Chronic Myeloid Leukemia
Conditions
Keywords
Peg-IFN, nilotinib, MR4.5, CML, chronic phase, first-line
Brief summary
This is a phase III trial comparing, for newly diagnosed chronic phase CML patients, nilotinib 600 mg BID as a standard arm and nilotinib 600 mg BID combined to interferon alfa 2 a (pegylated form improving tolerance and maybe enhancing is efficacy) at increased doses for a total of 24 months of combination, in a 1:1 randomized manner. The assessment for the primary efficacy endpoint will be performed at 12 months (since nilotinib initiation) and is the rate patients obtaining MR4.5 will be measured at this time point.
Interventions
DRUGNilotinib (Tasigna ®), capsules of 150 mg
Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months
DRUGNilotinib (Tasigna ®) and Pegylated interferon alfa 2a (Pegasys®)
* Nilotinib 2 capsules of 150 mg orally twice daily at 12 hours difference, fasting (minimum 1 hour before or 2 hours after a meal) for at least 36 months and * Pegylated interferon alfa 2a subcutaneously once a week (auto-injection syringes of 135 and 90 micrograms) at 30 micrograms/week the first month alone (= priming procedure), then at 30 micrograms/2weeks the first month of combination to nilotinib and then at 45 micrograms/week thereafter until month 24 after nilotinib initiation.
Sponsors
Novartis
Hospices Civils de Lyon
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male and female patients * CP-CML, positive Philadelphia chromosome or positive BCR-ABL (M-bcr transcript), diagnosed less than 3 months prior to study entry * Age of at least 18 years-old and less than 65 years * Patient for whom treatment with Nilotinib is expected * No other CML treatment except for hydroxyurea and/or anagrelide * No previous TKI treatment. * No previous treatment with IFN even for other purposes. * SGOT and SGPT \< 2.5 UNL * Serum creatinine \< 2 UNL * No planned allogeneic stem cell transplantation * Signed informed consent * ECOG score 0 to 2
Exclusion criteria
* Contra-indication to IFN * Transcripts other than M-Bcr * Pregnancy, lactation * HIV positivity, chronic hepatitis B or C. * Prior or concurrent malignancy other than CML (exceptions to be mentioned) * History of arterial occlusive disease or (peripheral, carotids or severe coronary heart disease). * Permanent elevation of total cholesterol and triglycerides despite treatment * Severe psychiatric/neurological disease (previous or ongoing) * Concomitant auto-immune disease * Other investigational product ongoing * Ongoing immunosuppressive treatment * Ongoing treatment at risk for inducing torsades de pointes * QTcF \> 450ms despite correction of predisposing factors (i.e electrolytes…) * Congenital long QTcF * Unstabilised thyroid disorder * No health insurance coverage
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Molecular response (MR) 4.5 at 12 months of nilotinib 300 mg twice a day versus a combination of low-dose Peg-Interferon (Peg-IFN) to nilotinib 300 mg twice a day in newly diagnosed CP-CML Chronic Phase Chronic Myelogenous Leukemia patients. | 12 months | Centralised assessment of the BCR-ABL transcripts at 12 months since nilotinib initiation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Major Molecular Response at 1, 2, 3, 6, 9, 12 months of nilotinib, and duration of MMR during the second year of treatment (18, 24 and 36 months). | 36 months | Centralised assessment of the BCR-ABL transcripts every month for 3 months and every three months until 12 months and thereafter every 6 months until 36 months assessment. |
| Rate of patients with BCR-ABL/ABL (IS) ≥10% at 3 months. | 3 months after nilotinib initiation | Centralised assessment of the BCR-ABL transcripts at 3 months. |
| Rate of CCyR (complete cytogenetic responses: bone marrow Philadelphie positive at 0 % on at least 20 metaphases) at 3, 6, 12 months of nilotinib. | Assessment at 3, 6 and 12 months | Local bone marrow cytogenetic assessment (on 20 metaphases) |
| Safety of the nilotinib combined to Peg-IFN or not (hematological and non-hematological adverse events (AE) graded according to the NCI CTC AE v3). | 36 months | Continuous evaluation of the AEs and SAEs reported during 36 months |
| Quality of life of patients treated in both arms | 36 months | EORTC-QLQ C30 and C24 questionnaire at months -1 (Arm B), month 0, 1, 6, 12, 24, 36. |
| Molecular Response 4.5 at 1, 2, 3, 6, 9, 12 months of nilotinib, and duration of MR4.5 during the second year of treatment (18, 24 and 36 months). | 36 months | Centralised assessment of the BCR-ABL transcripts every month for 3 months and every three months until 12 months and thereafter every 6 months until 36 months assessment. |
| Compliance to drugs in each arms | 36 months | Morisky questionnaire to be fulfilled at 1, 6, 12, 24 and 36 months after nilotinib initiation. |
| Molecular relapse rate at 6 and 12 months after nilotinib withdrawal in patients obtaining 2-year stable MR4.5. | 36 months | Local (but standardized) assessment of the BCR-ABL transcripts every months for 3 months. |
| Event-free survival. | 36 months | Survival since randomization without any event defined as loss of CHR, loss of PCyR or CCyR, death from any cause, progression towards accelerated phase or blast crisis. |
| Progression-free survival | 36 months | Survival without progression towards accelerated of blast phase, death. |
| Overall survival. | 36 months | Survival without death from any cause |
| Doses-reductions/interruptions of drugs in both arms. Mean daily doses of nilotinib and Peg-IFN administered. | 24 months for Peg-IFN, and 36 months for both drugs | Continuous recording of dose intensity along the study for 24-36 months. |
Countries
France
Outcome results
None listed