

Spain

Earliest CTIS Part Ii Submission Date

16-01-2024

Latest Decision Or Authorization Date

09-12-2025

Processing Time Days

693

Number Of Sites

2

Number Of Participants

3

Primary sponsor

Full Name

Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

Organisation Type

Hospital/Clinic/Other health care facility

Country Of Registered Address

Netherlands