E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with newly diagnosed chronic phase Chronic Myeloid Leukemia (CP-CML), not previously treated with Tyrosine Kinase Inhibitors (TKIs). First line therapy. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with newly diagnosed chronic phase Chronic Myeloid Leukemia (CP-CML), not previously treated with Tyrosine Kinase Inhibitors (TKIs). First line therapy. |
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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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10054352 |
E.1.2 | Term | Chronic phase chronic myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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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 primary objective of this study is to assess the efficacy of dasatinib combined to Peg-interferon-α2b on the cumulative rate of molecular response 4.5 (MR4.5) at 12 months, as frontline therapy for newly diagnosed CP-CML patients. |
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E.2.2 | Secondary objectives of the trial |
•To assess the rates of complete cytogenetic response (CCgR) at 3, 6, 12, 18, 24 months, and every 12 months thereafter.
•To assess the rates of major molecular responses (MMR) at 3, 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter.
•To assess the rate of molecular response 4.5 (MR4.5) at 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter.
•To assess the rates of molecular responses 5.0 (MR5.0) at 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter, for the patients who achieved MR4.5.
•To estimate the cumulative rates of CCR, MMR, MR4.5, MR5.0 within the same periods.
•Kinetics and duration of CCR, MMR, MR4.5MR5.0.
•To determine the safety and tolerability of the combination of PegIFN-α2b and dasatinib.
•To estimate the rate of PegIFN-α2b and dasatinib discontinuation, and dose reduction.
•To analyse the residual plasmatic levels (Cmin) of dasatinib.
•To estimate the progression free survival, event-free and overall survival.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Principal inclusion criteria
1) Signed Written Informed Consent: All patients must have read and sign the informed consent form (ICF) before any procedure related to the study, registration/inclusion in the study.
2) Target Population
a) Men and women, ages 18 to 69 years
b) Newly diagnosed (≤ 3 months) Philadelphia chromosome positive chronic phase chronic myeloid leukemia (CP-CML)
c) Major BCR-ABL transcripts (p210 b2a2 or b3a2)
d) Not previously treated for CML except with hydroxyurea or anagrelide
e) ECOG Performance Status (ECOG PS) ≤ 2
f) Adequate Organ Function.
i) Total bilirubin < 2.0 times the institutional Upper Limit of Normal (ULN)
ii) Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN
iii) Serum Na, K+, Mg2+, Phosphate and Ca2+ > Lower Limit of Normal (LLN)
iv) Serum Creatinine < 1.5 time the institutional ULN
g) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study. WOCBP include any woman who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or who is not post-menopausal. Post-menopause is defined as:
• Amenorrhea that has lasted for 12 consecutive months without another cause, or
• For women with irregular menstrual periods who are taking hormone replacement therapy (HRT), a documented serum follicle-stimulating hormone (FSH) level of greater than 35 mIU/mL.
Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or who are practicing abstinence or where their partner is sterile (e.g. vasectomy) should be considered to be of childbearing potential.
WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours before the start of the investigational product.
A male subject of fathering potential must use an adequate method of contraception to avoid conception throughout the study to minimize the risk of pregnancy.
3) Expected compliance to the treatment.
4) Health insurance coverage. |
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E.4 | Principal exclusion criteria |
1) Patients with BCR-ABL other than M-BCR-ABL, Philadelphia negative CML.
2) Patients previously treated with Tyrosine Kinase Inhibitors (TKIs).
3) Medical history and concurrent diseases:
a) Prior treatment with Interferon-α / Contraindication to interferon-α,
b) Concomitant immunosuppressive treatment or corticosteroids,
c) Preexisting thyroid disease unless it is controlled with conventional treatment, Auto-immune thyroiditis,
d) Autoimmune disorder, Chronic liver disease,
e) Prior or ongoing severe psychiatric disease,
f) Epilepsy or compromised central nervous system(CNS) function,
g) HIV positivity, chronic hepatitis B or C,
h) Uncontrolled or significant cardio vascular disease,
i) Uncontrolled angina, congestive heart failure or MI within 6 months,
ii) Echocardiography with LVF <45% or LLN,
iii) Pulmonary arterial hypertension (PAH),
iv) Any history of clinically significant ventricular or supraventricular arrhythmias,
v) Diagnosed congenital long QT syndrome,
vi) Prolonged QTc interval > 450 msec (Fredericia) on 3 pre-entry electrocardiogram,
vii) Subjects with hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib,
i) Other malignant disease during the last 5 years prior to the inclusion except basal cell carcinoma of the skin or carcinoma in situ of the cervix,
j) History of significant bleeding disorder unrelated to CML, including:
i) Diagnosed congenital bleeding disorders (e.g. von Willebrand’s disease),
ii) Diagnosed acquired bleeding disorder within one year (e.g. acquired anti-factor VIII antibodies),
iii) Ongoing or recent ( 3 months) significant gastrointestinal bleeding.
k) Another severe or life –threatening medical disease.
4) Women who are pregnant or breastfeeding, WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for at least 4 weeks after the last dose of study drug.
5) Prohibited treatments and/or therapies:
a) strong inhibitors of the CYP 3A4,
b) category I drugs that are generally accepted to have a risk of causing “Torsades de Pointes”. Patients must discontinue the drug minimum 7 days prior to starting dasatinib.
6) History /any condition for poor compliance to the treatment.
7) Inability to freely provide consent through judiciary or administrative condition.
8) Ongoing participation to another clinical trial. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the cumulative rate of molecular responses 4.5 (MR4.5) achieved at 12 months.
Centralized analyses of molecular response by RTQPCR will be performed for all molecular assessments in this study.
Molecular response 4.5 (MR4.5) is defined by either a positive BCR-ABL/ABL ratio ≤0.0032 on the international scale or by undetectable BCR-ABL with the analysis of at least 32000 copies of ABL (according to the ELN recommendations by N. Cross et al., leukemia 2012[26]).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months since enrolment |
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E.5.2 | Secondary end point(s) |
• The rates of complete cytogenetic response (CCgR) at 3, 6, 12, 18, 24 months and every 12 months thereafter.
• The rates of major molecular responses (MMR) at 3, 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter.
• The rate of molecular response 4.5 (MR4.5) at 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter.
• The rates of the molecular responses 5.0 (MR5.0) at 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter, for the patients who achieved MR4.5.
• The cumulative rates of CCR, MMR, MR4.5, MR5.0 within the same periods.
• Time to and duration of CCR, MMR, MR4.5MR5.0.
• Incidence and characteristics of severe adverse events (SAE) and adverse events (AE) related to the therapy, from clinical and biological assessments: type and grade according to the NCI CTCAE v4.0.
• The cumulative incidence of discontinuation for PegIFN-α2b or dasatinib during the first two years of study treatment. Time to and duration of discontinuation
• The dose intensity of PegIFN-α2b and dasatinib administered during the first two years of study treatment.
• The relationship between residual (Cmin) plasmatic levels and SAE related to dasatinib at M1, M6.
• The progression free survival, the event-free survival and the overall survival.
• Quality of life questionnaire (EORTC QLQ-C30) with PegIFN-α2b and dasatinib at Day 1, M3, M6, M12 and at the end of the study.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
12 months since enrolment |
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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) | 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 | No |
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 | 22 |
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 | 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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Duration of the study for one patient: four to five years including 24 months study therapy and 24 months follow-up. |
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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 | |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | |