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

NCT ID: NCT04258943

Last Updated: 2025-09-18

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-07-06
• Study Completion Date: 2028-07-31

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

Conditions

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

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Single Agent Bosutinib

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

Group Type: EXPERIMENTAL

Bosutinib

Intervention Type: DRUG

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)

Interventions

Bosutinib

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)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML[2] at either time of initial CML diagnosis or at time of study screening:

Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases.

Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I-FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted.

Qualitative RT-PCR should be performed on RNA extracted from freshly collected bone marrow or peripheral blood cells. It identifies the transcript type, either e14a2 or 13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCRABL protein weight (P210, rarely P230 or P190).

2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines[3]) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI) The 2013 European LeukemiaNet guidelines[3] will be used to define suboptimal response and failure to prior TKI therapy. Details are provided in appendices 3 (intolerance or failure after one TKI) and 4 (Failure after more than one TKIs).

Intolerance to prior TKI therapy will be determined by the treating investigator, but generally applies to patients who are unable to receive standard or reduced doses of a TKI due to significant drug-related toxicity and/or when the drug-related toxicity is not responding to appropriate medical management. Patients who enroll as a result of intolerance to prior TKI therapy may have any level of response to their prior therapy and still be eligible.

3. Age ≥1 and <18 years at day of attaining the informed consent.

4. Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age (appendix 5).

5. Adequate bone marrow function:

For second-line and third-line CP CML patients:

Absolute neutrophil count >1000/mm3 (>1.0 x109/L); Platelets ≥75,000/mm3 (≥75 x109/L) without any platelet transfusions during the preceding 7 days.

For fourth-line CP and all for all AP/BP CML patients:

Absolute neutrophil count >500/mm3 (>0.5 x109/L); Platelets ≥50,000/mm3 (≥50 x109/L) without any platelet transfusions during the preceding 7 days.

6. Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60mL/min/1.73 m2, using the Schwartz formula to estimate GFR (see appendix 11).

7. Adequate liver function, including:

AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver; Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.

8. Recovered to Grade 0-1, or to baseline, from any acute toxicities of prior chemotherapy, immunotherapy, radiotherapy, differentiation therapy, or biologic therapy, with the exception of alopecia.

9. Able to reliably swallow whole capsules, whole tablets; or drug added to a suitable foodstuff (from capsule contents, added to either apple sauce or yoghurt); or tablets and/or capsules dissolved in water as an oral syringe drinking solution, or tablets dissolved and administered by NG tube when needed.

10. Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.

11. Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.

12. Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)

13. Patients (including legally acceptable representative for minors where applicable) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

• Newly Diagnosed CML patients

1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML at either time of initial CML diagnosis or at time of study screening:

Cytogenetics must be performed by chromosome banding analysis (CBA) of bone marrow cell metaphases, and requires at least 20 metaphases.

Only if dividing marrow cells cannot be obtained, or if there is an insufficient number of metaphases, CBA can be substituted by interphase fluorescence in situ hybridization (I-FISH) of bone marrow or peripheral blood cells, using dual color dual fusion probes, that allow the detection of BCR-ABL+ nuclei; at least 200 nuclei should be counted.

Qualitative RT-PCR should be performed on RNA extracted from freshly collected bone marrow or peripheral blood cells. It identifies the transcript type, either e14a2 or e13a2 (also known as b3a2 and b2a2), or much more rarely e19a2, or e1a2, indicating the BCRABL protein weight (P210, rarely P230 or P190).

2. Newly diagnosed CP Ph+ CML of ≤ 6 months (from initial diagnosis) without any previous TKI treatment (with the exception of hydroxyurea and/or anagrelide) for CML. Diagnosis of CP CML will be defined as per Appendix 1.

3. Age ≥1 and <18 years at day of attaining the informed consent.

4. Lansky performance status ≥50% for patients ≤16 years of age, or Karnofsky scale ≥50% for patients >16 years of age (appendix 5).

5. Adequate Renal Function: Subjects must have a calculated creatinine clearance (CrCl) ≥ 60 mL/min/1.73 m2, using the Schwartz formula to estimate GFR (see appendix 11).

6. Adequate liver function, including:

AST/ALT ≤2.5 x upper limit normal (ULN) or ≤5 x ULN if attributable to disease involvement of the liver; Total bilirubin ≤1.5 x ULN unless the patient has documented Gilbert syndrome.

7. Able to reliably swallow whole capsules, whole tablets; or drug added to a suitable foodstuff (from capsule contents, added to either apple sauce or yogurt); or tablets and/or capsules dissolved as an oral syringe drinking solution, or tablets dissolved and administered by NG tube when needed.

8. Serum/urine pregnancy test (for all girls ≥ age of menarche) negative at screening.

9. Male and female patients of childbearing potential and at risk for pregnancy must agree to use a highly effective method of contraception throughout the study and for at least 30 days after the last dose of assigned treatment. A patient is of childbearing potential if, in the opinion of the Investigator, he/she is biologically capable of having children and is sexually active.

10. Written informed consent of parent(s)/legal guardian(s) and/or patients (when applicable depending on age and local law and regulations)

11. Patients (including legally acceptable representative for minors where applicable) who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

Exclusion Criteria

Patients presenting with any of the following will not be included in the study:

1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.

2. In patients with AP/BP CML: leptomeningeal leukemia, defined as positive cytology on lumbar puncture (including both CNS2 and CNS3 status), or clinical symptoms or signs present. This assessment is not required for inclusion of CP CML patients.

3. Extramedullary disease only.

4. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. This exclusion criterion is based on whether there is a known history of these mutations at the time of study entry. If these mutations become evident during the study the patient will go off study).

5. Any prior treatment with a TKI within 7 days prior to starting bosutinib treatment, or other antitumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to start of bosutinib treatment.

6. Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.

7. Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7 days prior and/or concomitant to bosutinib treatment

8. Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment.

9. Prior radiotherapy within 3 months prior to bosutinib treatment.

10. Allogeneic stem cell transplantation within 3 months prior to bosutinib treatment.

11. Donor lymphocyte infusion (DLI) within 1 month prior to bosutinib treatment.

12. Hereditary bone marrow failure disorder.

13. Graft-versus-host disease (GVHD) within 60 days prior to bosutinib treatment.

14. Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).

15. History of clinically significant or uncontrolled cardiac disease, including:

History of or active congestive heart failure; Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes); Diagnosed or suspected congenital or acquired prolonged QT syndrome; History of prolonged QTc.

16. Prolonged QTc (>450 msec, average of triplicate ECGs).

17. Need for medications known to prolong the QT interval.

18. Pregnant and/or nursing women

19. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.

20. Left ventricular ejection fraction <50% or shortening fraction <28%.

21. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.

22. Evidence of serious active or uncontrolled bacterial, fungal or viral infection.

23. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.

24. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.

• Newly Diagnosed CML patients:

Patients presenting with any of the following will not be included in the study:

1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.

2. Extramedullary disease only.

3. Documented prior history of T315I or V299L BCR-ABL1 mutations (Note: BCR-ABL1 mutation testing will be performed at screening for a baseline assessment, but results are not used to determine eligibility. This exclusion criterion is based on whether there is a known history of these mutations at the time of study entry. If these mutations become evident during the study the patient will go off study).

4. Any prior treatment with a TKI or other anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide)

5. Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.

6. Use of strong or moderate CYP3A4 inhibitors and inducers (see Appendix 8) within 7 days prior and/or concomitant to bosutinib treatment

7. Use of proton pump inhibitors (Ph-modifying agents) within 7 days prior and/or concomitant to bosutinib treatment)

8. Hereditary bone marrow failure disorder.

9. Major surgery within 14 days prior to bosutinib treatment (recovery from any previous surgery should be complete before day 1).

10. History of clinically significant or uncontrolled cardiac disease, including:

• History of or active congestive heart failure;
• Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
• Diagnosed or suspected congenital or acquired prolonged QT syndrome;
• History of prolonged QTc.

11. Prolonged QTc (>450 msec, average of triplicate ECGs).

12. Need for medications known to prolong the QT interval.

13. Pregnant and/or nursing women

14. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.

15. Left ventricular ejection fraction <50% or shortening fraction <28%.

16. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.

17. Evidence of serious active or uncontrolled bacterial, fungal or viral infection.

18. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.

19. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.

• Minimum Eligible Age: 1 Year
• Maximum Eligible Age: 17 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Erasmus Medical Center

OTHER

Sponsor Role: collaborator

Dutch Childhood Oncology Group

OTHER

Sponsor Role: collaborator

Innovative Therapies for Children with Cancer

UNKNOWN

Sponsor Role: collaborator

Pfizer

INDUSTRY

Sponsor Role: collaborator

Children's Oncology Group

NETWORK

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

Children's Hospital of Alabama

Birmingham, Alabama, United States

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Arkansas Children's Hospital

Little Rock, Arkansas, United States

Kaiser Permanente Downey Medical Center

Downey, California, United States

Loma Linda University Medical Center

Loma Linda, California, United States

Kaiser Permanene-Oakland

Oakland, California, United States

Children's Hospital of Orange County

Orange, California, United States

Lucile Packard Children's Hospital Stanford University

Palo Alto, California, United States

Alfred I duPont Hospital for Children

Wilmington, Delaware, United States

Golisano Children's Hospital of Southwest Florida

Fort Myers, Florida, United States

University of Florida Health Science Center - Gainesville

Gainesville, Florida, United States

Nemours Children's Hospital

Orlando, Florida, United States

Kapiolani Medical Center for Women and Children

Honolulu, Hawaii, United States

Riley Hospital for Children

Indianapolis, Indiana, United States

Blank Children's Hospital

Des Moines, Iowa, United States

Norton Children's Hospital

Louisville, Kentucky, United States

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, United States

Dana-Farber/Harvard Cancer Center

Boston, Massachusetts, United States

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States

Children's Specialty Center of Nevada II

Las Vegas, Nevada, United States

Hackensack University Medical Center

Hackensack, New Jersey, United States

Morristown Medical Center

Morristown, New Jersey, United States

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

New Brunswick, New Jersey, United States

Roswell Park Cancer Institute

Buffalo, New York, United States

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

New Hyde Park, New York, United States

Carolinas Medical Center/Levine Cancer Institute

Charlotte, North Carolina, United States

Children's Hospital Medical Center of Akron

Akron, Ohio, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Rainbow Babies and Childrens Hospital

Cleveland, Ohio, United States

Nationwide Children's Hospital

Columbus, Ohio, United States

Lehigh Valley Hospital-Cedar Crest

Bethlehem, Pennsylvania, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States

Rhode Island Hospital

Providence, Rhode Island, United States

East Tennessee Childrens Hospital

Knoxville, Tennessee, United States

Saint Jude Children's Research Hospital

Memphis, Tennessee, United States

Vanderbilt University/Ingram Cancer Center

Nashville, Tennessee, United States

Dell Children's Medical Center of Central Texas

Austin, Texas, United States

UT Southwestern/Simmons Cancer Center-Dallas

Dallas, Texas, United States

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, United States

M D Anderson Cancer Center

Houston, Texas, United States

Inova Fairfax Hospital

Falls Church, Virginia, United States

Children's Hospital of The King's Daughters

Norfolk, Virginia, United States

Seattle Children's Hospital

Seattle, Washington, United States

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, United States

CHU Lyon/Hospices Civils de Lyon

Lyon, , France

Hopital Armand Trousseau

Paris, , France

Hopital Robert Debré

Paris, , France

Universitätsklinikum Erlangen

Erlangen, , Germany

San Gerardo Hospital

Monza, , Italy

Ospedale Pediatrico Bambino Gesu

Rome, , Italy

Ospedale Regina Margerita

Torino, , Italy

Erasmus Medical Center - Sophia Children's Hospital

Rotterdam, , Netherlands

Prinses Maxima centrum voor kinderoncologie

Utrecht, , Netherlands

Hospital Universitari Vall d'Hebron

Barcelona, , Spain

Hospital Niño Jesús

Madrid, , Spain

University Children's Hospital

Zurich, , Switzerland

Birmingham Children's Hospital

Birmingham, , United Kingdom

The Royal Marsden NHS Foundation Trust

London, , United Kingdom

Countries

United States; France; Germany; Italy; Netherlands; Spain; Switzerland; United Kingdom

References

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.

Reference Type: BACKGROUND

PMID: 23803709 (View on PubMed)

Brivio E, Pennesi E, Willemse ME, Huitema ADR, Jiang Y, van Tinteren HDR, van der Velden VHJ, Beverloo BH, den Boer ML, Rammeloo LAJ, Hudson C, Heerema N, Kowalski K, Zhao H, Kuttschreuter L, Bautista Sirvent FJ, Bukowinski A, Rizzari C, Pollard J, Murillo-Sanjuan L, Kutny M, Zarnegar-Lumley S, Redell M, Cooper S, Bertrand Y, Petit A, Krystal J, Metzler M, Lancaster D, Bourquin JP, Motwani J, van der Sluis IM, Locatelli F, Roth ME, Hijiya N, Zwaan CM. Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921. J Clin Oncol. 2024 Mar 1;42(7):821-831. doi: 10.1200/JCO.23.00897. Epub 2023 Nov 30.

Reference Type: DERIVED

PMID: 38033284 (View on PubMed)

Related Links

https://onderzoekmetmensen.nl/en/trial/54687

DutchTrial Register

Other Identifiers

ITCC-054

Identifier Type: REGISTRY

Identifier Source: secondary_id

2015-002916-34

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

2023-504311-32-00

Identifier Type: OTHER

Identifier Source: secondary_id

NTR5501

Identifier Type: OTHER

Identifier Source: secondary_id

AAML1921

Identifier Type: -

Identifier Source: org_study_id