Bositinib in pediatric CML patients

Phase 1

• Conditions: Chronic Myeloid Leukemia; MedDRA version: 21.0Level: LLTClassification code 10009700Term: CMLSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2015-002916-34-DE
• Lead Sponsor: Erasmus MC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2017-01-18
• Last Update Posted: 13 November 2023

Recruitment & Eligibility

• Status: A
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML38 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 BCR-ABL protein weight (P210, rarely P230 or P190).
2. Resistance (suboptimal response or failure, as defined by 2013 European Leukemia Net guidelines24) or intolerance (with or without suboptimal response or failure) to at least one prior tyrosine kinase inhibitor (TKI).
• The 2013 European LeukemiaNet guidelines24 will be used to define suboptimal response and failure to prior TKI therapy. Details are provided in appendices 3 and 4.
-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) = 60 mL/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 substance added to a suitable foodstuff (from capsule contents, added to either apple sauce or yoghurt); or tablets and/or capsules dissolved 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

Exclusion Criteria

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 Excl. 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 anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or anagrelide) within 14 days prior to start of boutinib treatment
6. Prior growth factors or biologic agents within 7 days prior to bosutinib treatment.
7. Concomitant use of moderate or strong CYP3A4 inducers/inhibitors within 7 days prior and/or concomitant to bosutinib treatment
8. Use of proton pump inhibitors 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 I) 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, hepatitis C, or HIV infection or 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

For phase 2 ND patients
1. Diagnosis of primary Ph+ ALL
2. EMD only
3. Documented prior history of T315I or V299L BCR-ABL1 mutations
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 biological agents within 7 days prior to bosutinib treatment.
6. Use of strong or moder

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified