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

  • STATUS
    Recruiting
  • End date
    Dec 10, 2023
  • participants needed
    60
  • sponsor
    Children's Oncology Group
Updated on 10 July 2022
chronic myeloid leukemia
stem cell transplantation
graft versus host disease
myeloid leukemia
lymphoid leukemia
immunodeficiency
tyrosine
philadelphia chromosome
hydroxyurea
absolute neutrophil count
ejection fraction
biologic agent
bosutinib
heart failure
growth factor
leukemia
major surgery
anagrelide

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.

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

Details
Condition Philadelphia Chromosome Positive CML, Accelerated Phase Chronic Myelogenous Leukemia, Blastic Phase Chronic Myelogenous Leukemia, Chronic Phase Chronic Myelogenous Leukemia
Treatment bosutinib
Clinical Study IdentifierNCT04258943
SponsorChildren's Oncology Group
Last Modified on10 July 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Inclusion criteria Phase 1 (R/I patients only)
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 (IFISH) 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)
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
Age ≥1 and <18 years at day of attaining the informed consent
standard or reduced doses of a TKI due to significant drug-related toxicity
Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age (appendix 5)
and/or when the drug-related toxicity is not responding to appropriate medical
Adequate bone marrow function
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
Absolute neutrophil count >1000/mm3 (>1.0 x109/L); Platelets ≥75,000/mm3 (≥75
eligible
Absolute neutrophil count >500/mm3 (>0.5 x109/L); Platelets ≥50,000/mm3 (≥50
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)
For second-line and third-line CP CML patients
Adequate liver function, including
AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease
x109/L) without any platelet transfusions during the preceding 7 days
involvement of the liver; Total bilirubin ≤1.5 x ULN unless the patient has
For fourth-line CP and all for all AP/BP CML 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
x109/L) without any platelet transfusions during the preceding 7 days
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
Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening
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
Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)
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
documented Gilbert syndrome
Exclusion criteria Phase 1 (R/I patients only)
Patients presenting with any of the following will not be included in the
study
Diagnosis of primary Ph+ acute lymphoblastic leukemia
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
Extramedullary disease only
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)
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
Prior growth factors or biologic agents within 7 days prior to bosutinib treatment
Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7 days prior and/or concomitant to bosutinib treatment
Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment
Prior radiotherapy within 3 months prior to bosutinib treatment
Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment
Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment
Hereditary bone marrow failure disorder
Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment
Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1)
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
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
Age ≥1 and <18 years at day of attaining the informed consent
Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age (appendix 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)
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
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
Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening
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
Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)
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
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
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 (IFISH) 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)
Prolonged QTc (>450 msec, average of triplicate ECGs)
Need for medications known to prolong the QT interval
Pregnant and/or nursing women
Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval
Left ventricular ejection fraction <50% or shortening fraction <28%
Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug
Evidence of serious active or uncontrolled bacterial, fungal or viral infection
Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness
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
documented Gilbert syndrome
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
Diagnosis of primary Ph+ acute lymphoblastic leukemia
Extramedullary disease only
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)
Any prior treatment with a TKI or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide)
Prior growth factors or biologic agents within 7 days prior to bosutinib treatment
Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7 days prior and/or concomitant to bosutinib treatment
Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment)
Hereditary bone marrow failure disorder
Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1)
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
Prolonged QTc (>450 msec, average of triplicate ECGs)
Need for medications known to prolong the QT interval
Pregnant and/or nursing women
Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval
Left ventricular ejection fraction <50% or shortening fraction <28%
Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug
Evidence of serious active or uncontrolled bacterial, fungal or viral infection
Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness
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
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