Bosutinib study in patients with pediatric CML|
|- candidate number||22910|
|- NTR Number||NTR5501|
|- ISRCTN||ISRCTN no longer applicable|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||28-sep-2015|
|- Secondary IDs||ITCC-054 |
|- Public Title||Bosutinib study in patients with pediatric CML|
|- Scientific Title||“A Phase I/II study of Bosutinib in pediatric patients with Chronic Myeloid Leukemia who are resistant or intolerant to at least one prior Tyrosine Kinase Inhibitor therapy”,
|- Healt Condition(s) or Problem(s) studied||Chronic Myeloid Leukemia (CML)|
|- Inclusion criteria||1. Cytogenetic and molecular diagnosis of Philadelphia chromosome-positive CML38 at either time of initial CML diagnosis or at time of study enrollment: |
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 the time of study entry.
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: Serum creatinine level based on age/gender must be less than or equal to the following maximum upper limits:
Age Maximum Serum Creatinine (mg/dL and µmol/L)
mg/dL µmol/L mg/dL µmol/L
1 year to <2 years 0.6 53.0 0.6 53.0
2 to <6 years 0.8 70.7 0.8 70.7
6 to <10 years 1.0 88.4 1.0 88.4
10 to <13 years 1.2 106.1 1.2 106.1
13 to <16 years 1.5 132.6 1.4 123.8
≥16 years 1.7 150.3 1.4 123.8
The threshold creatinine values in this table were derived from the Schwartz formula for estimating GFR utilizing child length and stature.
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 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.
|- 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/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. Prior radiotherapy within 3 months prior to study entry.
8. Allogeneic stem cell transplantation within 3 months prior to study entry.
9. Donor lymphocyte infusion (DLI) within 1 month prior to study entry.
10. Hereditary bone marrow failure disorder.
11. Graft-versus-host disease (GVHD) within 60 days prior to study entry.
12. Major surgery within 14 days prior to study entry (recovery from any previous surgery should be complete before day 1).
13. 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.
14. Prolonged QTc (>450 msec, average of triplicate ECGs).
15. Need for medications known to prolong the QT interval
16. In phase I: need for proton-pump inhibitors
17. Uncorrected hypomagnesemia or hypokalemia due to potential effects on the QT interval.
18. Left ventricular ejection fraction <50% or shortening fraction <28%.
19. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with the intake or absorption of the drug.
20. Evidence of serious active or uncontrolled bacterial, fungal or viral infection.
21. Known history of hepatitis B (HBV), hepatitis C (HCV), or human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
22. 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.
|- mec approval received||no|
|- multicenter trial||yes|
|- Type||Single arm|
|- planned startdate ||1-feb-2016|
|- planned closingdate|
|- Target number of participants||34|
|- Interventions||Bosutinib one daily oral for maximum of 24 cycles|
|- Primary outcome||-Primary endpoints phase 1|
Dose-Limiting Toxicities (DLTs) assessed during the first 28 days of treatment.
Pharmacokinetic parameters of bosutinib: Cmax, AUC.
|- Secondary outcome||Secondary endpoints phase 1|
AEs, as characterized by type, frequency, severity (as graded using CTCAE version, v4.03), timing, seriousness, and relation to study therapy;
-Laboratory abnormalities as characterized by type, frequency, severity and timing;
-PK parameters of bosutinib: t1/2, tmax, CL/F, Vss/F will be assessed if possible;
-Overall cumulative disease response: complete hematologic response (CHR), major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR) and molecularly undetectable disease (definitions in appendix 2).
-Exploratory endpoints phase 1
Parameters of bone metabolism and growth, including linear growth bone age, bone density, physical signs of pubertal maturation, and hormones associated with growth and pubertal development (IGF-1, LH, FSH, estradiol for girls, and testosterone for boys).
Patient and/or caregiver-reported assessments of gastrointestinal symptoms, as measured by selected domains from the PedsQL Gastrointestinal Symptom Scale.
|- Timepoints||See protocol|
|- Trial web site||www.dcog-ectc.nl|
|- CONTACT FOR PUBLIC QUERIES||MD. PhD. C.M. Zwaan|
|- CONTACT for SCIENTIFIC QUERIES||MD. PhD. C.M. Zwaan|
|- Sponsor/Initiator ||Erasmus Medical Center, Rotterdam|
(Source(s) of Monetary or Material Support)
|- Brief summary|
|- Main changes (audit trail)|
|- RECORD||28-sep-2015 - 5-jan-2016|
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