Bosutinib in Pediatric Patients With Newly Diagnosed Chronic Phase or Resistant/Intolerant Ph + Chronic Myeloid Leukemia

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.

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.