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 |
Chronic myeloid leukemia, a type of chronic blood cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
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 |
Observe toxicity of drug combination See protocol
Observe effect measured as response by molecular assesment of BCR-ABL transcript. fraction in So called major molecular remission (i.e 3 log below debut levels) |
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E.2.2 | Secondary objectives of the trial |
Observe toxicity of drug combination See protocol
Observe fraction of patients who achieve a very good response (So called major molecular remission, which is less than a thousandth of the disease burden at diagnosis |
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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 |
Scientific substudies of lymphocyte and stem cell biology |
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E.3 | Principal inclusion criteria |
Inclusion Criteria:
1. Age ≥18- 70 years of age
2. Diagnosis of chronic myeloid leukemia in chronic phase (CML-CP) associated with BCR-ABL1 quantifiable by RQ-PCR (IS)
3. No other current or planned anti-leukemia therapies excluding hydroxyurea treatment for up to two months.
4. ECOG Performance status 0,1, or 2
5. Adequate organ function as defined by: Total bilirubin < 1.5 x ULN (ULN = upper limit of normal in a local institution lab) in absence of Gilbert genotype; ASAT and ALAT < 2.5 x ULN. Creatinine < 2x ULN. Potassium, magnesium and phosphate not below LLN (LLN= lower level of normal)
6. Life expectancy of more than 12 months in the absence of any intervention
7. Patient has given written informed consent to participate in the study
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E.4 | Principal exclusion criteria |
Exclusion criteria:
1. Prior accelerated phase or blast crisis
2. Uncontrolled or significant cardiovascular disease, including any of the following:
a. A myocardial infarction within 6 months
b. Uncontrolled angina within 3 months
c. Congestive heart failure within 3 months
d. Diagnosed or suspected congenital long QT syndrome
e. Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de Pointe)
f. Prolonged QTcF interval > 450 msec on pre-entry ECG
3. Atypical BCR-ABL1 transcript not quantifiable by RQ-PCR.
4. Another primary malignant disease, which requires systemic treatment (chemotherapy or radiation)
5. Severe and/or life-threatening medical disease including acute liver disease
6. History of significant congenital or acquired bleeding disorder unrelated to cancer
7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of dasatinib
8. Patients actively receiving therapy with strong CYP3A4 inhibitors and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
9. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
10. Female patients who are: pregnant, breast feeding or potentially fertile without a negative pregnancy test prior to baseline or unwilling to use contraception on trial
11. History of non-compliance, abuse of alcohol, illicit drugs, severe psychiatric disorders or other inability to grant informed consent.
12. Hypersensitivity to any interferon preparation;
13. Autoimmune hepatitis or a history of autoimmune disease;
14. Pre-existing thyroid disease unless it can be controlled with conventional treatment;
15. Epilepsy and/or compromised central nervous system (CNS) function;
16. HCV/HIV patients
17. Depression requiring treatment
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoint:
Safety endpoint in run-in phase (first 15 patients):
Study stops if four out of the first five, six of the first 10 or 8 of the first 15patients experience grade IV hematological toxicity, grade III non-hematological toxicity or grade II serosal effusions during first 6 months of treatment. Data will be evaluated by an independent safety committee.
Whole study efficacy endpoint:
Rate of MMR after 12 months.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
6 months for safety
12 months for efficacy |
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E.5.2 | Secondary end point(s) |
Secondary Endpoint (s)
• Rate of CCgR after 3, 6, 12 and 18 months
• Rate of MMR after 3, 6, 15, 18, and 24 months
• Rate of MR4.0 and MR4.5 after 3, 6, 12, 15, 18, and 24 months
• Rate of grade 2 non-hematological toxicity that poses a clinical problem (duration more than one month in spite of symptomatic treatment)
• Rate of grade 3-4 hematological toxicity
• Overall survival
• Rate of patients who complete 3, 6 and 12 months of PegIFN treatment
• QoL at 0, 3, 6, 12 and 18 months
• Progression to advanced disease phase.
• Comparison of safety and efficacy variables with historical cohorts from Nord CML006 and NordCML002
• Biomarkers of response, failure and toxicity. A) Fraction of leukemic cells in the stem cell (Ph+ CD34+CD38- cells) and progenitor cell (Ph+ CD34+CD38+) compartment at debut and 4 weeks of dasatinib treatment. B) Lymphocyte subpopulations at 0, 3 and 6 months by flow cytometry assay: Enumeration of CD4+ and CD8+ T-cells, NK-cells, NKT-cells, B-cells and regulatory T-cells. Correlation of these subpopulations to response. C) Functional assays of lymphocytes: Cytotoxicity of NK-cells. IFN-γ production by T cells after stimulation. Granzyme B staining for evaluating the cytotoxic potential of T-cells. Functional assays will be performed both from pre- and post-drug samples. D) Clonality: TCR γδ rearrangements by PCR E) Plasma cytokine array: Luminex multiplex system F) Proteomics
A simplified follow-up of treatment response by real-time quantitative reverse transcriptase PCR (RQ-PCR), treatment type, progression to advanced phase and survival will be performed yearly until end of year 5.
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of Life analysis is included
Several measurements of lymphocytes and stem cells for identification of good biomarkers. |
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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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Comparison with historical controls |
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E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 16 |
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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Study ends for toxicity reasons as stated under primary endpoint
Patients are otherwise followed for 5 years totally |
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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 |