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

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Children's Oncology Group

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Updated on 19 February 2024

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absolute neutrophil count

renal function

gilbert's syndrome

growth factor

heart failure

ejection fraction

stem cell transplantation

myeloid leukemia

lymphoid leukemia

graft versus host disease

chronic myeloid leukemia

hydroxyurea

karnofsky performance status

tyrosine kinase inhibitor

major surgery

bosutinib

tyrosine

leukemia

immunodeficiency

platelet transfusion

schwartz

philadelphia chromosome

anagrelide

molecular diagnosis

chronic phase chronic myeloid leukemia

platelet transfusions

biologic agent

immunodeficiencies

t315i mutation

pediatric

differentiation therapy

hair thinning

cml - philadelphia chromosome

chromosome banding

blastic phase chronic myeloid leukemia

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 95% CI for DLT-risk with The phase 2 part of the study will enroll the following patient populations.

Newly diagnosed (ND): newly diagnosed Ph + CML patients in chronic phase (CP) Bosutinib in pediatric CML: ITCC-054/AAML1921
Resistant/intolerant (R/I): chronic phase or advanced (accelerated (AP) or blast phase (BP) Ph+ CML patients with resistance or intolerance to at least 1 prior TKI.

Details

Condition	Blast Crisis, chronic phase chronic myelogenous leukemia, Accelerated Phase Chronic Myelogenous Leukemia, Philadelphia Chromosome Positive CML
Age	1-18 years
Treatment	Bosutinib
Clinical Study Identifier	NCT04258943
Sponsor	Children's Oncology Group
Last Modified on	19 February 2024

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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
	European LeukemiaNet guidelines[3] will be used to define suboptimal
	response and failure to prior TKI therapy. Details are provided in appendices
	(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
	\. 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 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
	\. 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)
	\. 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
	\. 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
	\. 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
	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
	\. 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
	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)
	\. 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
	documented Gilbert syndrome
	\. 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
	Exclusion criteria Phase 2
	Resistant/Intolerant CML patients: R/I 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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karnofsky performance status

tyrosine kinase inhibitor

philadelphia chromosome

anagrelide

molecular diagnosis

chronic phase chronic myeloid leukemia

platelet transfusions

differentiation therapy

hair thinning

cml - philadelphia chromosome

chromosome banding

blastic phase chronic myeloid leukemia

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