Clinical trial NCT04258943: Bosutinib in Pediatric Patients With Newly Diagnosed Chronic Phase or Resistant/Intolerant Ph + Chronic Myeloid Leukemia
Official title: A Phase I/II Study of Bosutinib in Pediatric Patients With Newly Diagnosed Chronic Phase or Resistant/Intolerant Ph + Chronic Myeloid Leukemia", Study ITCC-054/COG-AAML1921
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Philadelphia Chromosome Positive CML
Accelerated Phase Chronic Myelogenous Leukemia
Blastic Phase Chronic Myelogenous Leukemia
Chronic Phase Chronic Myelogenous Leukemia
Keywords: Philadelphia Chromosome Positive CML
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: Erasmus Medical Center
name: Dutch Childhood Oncology Group
name: Innovative Therapies for Children with Cancer
name: Pfizer
First posted: 2020-02-06
Enrollment: 60
Sex: ALL
Minimum age (years): 1
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 1-2, multicenter, international, single-arm, open-label study designed to identify a recommended dose of bosutinib administered orally once daily in pediatric patients with newly diagnosed chronic phase Ph+ CML (ND CML) and pediatric patients with Ph+CML who have received at least one prior TKI therapy (R/I CML), to preliminary estimate the safety and tolerability and efficacy, and to evaluate the PK of bosutinib in this patient population.

Detailed description: The Phase 1 part of the study employs a 6+4 design (no DLT in 6 patients or 1 DLT in 10 patients) and incorporates additional PK information before escalating to the next dose level. If there is unacceptable toxicity or if PK results have exceeded the acceptable exposure levels for the adult equivalent dose, further dose escalation will be prohibited. The Recommended Phase 2 Dose (RP2D) is defined as the dose that results in equivalent(approximately ±20% of the adult values) PK exposure to 500 mg/day in adults and with 0 of 6 or \<2 DLTs observed out of 10 evaluable patients with Ph+ CML and resistance or intolerance to prior TKI therapy. The phase 2 part of the study will enroll the following patient populations.

* Newly diagnosed (ND): newly diagnosed pediatric Ph + CML patients in chronic phase (CP)
* Resistant/intolerant (R/I): chronic phase or advanced (accelerated (AP) or blast phase (BP) pediatric Ph+ CML patients with resistance or intolerance to at least 1 prior TKI

Eligibility criteria: Inclusion Criteria:

Inclusion criteria Phase 1 (R/I patients only)

1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML\[2\] 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 BCRABL protein weight (P210, rarely P230 or P190).
2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines\[3\]) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI) The 2013 European LeukemiaNet guidelines\[3\] will be used to define suboptimal response and failure to prior TKI therapy. Details are provided in appendices 3 (intolerance or failure after one TKI) and 4 (Failure after more than one TKIs).

   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 \<18 years at day of attaining the informed consent.
4. Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients \>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) ≥ 60mL/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 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.
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 patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.
12. Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)
13. 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.

Exclusion criteria Phase 1 (R/I patients only)

Patients presenting with any of the following will not be included in the study:

1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. 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.
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 starting bosutinib treatment, or other antitumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to start of bosutinib treatment.
6. Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.
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 (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment.
9. Prior radiotherapy within 3 months prior to bosutinib treatment.
10. Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment.
11. Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment.
12. Hereditary bone marrow failure disorder.
13. Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment.
14. Major surgery within 14 days prior to bosutinib treatment (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.

Inclusion criteria Phase 2

* Resistant/Intolerant CML patients: R/I The inclusion criteria for the R/I patients in Phase 2 are identical to the Phase 1 inclusion criteria.
* Newly Diagnosed CML patients

  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 e13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCRABL protein weight (P210, rarely P230 or P190).
  2. 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. Diagnosis of CP CML will be defined as per Appendix 1.
  3. Age ≥1 and \<18 years at day of attaining the informed consent.
  4. Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients \>16 years of age (appendix 5).
  5. 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).
  6. 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.
  7. 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.
  8. Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.
  9. 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.
  10. Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)
  11. 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.

Exclusion criteria Phase 2

* Resistant/Intolerant (R/I) CML patients: The exclusion criteria for the R/I cohort in Phase 2 are identical to the Phase 1 exclusion criteria.
* Newly Diagnosed CML patients:

Patients presenting with any of the following will not be included in the study:

1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. Extramedullary disease only.
3. 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).
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 biologic agents within 7 days prior to bosutinib treatment.
6. Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7 days prior and/or concomitant to bosutinib treatment
7. Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment)
8. Hereditary bone marrow failure disorder.
9. Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).
10. 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.
11. Prolonged QTc (\>450 msec, average of triplicate ECGs).
12. Need for medications known to prolong the QT interval.
13. Pregnant and/or nursing women
14. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
15. Left ventricular ejection fraction \<50% or shortening fraction \<28%.
16. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.
17. Evidence of serious active or uncontrolled bacterial, fungal or viral infection.
18. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
19. 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.

Primary outcomes:
measure: 1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.
timeFrame: First 28 days of treatment (first cycle)
measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days); unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib:Time to Cmax (Tmax)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib: Apparent clearance (CL/F).
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: 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).
timeFrame: AE's will be collected from signing informed consent continuously during the study until 28 days after last dose (on average, 2 years).
measure: PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 & and before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib:Time to Cmax (Tmax)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib: Pre-dose concentration (Ctrough)
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: PK parameters of bosutinib: Apparent clearance (CL/F).
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing (each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Phase 2
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose & before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days); for unexpected and/or serious bosutinib-related AEs: when AE is detected
measure: Population PK parameters of bosutinib including clearance based on combined PK data from Phase 1 and Phase 2
timeFrame: Cycle 1 Day 14: pre-dose & 1, 3, 6, 8, & 24 hours post-dose and before day 15 dosing; Cycles 2, 3 & 4, Day 1: 24 hours post Day 14 dose & before Day 15 dosing(each cycle is 28 days);for unexpected and/or serious bosutinib-related AEs: when AE is detected
Secondary outcomes:
measure: AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;
timeFrame: From signing informed consent, continuously during the study until 28 days after last dose (on average 2 years).
measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table
timeFrame: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: QT interval
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: RR interval
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: PR interval
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: QRS duration
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: Performance status abnormalities
timeFrame: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)
measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response
timeFrame: Hematologic response:Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response
timeFrame: Screening; Cycles 2 to 7: start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days).]
measure: Time to the respective responses by line of therapy
timeFrame: Through study completion, a maximum of around 10 years
measure: Duration of the respective responses by line of therapy
timeFrame: Through study completion, a maximum of around 10 years
measure: Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2).
timeFrame: Through study completion, a maximum of around 10 years
measure: Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy
timeFrame: Through study completion, a maximum of around 10 years
measure: Occurrence of laboratory abnormalities of hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy tests values, as characterized by type, frequency, severity and timing summarized in an overview table
timeFrame: Screening; cycle 1 days 1, 8, 14, 22; cycles 2 to 7: at start of every cycle; cycle 8 and higher: every 3 cycles; End of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: QT interval
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: RR interval
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: PR interval
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: ECG abnormalities: QRS duration
timeFrame: For ECG: Screening; Cycle 1, day 14; Cycles 2, 3 and 4, day 1; end of treatment: within 28 days after last dose (each cycle is 28 days)
measure: Performance status abnormalities
timeFrame: Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)
Other outcomes:
measure: Parameters of bone metabolism and growth: linear growth
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: bone age
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys),
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys)
timeFrame: [Time Frame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale
timeFrame: Through study completion, a maximum of around 10 years
measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age.
timeFrame: Through study completion, a maximum of around 10 years
measure: Parameters of bone metabolism and growth: linear growth
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: bone age
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: bone mineral density of lumbar spine
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys)
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).
timeFrame: Screening; Start cycle 7; Cycle 8 and higher: every 12 months since start of therapy or every 6 months from cycle 7; end of treatment: within 28 days after last dose (each cycle is 28 days).
measure: Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale.
timeFrame: Through study completion, a maximum of around 10 years
measure: Patient and/or caregiver-reported assessment of the taste and ability to swallow the medicine, as measured by the Palatability Questionnaire for Bosutinib in patients aged 4-18 years of age.
timeFrame: Through study completion, a maximum of around 10 years
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Phoenix
country: United States
facility: Phoenix Childrens Hospital
state: Arizona
city: Little Rock
country: United States
facility: Arkansas Children's Hospital
state: Arkansas
city: Downey
country: United States
facility: Kaiser Permanente Downey Medical Center
state: California
city: Loma Linda
country: United States
facility: Loma Linda University Medical Center
state: California
city: Oakland
country: United States
facility: Kaiser Permanene-Oakland
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: Palo Alto
country: United States
facility: Lucile Packard Children's Hospital Stanford University
state: California
city: Wilmington
country: United States
facility: Alfred I duPont Hospital for Children
state: Delaware
city: Fort Myers
country: United States
facility: Golisano Children's Hospital of Southwest Florida
state: Florida
city: Gainesville
country: United States
facility: University of Florida Health Science Center - Gainesville
state: Florida
city: Orlando
country: United States
facility: Nemours Children's Hospital
state: Florida
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Des Moines
country: United States
facility: Blank Children's Hospital
state: Iowa
city: Louisville
country: United States
facility: Norton Children's Hospital
state: Kentucky
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center
state: Massachusetts
city: Kansas City
country: United States
facility: Children's Mercy Hospitals and Clinics
state: Missouri
city: Las Vegas
country: United States
facility: Children's Specialty Center of Nevada II
state: Nevada
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Morristown
country: United States
facility: Morristown Medical Center
state: New Jersey
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New Hyde Park
country: United States
facility: The Steven and Alexandra Cohen Children's Medical Center of New York
state: New York
city: Charlotte
country: United States
facility: Carolinas Medical Center/Levine Cancer Institute
state: North Carolina
city: Akron
country: United States
facility: Children's Hospital Medical Center of Akron
state: Ohio
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Cleveland
country: United States
facility: Rainbow Babies and Childrens Hospital
state: Ohio
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Bethlehem
country: United States
facility: Lehigh Valley Hospital-Cedar Crest
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Knoxville
country: United States
facility: East Tennessee Childrens Hospital
state: Tennessee
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt University/Ingram Cancer Center
state: Tennessee
city: Austin
country: United States
facility: Dell Children's Medical Center of Central Texas
state: Texas
city: Dallas
country: United States
facility: UT Southwestern/Simmons Cancer Center-Dallas
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Houston
country: United States
facility: M D Anderson Cancer Center
state: Texas
city: Falls Church
country: United States
facility: Inova Fairfax Hospital
state: Virginia
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Milwaukee
country: United States
facility: Children's Hospital of Wisconsin
state: Wisconsin
Study officials:
References:
citation: Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, Cervantes F, Clark RE, Cortes JE, Guilhot F, Hjorth-Hansen H, Hughes TP, Kantarjian HM, Kim DW, Larson RA, Lipton JH, Mahon FX, Martinelli G, Mayer J, Muller MC, Niederwieser D, Pane F, Radich JP, Rousselot P, Saglio G, Saussele S, Schiffer C, Silver R, Simonsson B, Steegmann JL, Goldman JM, Hehlmann R. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood. 2013 Aug 8;122(6):872-84. doi: 10.1182/blood-2013-05-501569. Epub 2013 Jun 26.