E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic Phase Chronic myelogenous leukaemia( CP-CML) patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st or 2nd line therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Chronic Phase Chronic myelogenous leukaemia( CP-CML) patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st or 2nd line therapy. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of the BODO trial is to assess the tolerability and efficacy of a step-in dosing concept of the dual SRC-ABL kinase inhibitor Bosutinib in CP-CML patients who either developed intolerance or treatment failure to previous Imatinib, Dasatinib or Nilotinib as 1st or 2nd line therapy
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E.2.2 | Secondary objectives of the trial |
To assess: • Tolerability (i.e. all grade, grade 2 to 4 and grade 3 and 4 toxicities) at month 6, 12 and 24 • Efficacy parameters: MMR (Major Molecular Response), MR4 (Molecular Response with a sensitivity of 1:10000), MR4.5 (Molecular Response with a sensitivity of 1:50000) and CCyR (Complete Cytogenetic Response) rate at month 3, 6, 12, 18 and 24 • Patient-reported outcome measures (QoL) • Progression-free survival (PFS) • Overall survival (OS) • The rate of emerging mutations during Bosutinib treatment
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Version of all substudies is V2.0, release date 15th of August 2015: Substudy 1:Vascular biology substudy: • Effects of previous therapy on the baseline vascular risk profile (i.e. Nilotinib- vs. Dasatinib-pre-treatment) • Biological and clinical surrogates for vascular alterations during Bosutinib therapy at baseline, months 6, 12, and 24 Substudy 2:Pharmacokinetic (PK), pharmacodynamic (PD) sub- study: • Correlation of PK with response and toxicity • Correlation of PK with PD (i.e. phosphoproteomic changes) in immune cell populations • Correlation of PD changes in immune cell populations with response Substudy 3:Ultra-deep next-generation sequencing (UD-NGS) • Documentation of subclone evolution or elimination during Bosutinib treatment Substudy 4:telomere substudy: • Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response and of (haematological and nonhematological) toxicity experienced under Bosutinib Substudy 5: Assessment of patients comorbidities and correlation to individual patient´s adverse side effect profile substudy: • Documentation of patient´s comorbidity profile using 3 different comorbidity scales • Assessment of adverse side effects throughout study • Correlation between both profiles Substudy 6:Transport mechanisms of Bosutinib and mechanisms of diarrhea substudy: Investigation the role of the 5-HT pathway in directing bosutinib induced diarrhea by assessment of 5-HT and certain cytokine levels and genetic analysis including Single Nucleotide Polymorphism and genome-wide association study.
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E.3 | Principal inclusion criteria |
1. Signed written informed consent 2. Male or female patients aged ≥18 years 3. ECOG performance status of 0 to 2 4. CML in 1st or late chronic phase 5. Intolerant* or resistant** to pretreatment with one or two of the approved first line TKI (Imatinib, Nilotinib or Dasatinib). Imatinib therapy prior to 2nd generation TKI therapy for a maximum of 6 weeks is allowed. 6. Patients must have a serum creatinine of ≤ 2 x ULN, SGOT/SGPT ≤ 3 x ULN, total bilirubin ≤ 2 x ULN (except known Gilbert’s syndrome), and Lipase ≤ 1.5 x ULN 7. Female patients of childbearing potential must have a negative pregnancy test performed during screening period 8. Male and female patients of reproductive potential must agree to employ a highly effective contraceptive method*** throughout the study and for 6 months following discontinuation of study drug.
* Intolerance is defined as discontinuation of Imatinib OR Nilotinib OR Dasatinib due to grade 3 or 4-related adverse event (AE), despite optimal supportive care, or because of a persistent grade 2-related AE, despite optimal supportive care, which persists ≥1 month or recurs >2 times with TKI dose reduction or which is medically significant (independent of grade) and according to investigator´s opinion should lead to change of TKI.
** Resistance is defined as not achieving optimal response to Imatinib OR Nilotinib OR Dasatinib according to ELN2013-defined recommendations (Baccarani, Blood 2013). Optimal response is defined as: - BCR-ABL1 ≤ 10% and/or Ph+ ≤ 35% at 3 months - BCR-ABL1 < 1%, and/or Ph + 0% at 6 months - BCR-ABL1 ≤ 0,1% (MMR) at 12 months - BCR-ABL1 ≤ 0.1% (MMR) after 12 months - no loss of MMR (Major Molecular Response) - no loss of CCyR (Complete Cytogenetic Response) - no loss of complete hematologic response (CHR)
*** Highly effective contraceptive methods (Pearl Index <1) are surgical sterilization, hormonal contraceptives, intrauterine devices and sexual abstinence. Oral contraceptives shall be used in conjunction with barrier methods (i.e. condoms) during study treatment.
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E.4 | Principal exclusion criteria |
1. Hypersensitivity against Bosutinib or other ingredients of the medicinal product 2. Evidence of features of accelerated (AP) or blast phase (BC) at any time before inclusion 3. Patients with BCR-ABL negative CML 4. Patients having received Imatinib for more than 6 weeks prior to initiation of 2nd generation TKI (either Nilotinib or Dasatinib) 5. Patients with known T315I or V299L mutation 6. Concomitant medications known to be strong inducers or inhibitors of P450 isoenzyme CYP3A4 (see www.drug-interactions.com) 7. History of pancreatitis, inflammatory bowel disease requiring systemic or topical immunosuppressive therapy within the last 12 months 8. Impaired cardiac function, including any of the following: a. History of or presence of complete left bundle branch block, right bundle branch block plus left anterior hemiblock, bifascicular block in screening ECG b. ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more contiguous leads in screening ECG c. Congenital long QT syndrome d. QTc> 450 msec in the screening ECG e. QT-prolonging concomitant medication f. History of or presence of significant ventricular or atrial tachyarrhythmias in screening ECG g. History of or presence of clinically significant resting bradycardia (< 50 beats per minute) h. Myocardial infarction within 6 months prior to inclusion i. Unstable angina diagnosed or treated during the past 12 months j. Uncontrolled hypertension, history of labile hypertension
9. Known HIV and/or active viral hepatitis (hepatitis B or C). Hepatitis B screening will be performed at screening. Patients with a history of hepatitis B with negative HBV DNA may be included when using antiviral prophylaxis. 10. Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinoma of the skin 11. Treatment with another investigational product during this study or during the last 30 days prior to study start except treatment with interferon-alpha within the TIGER (CML V) protocol, which must be stopped at least 7 days prior to study start 12. Any circumstance at the time of study entry that would preclude completion of the study or the required follow-up prohibits inclusion into this study 13. Patient must not have any active bacterial, viral or fungal infection at screening 14. Patient must not have severe cerebral dysfunction and/or legal incapacity 15. Conditions which interfere with the study treatment at the discretion of the investigator 16. Women who are pregnant or breast feeding
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E.5 End points |
E.5.1 | Primary end point(s) |
Rate of GI-Toxicity (i.e. incidence and severity of grade 2 to 4 toxicities) within the first 6 months of treatment |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at Screening (visit 1), first application of IMP = Day 1 (visit 2), during dose escalation every 14 days until end of month 3 (visit 3 to 7), end of month 3 (visit 8) and end of month 6 (visit 9)
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E.5.2 | Secondary end point(s) |
• Tolerability (i.e. all grade, grade 2 to 4 as well as grade 3 and 4 toxicities) • Efficacy parameters: MMR (Major Molecular Response), MR4 (Molecular Response with a sensitivity of 1:10000), MR4.5 (Molecular Response with a sensitivity of 1:50000) and CCyR (Complete Cytogenetic Response) rate • Patient-reported outcome measures (QoL) • Progression-free survival (PFS) • Overall survival (OS) • The rate of emerging mutations during Bosutinib treatment
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Tolerability (i.e. all grade, grade 2 to 4 as well as grade 3 and 4 toxicities) at 6, 12 and 24 months (visit 9, 11 and 15) • Efficacy parameters: MMR, MR4, MR4.5 and CCyR rate at month 3, 6, 12, 18 and 24 (visit 8, 9, 11, 13 and 15) • Patient-reported outcome measures (QoL) at Screening (visit 1), first application of IMP = Day 1 (visit 2), during dose escalation every 14 days until end of month 3 (visit 3 to 7), every 3 month until end of study (visit 8 to 15) • Progression-free survival (PFS), Overall survival (OS) and the rate of emerging mutations during Bosutinib treatment during dose escalation every 14 days until end of month 3 (visit 3 to 7), every 3 month until end of study (visit 8 to 15)
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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 | Yes |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Substudy 4: Assessment of telomere length in normal and leukemic cells as potential new biomarker for prognosis, prediction of response and of (haematological and nonhematological) toxicity experienced under Bosutinib |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
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
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 17 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |