A Phase I/II study of Bosutinib in pediatric patients with newly diagnosed chronic phase or resistant/intolerant Ph+ Chronic Myeloid Leukemia,ITCC-054/AAML1921
- Conditions
- bone marrow cancercml10024324
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 10
Phase 1 (R/I patients only)
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 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 guidelines) or intolerance (with or without suboptimal
response or failure) to at least one prior tyrosine kinase inhibitor (TKI).
• The 2013 European LeukemiaNet guidelines 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
(from capsule contents) added to a suitable foodstuff.
10. Serum/urine pregnancy test (for all girls >= age of menarche) negative at
screening.
11. Male and female patients of c
Phase 1 (R/I patients only):
1. Diagnosis of primary Ph+ acute lymphoblastic leukemia.
2. In patients with AP/BC 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 study entry, or other
anti-tumor or anti-leukemia treatment (with the exception of hydroxyurea and/or
anagrelide) within 14 days prior to study entry.
6. Prior growth factors or biologic agents within 7 days prior to study entry.
7. Concomittant use of moderate or strong CYP3A inducers/inhibitors (see
appendix 8)within 7 days prior to study entry and during treatment.
8. Concomittant use of proton pump inhibitors within 7 days prior to study
entry and during treatment.
9. Prior radiotherapy within 3 months prior to study entry.
10. Allogeneic stem cell transplantation within 3 months prior to study entry.
11. Donor lymphocyte infusion (DLI) within 1 month prior to study entry.
12. Hereditary bone marrow failure disorder.
13. Graft-versus-host disease (GVHD) within 60 days prior to study entry.
14. Major surgery within 14 days prior to study entry (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.
For phase 2 ND patients:
1. Diagnosis of primary Ph+ ALL
2. EMD only.
3. Documented prior history of T315I or V299
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method
- Secondary Outcome Measures
Name Time Method