E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML) |
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E.1.1.1 | Medical condition in easily understood language |
CHRONIC PHASE CHRONIC MYELOGENOUS LEUKAEMIA (CP-CML) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10058246 |
E.1.2 | Term | Chronic myelogenous leukaemia |
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 |
To select molecules in combination or sequentially with imatinib, nilotinib, dasatinib, bosutinib or ponatinib potentially able to produce a 25% increase in the Cumulative Incidence of MR4.5 as compare to control. |
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E.2.2 | Secondary objectives of the trial |
A. To determine the safety of selected therapies
B. To determine the rate of MR4 by 12, 24, 36, 48 months in experimental and control arms
C. To determine the rates of MR4.5 by 24, 36, 48 months in experimental and control arms
D. To determine the rate of undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
E. To estimate treatment free remission (TFR) in patients eligible for discontinuation studies
F. To investigate the relationship between biological activity and the clinical efficacy of the selected therapies
G. To assess the effects of the treatments on the number and clonogenicity of CML stem cells and other biological markers of interest
H. To estimate duration of response, progression-free survival, event free survival and overall survival.
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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 |
The kinase activity of BCR-Abl and STAT5 will be assessed by respectively STAT5 and CrkL phosphorylation. The rate of phosphorylation of these proteins will perfom by western blot using PathScan® BCR/Abl Activity Assay (Cell Signaling hysically®).
Efficacy of the combination therapy with tyrosine kinase inhibitors and pioglitazone will be assessed by monitoring by RTQ-PCR BCR-ABL/ABL ratio and STAT5 rate in CD34 positives cells every six months.
STAT5 expression in CD34 positive cells will be assessed at month 6 and 12 by immunofluorence unsing STAT5 antibodies.
To assess the persistence of leukemic stem cell under the complete molecular response, CD34+ cells from patients were transplanted into NOD/SCID-b2m-/- mice (intra-femoral injection, 5-104 cells). The proportion and phenotype of human cells present in the bone marrow of the mice after 5 weeks were assessed by FACS analysis. To determine the proportion of leukemic cells present, human CD45+ cells were isolated by FACS and sorted cell fraction were analysed by RT-QPCR.
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E.3 | Principal inclusion criteria |
These inclusion criteria will apply for all arms. Specific criteria may apply for each experimental arm.
1. Patient aged 18y or more
2. Signed informed consent
3. Patient with Philadelphia chromosome positive chronic phase CML and M BCR-ABL1 transcript positivity
4. Treatment with imatinib, nilotinib, dasatinib, bosutinib or ponatinib for more than 2 years overall
5. No switch between tyrosine kinase inhibitors within the last 3 months
6. No dose modification within the last 3 months
7. Complete cytogenetic response or BCR-ABLIS ≤ 1%
8. Detectable BCR-ABL1 with BCR-ABLIS > 0.0032% (less than MR4.5)
9. ECOG grade 0 to 2
10. ASAT and ALAT ≤ 2.5 N
11. Bilirubin in serum ≤ 2.5 N
12. Women of childbearing potential must be using an adequate method of contraception
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating women,
2. Participation in another clinical trial with any investigative drug within 30 days prior to study enrolment,
3. Patient requiring anti-diabetic medication
4. Prior history of hematopoietic stem cell transplantation (autologous or allogenic)
5. Cardiovascular disease:
• Stage II to IV congestive heart failure (CHF) as determined by the New York Heart Association (NYHA) classification system for heart failure.
• Myocardial infarction within the previous 6 months
• Symptomatic cardiac arrhythmia requiring treatment
6. Grade III or IV fluid retention
7. Known BCR-ABL kinase domain mutation
8. CML patient not in chronic phase at diagnosis
9. Individuals with an active malignancy
10. Kown HIV-positivity
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end-point is the cumulative incidence of patients achieving a deep molecular response defined by MR4.5 or deeper (BCR-ABLIS ≤ 0.0032 %) by 12 months. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. Adverse events
2. The cumulative rate of patients achieving MR4.5 by 24, 36, 48 months in experimental and control arms
3. The cumulative rate of patients achieving MR4 by 12, 24, 36, 48 months in experimental and control arms
4. The cumulative rate of patients with undetectable BCR-ABL1 transcript (sensitivity 40000 ABL copies) by 12, 24, 36, 48 months in experimental and control arms
5. The rate of patients in treatment free remission during follow-up
6. Measurement of number and clonogenicity of CML stem cells using the leukemic stem cell markers followed by flow cytometry analysis and the LTC-IC assay and others markers (ancillary study)
7. Survival, progression free survival, event free survival, duration of response
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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 | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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) | 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 | Yes |
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 | 25 |
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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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 | 7 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |