Back to results

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

Primary Purpose

Philadelphia Chromosome Positive CML, Accelerated Phase Chronic Myelogenous Leukemia, Blastic Phase Chronic Myelogenous Leukemia

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Bosutinib

About this trial

This is an interventional treatment trial for Philadelphia Chromosome Positive CML focused on measuring Philadelphia Chromosome Positive CML

Eligibility Criteria

1 Year - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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 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
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 (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).
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:

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.

Sites / Locations

Children's Hospital of Alabama
Phoenix Childrens Hospital
Arkansas Children's Hospital
Kaiser Permanente Downey Medical Center
Loma Linda University Medical Center
Kaiser Permanene-Oakland
Children's Hospital of Orange County
Lucile Packard Children's Hospital Stanford University
Alfred I duPont Hospital for Children
Golisano Children's Hospital of Southwest Florida
University of Florida Health Science Center - Gainesville
Nemours Children's Hospital
Kapiolani Medical Center for Women and Children
Riley Hospital for Children
Blank Children's Hospital
Norton Children's Hospital
Johns Hopkins University/Sidney Kimmel Cancer Center
Dana-Farber/Harvard Cancer Center
Children's Mercy Hospitals and Clinics
Children's Specialty Center of Nevada II
Hackensack University Medical Center
Morristown Medical Center
Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital
Roswell Park Cancer Institute
The Steven and Alexandra Cohen Children's Medical Center of New York
Carolinas Medical Center/Levine Cancer Institute
Children's Hospital Medical Center of Akron
Cincinnati Children's Hospital Medical Center
Rainbow Babies and Childrens Hospital
Nationwide Children's Hospital
Lehigh Valley Hospital-Cedar Crest
Children's Hospital of Philadelphia
Children's Hospital of Pittsburgh of UPMC
Rhode Island Hospital
East Tennessee Childrens Hospital
Saint Jude Children's Research Hospital
Vanderbilt University/Ingram Cancer Center
Dell Children's Medical Center of Central Texas
UT Southwestern/Simmons Cancer Center-Dallas
Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
M D Anderson Cancer Center
Inova Fairfax Hospital
Children's Hospital of The King's Daughters
Seattle Children's Hospital
Children's Hospital of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single Agent Bosutinib

Arm Description

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). A treatment cycle is defined as 28 days

Outcomes

Primary Outcome Measures

1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.

Data from Phase 1; Dose-limiting toxicities determined as adverse events occurring in the first cycle (28 days) of treatment, which are attributable to bosutinib. Assessment will be done according the following DLT definition: Non-hematologic AEs: grade ≥3 toxicities, except those that have not been optimally treated; any grade ≥2 toxicity requiring discontinuation/interruption for ≥7 days during the first 28 days of treatment; clinically significant laboratory abnormalities grade ≥3 or lasting ≥7 days despite optimal treatment Hematologic AEs: grade 4 neutropenia or thrombocytopenia lasting ≥7 days (not explained by persistent leukemia).

PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Data from Phase 1; Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time postdose and actual dose will be used for all calculations.

PK parameters of bosutinib:Time to Cmax (Tmax)

Data from Phase 1; Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.

PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Data from Phase 1; Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.

PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Data from Phase 1; Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post dose and actual dose will be used for all calculations.

PK parameters of bosutinib: Apparent clearance (CL/F).

Data from Phase 1; Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

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).

Data from Phase 2; AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).

PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Data from Phase 2; subset of newly diagnosed patients. Maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

PK parameters of bosutinib:Time to Cmax (Tmax)

Data from Phase 2; subset of newly diagnosed patients. Time to maximum plasma concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.]

PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Data from Phase 2; subset of newly diagnosed patients. Area under the plasma concentration versus time curve from time zero to the dosing interval calculated from the plasma concentration-time data by linear trapezoidal rule during the ascending phase and log trapezoidal rule during the descending phase.

PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Data from Phase 2; subset of newly diagnosed patients. Pre-dose concentration of bosutinib calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

PK parameters of bosutinib: Apparent clearance (CL/F).

Data from Phase 2; subset of newly diagnosed patients. Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Phase 2

Data from Phase1 and Phase 2. Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Data from Phase1 and Phase 2. Volume of distribution are calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations.

Population PK parameters of bosutinib including clearance based on combined PK data from Phase 1 and Phase 2

Data from Phase1 and Phase 2. Clearance is calculated from the plasma concentration-time data using noncompartmental analysis (NCA). The calculated elapsed time post-dose and actual dose will be used for all calculations

Secondary Outcome Measures

AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;

Data from Phase 1. AEs will be graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 and coded using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment emergent AEs (TEAEs) are defined as those with initial onset or increasing in severity after the first dose of study medication. Endpoints include maximum toxicity, time to first event (time from first dose to date of first event including only non-partial dates), duration of any stage/grade event (time from start date to stop date including only non-partial dates).]

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

Data from Phase 1. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6

ECG abnormalities: QT interval

Data from Phase 1. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points. Kamofsky or Lansky performance score is collected to evaluate performance status.

ECG abnormalities: RR interval

ECG abnormalities: PR interval

ECG abnormalities: QRS duration

Performance status abnormalities

Data from Phase 1. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status

Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Data from Phase 1. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).]

Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Data from Phase 2. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).

Time to the respective responses by line of therapy

Time to response is defined as the time period from start of treatment with bosutinib to first response, unconfirmed for molecular and cytogenetic and confirmed for hematologic. Patients without events are censored at the last molecular, cytogenetic, or hematologic assessment where response could be assessed for the respective endpoint

Duration of the respective responses by line of therapy

Data from Phase 2. Duration of response is defined is defined as the time period from the date of the earliest demonstration of a response until the earliest date of confirmed loss of that response.

Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2).

Data from Phase 2. EFS is defined as the interval from the date of first dose of bosutinib until the earlier date of EFS events. Patients without the event will be censored at the last evaluation date.

Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy

Data from Phase 2. OS or survival time is defined as the interval from the date of first dose of bosutinib until the date of death due to any cause. Patients without the event will be censored at the last evaluation date

Data from Phase 2. Pooled across ND and R/I CML and by line of therapy. Test abnormalities in hematology, blood chemistry, liver functions, coagulation, HbsAg, urinalysis and pregnancy test and contraception will be recorded. Severity of laboratory test abnormalities will be graded using NCI CTCAE version, v4.03. For those laboratory abnormalities without CTCAE grade definitions, results will be categorized as normal, abnormal or not done. Coagulation and HBsAG only tested at screening. Urinalysis and pregnancy test and contraception check not tested at days 8, 14, 15 and 22 of cycle 1. Urinalysis not performed at beginning of cycles 2, 3, 5 and 6

ECG abnormalities: QT interval

Data from Phase 2. ECG measurements (an average of the triplicate measurements) will be used for the statistical analysis and all data presentations. Any data obtained from ECGs repeated for safety reasons after the nominal time points will not be averaged along with the preceding triplicates. Interval measurements from repeated ECGs will be included in the outlier analysis (categorical analysis) as individual values obtained at unscheduled time points

ECG abnormalities: RR interval

ECG abnormalities: PR interval

ECG abnormalities: QRS duration

Performance status abnormalities

Data from Phase 2. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status.

Full Information

NCT ID

NCT04258943

First Posted

January 16, 2020

Last Updated

August 29, 2023

Sponsor

Children's Oncology Group

Collaborators

Erasmus Medical Center, Dutch Childhood Oncology Group, Innovative Therapies for Children with Cancer, Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT04258943

Brief Title

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

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

April 6, 2020 (Actual)

Primary Completion Date

December 2023 (Anticipated)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Children's Oncology Group

Collaborators

Erasmus Medical Center, Dutch Childhood Oncology Group, Innovative Therapies for Children with Cancer, Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Philadelphia Chromosome Positive CML, Accelerated Phase Chronic Myelogenous Leukemia, Blastic Phase Chronic Myelogenous Leukemia, Chronic Phase Chronic Myelogenous Leukemia

Keywords

Philadelphia Chromosome Positive CML

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

60 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Single Agent Bosutinib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Bosutinib

Intervention Description

Patients with R/I disease are enrolled at a dose of 400 mg/m2 (DL2B) based on tolerability and PK analysis. Once the RP2D for R/I patients (RP2DR/I) is determined in the Phase 1, subsequent patients with R/I disease will be enrolled at the RP2DR/I for this subpopulation for the Phase 2 component of the study (see section 1.6.3 and section 3 for details). - Patients with newly diagnosed disease are being enrolled on Phase 2 component only, at RP2DND dose of 300 mg/m2. (see section 1.6.3 and section 3 for details)

Primary Outcome Measure Information:

Title

1. Incidence (and severity) of Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.

Description

Time Frame

First 28 days of treatment (first cycle)

Title

PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Description

Time Frame

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

Title

PK parameters of bosutinib:Time to Cmax (Tmax)

Description

Time Frame

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

Title

PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Description

Time Frame

Title

PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Description

Time Frame

Title

PK parameters of bosutinib: Apparent clearance (CL/F).

Description

Data from Phase 1; Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Time Frame

Title

Description

Time Frame

AE's will be collected from signing informed consent continuously during the study until 28 days after last dose (on average, 2 years).

Title

PK parameters of bosutinib: Maximum observed plasma concentration (Cmax)

Description

Time Frame

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

Title

PK parameters of bosutinib:Time to Cmax (Tmax)

Description

Time Frame

Title

PK parameters of bosutinib: Area under the plasma concentration versus time curve from time zero to the dosing interval (AUCτ)

Description

Time Frame

Title

PK parameters of bosutinib: Pre-dose concentration (Ctrough)

Description

Time Frame

Title

PK parameters of bosutinib: Apparent clearance (CL/F).

Description

Data from Phase 2; subset of newly diagnosed patients. Apparent clearance of the drug from plasma after oral administration, calculated as Dose/AUCt.

Time Frame

Title

Population PK parameters of bosutinib including volume of distribution based on combined PK data from Phase 1 and Phase 2

Description

Time Frame

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

Title

Population PK parameters of bosutinib including clearance based on combined PK data from Phase 1 and Phase 2

Description

Time Frame

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 Outcome Measure Information:

Title

AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;

Description

Time Frame

From signing informed consent, continuously during the study until 28 days after last dose (on average 2 years).

Title

Description

Time Frame

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)

Title

ECG abnormalities: QT interval

Description

Time Frame

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)

Title

ECG abnormalities: RR interval

Description

Time Frame

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)

Title

ECG abnormalities: PR interval

Description

Time Frame

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)

Title

ECG abnormalities: QRS duration

Description

Time Frame

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)

Title

Performance status abnormalities

Description

Data from Phase 1. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status

Time Frame

Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)

Title

Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Description

Data from Phase 1. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).]

Time Frame

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).

Title

Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), major molecular response (MMR) and deep molecular response

Description

Data from Phase 2. MCyR is defined as complete cytogenetic response [CCyR] plus partial cytogenetic response [PCyR]. (definitions in appendix 2).

Time Frame

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).]

Title

Time to the respective responses by line of therapy

Description

Time Frame

Through study completion, a maximum of around 10 years

Title

Duration of the respective responses by line of therapy

Description

Data from Phase 2. Duration of response is defined is defined as the time period from the date of the earliest demonstration of a response until the earliest date of confirmed loss of that response.

Time Frame

Through study completion, a maximum of around 10 years

Title

Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2).

Description

Time Frame

Through study completion, a maximum of around 10 years

Title

Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy

Description

Time Frame

Through study completion, a maximum of around 10 years

Title

Description

Time Frame

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)

Title

ECG abnormalities: QT interval

Description

Time Frame

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)

Title

ECG abnormalities: RR interval

Description

Time Frame

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)

Title

ECG abnormalities: PR interval

Description

Time Frame

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)

Title

ECG abnormalities: QRS duration

Description

Time Frame

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)

Title

Performance status abnormalities

Description

Data from Phase 2. Kamofsky or Lansky (depending on age) performance score as assessed by physician is collected to evaluate performance status.

Time Frame

Screening; on day 1 of every subsequent cycle end of treatment (each cycle is 28 days)

Other Pre-specified Outcome Measures:

Title

Parameters of bone metabolism and growth: linear growth

Description

Data from Phase 1 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).

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).

Title

Parameters of bone metabolism and growth: bone age

Description

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).

Title

Parameters of bone metabolism and growth: bone mineral density of lumbar spine

Description

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).

Title

Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys),

Description

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).

Title

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)

Description

Time Frame

[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).

Title

Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Description

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).

Title

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

Description

Data from Phase 1. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. ON a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'

Time Frame

Through study completion, a maximum of around 10 years

Title

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.

Description

Data from Phase 1. A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.

Time Frame

Through study completion, a maximum of around 10 years

Title

Parameters of bone metabolism and growth: linear growth

Description

Data from Phase 2 that includes linear growth, bone age, bone mineral density of lumbar spine, physical signs of pubertal maturation (Tanner stage and testicular volume of boys), and hormones associated with growth and pubertal development (IGF-1, T4, TSH and LH, FSH, estradiol for girls, and testosterone for boys) and a marker of bone formation and bone resorption (bone alkaline phosphatase and CTX). The analysis of bone age, pubertal status and results of serum chemistry tests will be descriptive. Height (cm), weight (kg), bone age (yr), Tanner stage, serum chemistry and bone densitometry scan results [Lumbar Spine (L1-L4) (g/cm2)] will be provided in listings and summarized by study visit (including change from baseline).

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).

Title

Parameters of bone metabolism and growth: bone age

Description

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).

Title

Parameters of bone metabolism and growth: bone mineral density of lumbar spine

Description

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).

Title

Parameters of bone metabolism and growth: physical signs of pubertal maturation (Tanner stage and testicular volume of boys

Description

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).

Title

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)

Description

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).

Title

Parameters of bone metabolism and growth: markers of bone formation and bone resorption (bone alkaline phosphatase and CTX).

Description

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).

Title

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.

Description

Data from Phase 2. Pediatric quality of life inventory ™ (PedsQL) Gastrointestinal Symptom Scale questionnaires will be used to assess gastrointestinal symptoms. On a scale of 0 to 4, with 0 being: 'never' and 4 being: 'almost always'

Time Frame

Through study completion, a maximum of around 10 years

Title

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.

Description

Data from Phase 2 A questionnaire with different kind of questions, using a 1 to 3 score on difficulty to swallow, with 1 being' difficult to swallow' and 3 being:' no trouble, easy to swallow' and a 1 to 5 score on assessment of taste and overall ease, with 1 being: 'dislike very much' and 5 being: ' like very much'.

Time Frame

Through study completion, a maximum of around 10 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Year

Maximum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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 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 (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.

Facility Information:

Facility Name

Children's Hospital of Alabama

City

Birmingham

State/Province

Alabama

ZIP/Postal Code

35233

Country

United States

Facility Name

Phoenix Childrens Hospital

City

Phoenix

State/Province

Arizona

ZIP/Postal Code

85016

Country

United States

Facility Name

Arkansas Children's Hospital

City

Little Rock

State/Province

Arkansas

ZIP/Postal Code

72202-3591

Country

United States

Facility Name

Kaiser Permanente Downey Medical Center

City

Downey

State/Province

California

ZIP/Postal Code

90242

Country

United States

Facility Name

Loma Linda University Medical Center

City

Loma Linda

State/Province

California

ZIP/Postal Code

92354

Country

United States

Facility Name

Kaiser Permanene-Oakland

City

Oakland

State/Province

California

ZIP/Postal Code

94611

Country

United States

Facility Name

Children's Hospital of Orange County

City

Orange

State/Province

California

ZIP/Postal Code

92868

Country

United States

Facility Name

Lucile Packard Children's Hospital Stanford University

City

Palo Alto

State/Province

California

ZIP/Postal Code

94304

Country

United States

Facility Name

Alfred I duPont Hospital for Children

City

Wilmington

State/Province

Delaware

ZIP/Postal Code

19803

Country

United States

Facility Name

Golisano Children's Hospital of Southwest Florida

City

Fort Myers

State/Province

Florida

ZIP/Postal Code

33908

Country

United States

Facility Name

University of Florida Health Science Center - Gainesville

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Facility Name

Nemours Children's Hospital

City

Orlando

State/Province

Florida

ZIP/Postal Code

32827

Country

United States

Facility Name

Kapiolani Medical Center for Women and Children

City

Honolulu

State/Province

Hawaii

ZIP/Postal Code

96826

Country

United States

Facility Name

Riley Hospital for Children

City

Indianapolis

State/Province

Indiana

ZIP/Postal Code

46202

Country

United States

Facility Name

Blank Children's Hospital

City

Des Moines

State/Province

Iowa

ZIP/Postal Code

50309

Country

United States

Facility Name

Norton Children's Hospital

City

Louisville

State/Province

Kentucky

ZIP/Postal Code

40202

Country

United States

Facility Name

Johns Hopkins University/Sidney Kimmel Cancer Center

City

Baltimore

State/Province

Maryland

ZIP/Postal Code

21287

Country

United States

Facility Name

Dana-Farber/Harvard Cancer Center

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Children's Mercy Hospitals and Clinics

City

Kansas City

State/Province

Missouri

ZIP/Postal Code

64108

Country

United States

Facility Name

Children's Specialty Center of Nevada II

City

Las Vegas

State/Province

Nevada

ZIP/Postal Code

89109

Country

United States

Facility Name

Hackensack University Medical Center

City

Hackensack

State/Province

New Jersey

ZIP/Postal Code

07601

Country

United States

Facility Name

Morristown Medical Center

City

Morristown

State/Province

New Jersey

ZIP/Postal Code

07960

Country

United States

Facility Name

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

City

New Brunswick

State/Province

New Jersey

ZIP/Postal Code

08903

Country

United States

Facility Name

Roswell Park Cancer Institute

City

Buffalo

State/Province

New York

ZIP/Postal Code

14263

Country

United States

Facility Name

The Steven and Alexandra Cohen Children's Medical Center of New York

City

New Hyde Park

State/Province

New York

ZIP/Postal Code

11040

Country

United States

Facility Name

Carolinas Medical Center/Levine Cancer Institute

City

Charlotte

State/Province

North Carolina

ZIP/Postal Code

28203

Country

United States

Facility Name

Children's Hospital Medical Center of Akron

City

Akron

State/Province

Ohio

ZIP/Postal Code

44308

Country

United States

Facility Name

Cincinnati Children's Hospital Medical Center

City

Cincinnati

State/Province

Ohio

ZIP/Postal Code

45229

Country

United States

Facility Name

Rainbow Babies and Childrens Hospital

City

Cleveland

State/Province

Ohio

ZIP/Postal Code

44106

Country

United States

Facility Name

Nationwide Children's Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43205

Country

United States

Facility Name

Lehigh Valley Hospital-Cedar Crest

City

Bethlehem

State/Province

Pennsylvania

ZIP/Postal Code

18017

Country

United States

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

Children's Hospital of Pittsburgh of UPMC

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15224

Country

United States

Facility Name

Rhode Island Hospital

City

Providence

State/Province

Rhode Island

ZIP/Postal Code

02903

Country

United States

Facility Name

East Tennessee Childrens Hospital

City

Knoxville

State/Province

Tennessee

ZIP/Postal Code

37916

Country

United States

Facility Name

Saint Jude Children's Research Hospital

City

Memphis

State/Province

Tennessee

ZIP/Postal Code

38105

Country

United States

Facility Name

Vanderbilt University/Ingram Cancer Center

City

Nashville

State/Province

Tennessee

ZIP/Postal Code

37232

Country

United States

Facility Name

Dell Children's Medical Center of Central Texas

City

Austin

State/Province

Texas

ZIP/Postal Code

78723

Country

United States

Facility Name

UT Southwestern/Simmons Cancer Center-Dallas

City

Dallas

State/Province

Texas

ZIP/Postal Code

75390

Country

United States

Facility Name

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

M D Anderson Cancer Center

City

Houston

State/Province

Texas

ZIP/Postal Code

77030

Country

United States

Facility Name

Inova Fairfax Hospital

City

Falls Church

State/Province

Virginia

ZIP/Postal Code

22042

Country

United States

Facility Name

Children's Hospital of The King's Daughters

City

Norfolk

State/Province

Virginia

ZIP/Postal Code

23507

Country

United States

Facility Name

Seattle Children's Hospital

City

Seattle

State/Province

Washington

ZIP/Postal Code

98105

Country

United States

Facility Name

Children's Hospital of Wisconsin

City

Milwaukee

State/Province

Wisconsin

ZIP/Postal Code

53226

Country

United States

12. IPD Sharing Statement

Citations:

PubMed Identifier

23803709

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.

Results Reference

background

Learn more about this trial

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

We'll reach out to this number within 24 hrs