| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009700 |
| E.1.2 | Term | CML |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary objective phase 1:
- To determine the Recommended Phase 2 Dose (RP2D) of bosutinib for R/I (RP2DR/I) and ND chronic phase (RP2DND) pediatric patients with CML, based on the pharmacokinetic, safety and tolerability profile of bosutinib observed at various dose levels in pediatric patients with CML who are resistant or intolerant to prior TKI therapy
Primary Objectives phase 2:
- To assess the PK of bosutinib at the RP2DND and RP2DR/I in pediatric patients with ND or R/I Ph+ CML.
- To assess the population PK of bosutinib
- To assess the pooled safety and tolerability profile (based on AEs) of bosutinib in pediatric patients with ND and R/I Ph+ CML.
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives phase 1:
- To evaluate the overall safety profile during the first cycle of therapy (28 days)
- Too evaluate the safety and tolerability profile during the prolonged exposure to bosutinib
- To preliminary evaluate the anti-leukemic activity in pediatric patients with Philadelphia chromosome positive CML following resistance or intolerance to one or more TKIs
Secondary Objectives phase 2:
- To describe the clinical efficacy of bosutinib in pediatric patients with newly diagnosed Ph+ CML in chronic phase
- To describe the clinical efficacy of bosutinib in pediatric patients with Ph+ CML in any phase of disease following resistance or intolerance to one or more TKIs
- To assess other safety parameters of bosutinib
- To assess the relationship between the PK of bosutinib and key safety and efficacy metrics
Exploratory:
- Evaluate effects on growth bone metabolism
- Assess changes in GI symptoms during therapy
- Assess palatability of bosutinib
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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).
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
For phase 2 ND patients:
Criterion 2 replaced with: 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.
Criterion 5 deleted
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| E.4 | Principal 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 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 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 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 (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
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 moderate CYP3A4 inhibitors and inducers within 7 days prior and/or concomitant to bosutinib treatment
7.Use of proton pump inhibitors 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
10.History of clinically significant or uncontrolled cardiac disease
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 immune-deficiency 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 judgement of the Investigator, would make the patient inappropriate for entry into this study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
Primary endpoints
- Incidence and severity of dose-limiting toxicities (DLTs) assessed during the first 28 days of treatment.
- PK parameters of bosutinib: maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time zero to the dosing interval (AUCT), pre-dose concentration (Ctrough) and apparent clearance (CL/F).
Phase 2:
Primary endpoints
- AEs, as characterized by type, frequency, severity (as graded using CTCAE version V4.03, timing, seriousness and relation to study therapy (pooled across ND and R/I CML patients and by line of therapy).
- PK parameters of bosutinib: maximum observed plasma concentration (Cmax), time to Cmax (Tmax), area under the plasma concentration versus time curve from time zero to the dosing interval (AUCT), pre-dose concentration (Ctrough) and apparent clearance (CL/F).
- Population PK parameters of bosutinib including clearance and volume of distribution based on combined PK data from Phase 1 and Phase 2.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
After first cycle regarding DLTs
PK sampling per patient: After day 1 of 4th cycle. Evaluation of the PK results: after completion of a dose level in Phase 1.
Continuously during phase 2
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| E.5.2 | Secondary end point(s) |
Phase 1:
(endpoint already correct)
Phase 2:
- Overall cumulative disease response by the line of therapy: complete hematologic response (CHR), major cytogenic response (MCyR, defined as complete cytogenic response [CCyR] plus partial cytogenic response [PCyR]), CCyR, major molecular response (MMR) and deep molecular response.
- Time to and duration of the respective responses by line of therapy.
- Event-free survival (EFS; including time to transformation to AP and BP CML) by line of therapy (definition in appendix 2).
- Overall survival (OS) in pediatric patients with Ph+ CML by line of therapy.
- Laboratory abnormalities as characterized by type, frequency, severity and timing (pooled across ND and R/I CML and by line of therpy).
- ECG and performance status abnormalities
- Relationships between PK parameters of bosutinib
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | Yes |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Israel |
| Switzerland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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