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Not Recruiting

Phase I/II Evaluation of Bosutinib in Pediatric Patients with Newly Diagnosed or Resistant/Intolerant Ph+ Chronic Myeloid Leukemia

Trial ID: 2023-504311-32-00
Protocol: ITCC-054/AAML1921
Sponsor: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)

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Diseases & Conditions

Chronic myeloid leukaemia

Objectives

The primary objective of this study is to determine the **Recommended Phase 2 Dose (RP2D)** of bosutinib for pediatric patients with Chronic Myeloid Leukemia (CML) who are either newly diagnosed in the chronic phase or resistant/intolerant to prior tyrosine kinase inhibitor (TKI) therapy. This determination is based on the pharmacokinetic, safety, and tolerability profile of bosutinib observed at various dose levels. Additionally, the study aims to assess the pharmacokinetics (PK) of bosutinib at the RP2D in these patient populations and evaluate the pooled safety and tolerability profile based on adverse events.

Secondary objectives include: - Phase 1: Evaluating the overall safety profile during the first cycle of therapy (28 days) and during prolonged exposure to bosutinib, as well as preliminarily assessing the anti-leukemic activity in pediatric patients with Philadelphia chromosome-positive CML following resistance or intolerance to one or more TKIs. - Phase 2: Describing the clinical efficacy of bosutinib in pediatric patients with newly diagnosed Ph+ CML in the chronic phase and in any phase of the disease following resistance or intolerance to one or more TKIs. Additionally, the study aims to assess other safety parameters of bosutinib and the relationship between the PK of bosutinib and key safety and efficacy metrics.

Participants

The clinical trial involves a total of **30 participants** diagnosed with **Chronic Myeloid Leukemia** (CML). The study population includes both male and female pediatric patients, aged between 1 and 18 years. Participants are selected based on their diagnosis of Philadelphia chromosome-positive CML, either newly diagnosed or resistant/intolerant to prior tyrosine kinase inhibitor (TKI) therapy. The trial includes a vulnerable population, as it involves children. Participants are required to have adequate renal and liver function, and a performance status of at least 50% on the Lansky or Karnofsky scale, depending on age. Lifestyle considerations such as diet or physical activity are not specified. The selection criteria ensure that participants can comply with the study's requirements, including the ability to swallow medication in various forms. The sponsor has not provided additional information regarding specific lifestyle factors or other health conditions of the participants.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy and safety of **bosutinib**, a tyrosine kinase inhibitor, in pediatric patients with newly diagnosed or resistant/intolerant Philadelphia chromosome-positive **Chronic Myeloid Leukemia** (CML). This is a Phase I/II study, which is randomized, double-blind, and controlled, aiming to determine the recommended Phase 2 dose (RP2D) based on pharmacokinetic, safety, and tolerability profiles. The trial is expected to run from February 2016 to March 2029, with participant involvement varying based on individual response and tolerance to the treatment.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on cytogenetic and molecular diagnosis criteria. The trial includes multiple follow-up visits to monitor the incidence and severity of dose-limiting toxicities, pharmacokinetic parameters, and overall safety and efficacy. The end-of-study visit will assess the cumulative disease response and any long-term effects of the treatment. The expected length of participant involvement is contingent upon the individual's response to the treatment and adherence to the study protocol.

Participants may be subject to early termination from the study if they experience significant adverse events, fail to comply with the study protocol, or if the investigator deems it in the participant's best interest. The study will adhere to strict inclusion criteria, such as age, performance status, and adequate organ function, to ensure participant safety and data integrity. The trial will also evaluate secondary endpoints, including overall survival, event-free survival, and the relationship between pharmacokinetic parameters and key safety and efficacy metrics.

Treatment

The clinical trial involves the administration of **Bosutinib**, a tyrosine kinase inhibitor, as the experimental medication. Bosutinib is provided in two pharmaceutical forms: capsules and film-coated tablets. The capsules are manufactured by Pfizer Inc., while the film-coated tablets are produced by Pfizer Europe MA EEIG. Both forms contain the active substance bosutinib, which is of chemical origin. The administration route for both the capsule and tablet forms is oral. The trial does not specify a pediatric formulation, and the medication is not classified as an orphan drug. The trial aims to determine the recommended phase 2 dose for pediatric patients with chronic myeloid leukemia (CML) who are either newly diagnosed or resistant/intolerant to prior tyrosine kinase inhibitor therapy.

The Bosutinib capsules are identified by the sponsor product code PF-05208763 and are authorized under the product number PRD10594471. The film-coated tablets are available in two dosages: 100 mg and 500 mg. The 100 mg tablets are authorized under product numbers PRD6509778, PRD6509779, and PRD6508671, while the 500 mg tablets are authorized under product numbers PRD6510502 and PRD6510504. The film-coated tablets are marketed under the name Bosulif, with marketing authorization numbers EU/1/13/818/001 to EU/1/13/818/005. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

Efficacy

The efficacy of Bosutinib in pediatric patients with Philadelphia chromosome-positive Chronic Myeloid Leukemia (Ph+ CML) will be assessed through a series of primary and secondary endpoints. In Phase 1, the primary endpoints include the incidence and severity of Dose-Limiting Toxicities (DLTs) during the first 28 days of treatment, as well as pharmacokinetic (PK) parameters such as maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve (AUCτ), pre-dose concentration (Ctrough), and apparent clearance (CL/F). In Phase 2, primary endpoints focus on adverse events (AEs) characterized by type, frequency, severity, timing, seriousness, and relation to study therapy, along with PK parameters and population PK parameters of Bosutinib.

Secondary endpoints in Phase 1 include AEs, laboratory abnormalities, ECG and performance status abnormalities, and overall cumulative disease response, which encompasses complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), and deep molecular response. In Phase 2, secondary endpoints extend to overall cumulative disease response by line of therapy, time to and duration of responses, event-free survival (EFS), overall survival (OS), laboratory abnormalities, ECG and performance status abnormalities, and relationships between PK parameters and key safety and efficacy metrics.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Phase 1 and Phase 2 (R/I patients): Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML at either time of initial CML diagnosis or at time of study screening: 1. Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases. 2. Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I- FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted. 3. 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 BCR- ABL protein weight (P210, rarely P230 or P190).
Phase 1 and Phase 2 (R/I patients): Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI): 1. The 2013 European LeukemiaNet guidelines will be used to define suboptimal response and failure to prior TKI therapy. 2. 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.
Phase 1 and Phase 2 (R/I patients): Age ≥1 and <18 years at day of attaining the informed consent.
Phase 1 and Phase 2 (R/I patients): Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age.
Phase 1 and Phase 2 (R/I patients): Adequate bone marrow function: 1. For second-line and third-line CP CML patients: a. Absolute neutrophil count >1000/mm3 (>1.0 x109/L); b. Platelets ≥75,000/mm3 (≥75 x109/L) without any platelet transfusions during the preceding 7 days. 2. For fourth-line CP and all for all AP/BP CML patients: a. Absolute neutrophil count >500/mm3 (>0.5 x109/L); b. Platelets ≥50,000/mm3 (≥50 x109/L) without any platelet transfusions during the preceding 7 days.
Phase 1 and Phase 2 (R/I patients): Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR.
Phase 1 and Phase 2 (R/I patients): Adequate liver function, including: 1. AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver; 2. Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.
Phase 1 and Phase 2 (R/I 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.
Phase 1 and Phase 2 (R/I patients): 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.
Phase 1 and Phase 2 (R/I patients): Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.
Phase 1 and Phase 2 (R/I patients): 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.
Phase 1 and Phase 2 (R/I patients): Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations).
Phase 1 and Phase 2 (R/I patients): 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.
Phase 2 (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: 1. Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases. 2. Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I- FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted. 3. 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 BCR- ABL protein weight (P210, rarely P230 or P190).
Phase 2 (Newly Diagnosed CML patients): 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.
Phase 2 (Newly Diagnosed CML patients): Age ≥1 and <18 years at day of attaining the informed consent.
Phase 2 (Newly Diagnosed CML patients): Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age.
Phase 2 (Newly Diagnosed CML patients): Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR.
Phase 2 (Newly Diagnosed CML patients): Adequate liver function, including: 1. AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver; 2. Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.
Phase 2 (Newly Diagnosed CML patients): 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.
Phase 2 (Newly Diagnosed CML patients): Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.
Phase 2 (Newly Diagnosed CML patients): 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.
Phase 2 (Newly Diagnosed CML patients): Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations).
Phase 2 (Newly Diagnosed CML patients): 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.

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Exclusion Criteria

Phase 1 and Phase 2 (R/I patients): Diagnosis of primary Ph+ acute lymphoblastic leukemia.
Phase 1 and Phase 2 (R/I patients): Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Hereditary bone marrow failure disorder.
Phase 1 and Phase 2 (R/I patients): Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).
Phase 1 and Phase 2 (R/I patients): History of clinically significant or uncontrolled cardiac disease, including: 1. History of or active congestive heart failure; 2. Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); 3. Diagnosed or suspected congenital or acquired prolonged QT syndrome; 4 History of prolonged QTc
Phase 1 and Phase 2 (R/I patients): Prolonged QTc (>450 msec, average of triplicate ECGs).
Phase 1 and Phase 2 (R/I patients): Need for medications known to prolong the QT interval.
Phase 1 and Phase 2 (R/I patients): Pregnant and/or nursing women.
Phase 1 and Phase 2 (R/I patients): Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
Phase 1 and Phase 2 (R/I patients): 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.
Phase 1 and Phase 2 (R/I patients): Left ventricular ejection fraction <50% or shortening fraction <28%.
Phase 1 and Phase 2 (R/I patients): Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.
Phase 1 and Phase 2 (R/I patients): Evidence of serious active or uncontrolled bacterial, fungal or viral infection.
Phase 1 and Phase 2 (R/I patients): Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
Phase 1 and Phase 2 (R/I patients): 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.
Phase 2 (Newly Diagnosed CML patients): Diagnosis of primary Ph+ acute lymphoblastic leukemia.
Phase 2 (Newly Diagnosed CML patients): Extramedullary disease only.
Phase 2 (Newly Diagnosed CML patients): 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).
Phase 2 (Newly Diagnosed CML patients): Any prior treatment with a TKI or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide).
Phase 2 (Newly Diagnosed CML patients): Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Extramedullary disease only.
Phase 2 (Newly Diagnosed CML patients): Use of strong or moderate CYP3A4 inhibitors and inducers within 7 days prior and/or concomitant to bosutinib treatment.
Phase 2 (Newly Diagnosed CML patients): Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment).
Phase 2 (Newly Diagnosed CML patients): Hereditary bone marrow failure disorder.
Phase 2 (Newly Diagnosed CML patients): Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).
Phase 2 (Newly Diagnosed CML patients): History of clinically significant or uncontrolled cardiac disease, including: 1. History of or active congestive heart failure; 2. Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); 3. Diagnosed or suspected congenital or acquired prolonged QT syndrome; 4. History of prolonged QTc.
Phase 2 (Newly Diagnosed CML patients): Prolonged QTc (>450 msec, average of triplicate ECGs).
Phase 2 (Newly Diagnosed CML patients): Need for medications known to prolong the QT interval.
Phase 2 (Newly Diagnosed CML patients): Pregnant and/or nursing women.
Phase 2 (Newly Diagnosed CML patients): Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
Phase 2 (Newly Diagnosed CML patients): Left ventricular ejection fraction <50% or shortening fraction <28%.
Phase 1 and Phase 2 (R/I patients): 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).
Phase 2 (Newly Diagnosed CML patients): Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.
Phase 2 (Newly Diagnosed CML patients): Evidence of serious active or uncontrolled bacterial, fungal or viral infection.
Phase 2 (Newly Diagnosed CML patients): Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
Phase 2 (Newly Diagnosed CML patients): 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.
Phase 1 and Phase 2 (R/I patients): Any prior treatment with a TKI within 7 days prior to starting bosutinib treatment, or other anti- tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to start of bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Use of strong or moderate CYP3A4 inhibitors and inducers within 7 days prior and/or concomitant to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Prior radiotherapy within 3 months prior to bosutinib treatment.
Phase 1 and Phase 2 (R/I patients): Known hypersensitivity to the active substance or to any of the excipients
Phase 2 (Newly Diagnosed CML patients): Known hypersensitivity to the active substance or to any of the excipients

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
France	Not Recruiting	01 Feb 2016	4
Germany	Not Recruiting	01 Feb 2016	1
Italy	Not Recruiting	01 Feb 2016	12
The Netherlands	Not Recruiting	01 Feb 2016	—
Spain	Not Recruiting	01 Feb 2016	3
Netherlands	—	—	10

Sites & Investigators

Research sites

Hospital Vall d’Hebron Universitaetsklinikum Erlangen AöR Hospices Civils De Lyon Assistance Publique Hopitaux De Paris

Investigators

Franco L.Laura M. S.Carmelo R.Nicoletta B.

Investigational Products

Details about the medicinal products being studied in this clinical trial.

Product Name	Role in Trial	Formulation	Administration	Max Daily Dose	Treatment Duration	EU MP Number
Bosutinib	Test	CAPSULE	ORAL	—	—	PRD10594332
Bosulif 100 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL	—	—	PRD6509779
Bosulif 500 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL	—	—	PRD6510504
Bosulif 100 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL	—	—	PRD6508671
Bosulif 500 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL	—	—	PRD6510502
Bosutinib	Test	CAPSULE	ORAL	—	—	PRD10594471
Bosulif 100 mg film-coated tablets	Test	FILM-COATED TABLETS	ORAL	—	—	PRD6509778

Conditions Studied in This Trial

Interventions Studied in This Trial

vaccines

Bosutinib

7 trials

Also investigated for

Chronic myeloid leukaemia 7