E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic myeloid leukemia at diagnosis-chronich phase |
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E.1.1.1 | Medical condition in easily understood language |
Chronic myeloid leukemia, a type of blood cancer |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009015 |
E.1.2 | Term | Chronic myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 estimate efficacy of the addition of RoPegIFN to BOS in terms of deep molecular response with the aim of increasing the proportion of patients who may achieve treatment free remission. |
Å vurdere effekten av å legge til RoPeginterferon til bosutinib for å oppnå meget god respons med målsetning å øka andel pasienter som kan slutte med medisin uten å få tilbakefall (behandlingsfri remisjon) |
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E.2.2 | Secondary objectives of the trial |
• To compare cytogenetic and molecular response including kinetics through the treatment course. • To assess the proportion of patients eligible for randomization after the initial 3 months of BOS. • To determine and to compare safety and tolerability of the treatment in each arm. • To estimate reasons and cumulative rates of RoPegIFN and BOS discontinuation and the median dose of each drug by study arm. • To evaluate the tolerability, of a step-by-step dose schedule for BOS initiation (BOSUSTEP substudy) • To estimate the progression free, event-free and overall survival in each arm. • To estimate the proportion of patients achieving a durable deep molecular response and secondary eligibility for treatment discontinuation. • To compare the measurement of deep molecular response (by standard RTQPCR and digital droplet PCR (ddPCR), • To estimate and compare the rate of successful treatment discontinuation after M48 in each arm
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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 |
A substudy of immunological parameters and a proteomic approach for identification of tumour markers is planned |
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E.3 | Principal inclusion criteria |
1) Signed written informed consent form (ICF) before any procedure related to the study 2) Target Population a) Men and women, ages 18 to 75 years b) Newly diagnosed (≤ 3 months) BCR-ABL positive chronic myeloid leukemia in chronic phase c) Major BCR-ABL transcripts (p210 b2a2(e13a2) and/or b3a2(e14a2)) 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 < 1,5 times the institutional Upper Limit of Normal (ULN) ii. Hepatic enzymes ASAT and ALAT < 2 times the institutional ULN iii. Serum Creatinine < 1.5 time the institutional ULN iv. Lipase < 1.5 time the institutional ULN 3) Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study. 4) WOCBP must have a negative serum or urine pregnancy test at screening. 5) 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. 6) Free subject, without guardianship nor subordination 7) Health insurance coverage.
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E.4 | Principal exclusion criteria |
1) Patients with BCR-ABL transcript other than M-BCR-ABL 2) Patients previously treated with tyrosine kinase inhibitors (TKIs). 3) Medical history and concurrent diseases: a) Hypersensitivity to any of the excipients of BOS or RoPegIFN b) Prior treatment with Interferon-α, contraindication to interferon-α, c) Autoimmune disorder, concomitant immunosuppressive treatment or corticosteroids, d) Pre-existing thyroid disease unless controlled with conventional treatment, auto-immune thyroiditis e) Chronic liver disease, f) Prior or ongoing severe psychiatric disease g) HIV positivity, chronic hepatitis B or C h) Uncontrolled or severe cardiac (NYHA Class III or IV) or pulmonary disease, Echocardiography with LVF < 45% or LLN, peak velocity of tricuspid regurgitant flow > 2,8 m/s Pulmonary arterial hypertension (PAH), QTc>450 ms (by Barrets correction) i) Other malignant disease during the last 5 years prior to the inclusion except non-melanoma skin carcinoma or carcinoma in situ of the cervix, j) History of significant bleeding disorder unrelated to CML or diagnosed congenital bleeding disorder, k) Subjects with an uncontrolled undercurrent illness or any concurrent condition that, in the investigator’s opinion, would jeopardize the safety of the subject or compliance with the protocol. 4) Prohibited treatments and/or therapies: strong inhibitors/inducers of the CYP 3A4, 5) History / any condition for poor compliance to medical treatment. 6) Women who are pregnant or breastfeeding are not eligible for this study 7) Inability to freely provide consent through judiciary or administrative condition. 8) Ongoing participation to another clinical investigational study.
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E.5 End points |
E.5.1 | Primary end point(s) |
To compare the rate of molecular response 4 (MR4) at 12 months in each treatment arm. |
Å sammenligne andel av pasienter, i hver studiearm for seg, vedrørende oppnåelse av molekylærrespons 4 (MR4) 12 måneder etter oppstart i studien |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months of treatment |
Etter 12 mnd behandling |
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E.5.2 | Secondary end point(s) |
• The rates of molecular responses MR2, MR3, MR4, MR4.5, at 1, 2, 3, 6, 9, 12, 15, 18, 21, 24 months and every 6 months thereafter in each arm. • The cumulative incidence of MR3, MR4, MR4.5 within the same periods in each arm. • The rates of complete cytogenetic response (CCyR) at 3, 6, 12 months. • The rates of undetectable molecular responses for the patients who achieved an MR4 and an MR4.5 in each arm. • The rates of MR4 and MR4.5 by standard RTQPCR IS and digital droplet PCR (ddPCR) on the centralized molecular samples, for the patients who achieve an MR4 or better: comparison for sensitivity and accuracy of the 2 methods at key time points to be decided (ie Month 12 and Month 48) • Time to and duration of CCyR, MR3, MR4, MR4.5. • The proportion of patients eligible for randomization after 3 months of BOS • The rates and characteristics of severe adverse events (SAE) and adverse events (AE) related to BOS and RoPegIFN, from clinical and biological assessments: type and grade according to the NCI CTCAE v4.03. • The dose intensity of RoPegIFN and BOS administered during the first two years of study treatment. The cumulative incidence of discontinuation of the therapies. Reasons of discontinuation. • Other endpoints for the BOSUSTEP substudy within the first three months of BOS: - Any grade of diarrhea and GI toxicity - Other AE > grade 1 related to BOS - The final dose level of BOS by 3 months - The proportion of patients with transient treatment discontinuation - The proportion of patients with permanent treatment discontinuation - Cytogenetic and Molecular responses assessed by BCR-ABL IS at M3 and M6 - The relationship between plasma residual concentration (Cmin) after dose escalation steps and tolerance / efficacy of BOS in a subset of patients (French cohort), and at M3 for Nordic patients who take part in ancillary projects. • The progression free survival, the event-free survival and the overall survival. Occurrence and type of BCR-ABL TK mutation • Quality of life assessment by QLQC30 and CML24 questionnaires at key time point (Day 1, M3, M6, M12, M24, M48, M54, M72) • The proportion of patients achieving a durable deep molecular response and being eligible for treatment discontinuation at month 48. Sustained deep molecular response criteria will be defined according updated data and ELN guidelines before the first patient will achieve Month 48 (at least a MR4 over a 12 months period and confirmed on the last centralized measurement at M48) • The proportion of patients in treatment free remission after 6, 12, 24 and 36 months of BOS discontinuation, from M48.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
See text above in E5.2.Many time points |
Se E5.2 |
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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 | 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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 7 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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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LPLV q3 2028 |
Sidste lægebesøg i studiet q3 2028 |
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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 | 9 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 9 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |