| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic phase Chronic Myeloid Leukaemia |
|
| E.1.1.1 | Medical condition in easily understood language |
| early stages of myeloid (bone marrow) leukaemia (blood cancer) which originates in the bone marrow. |
|
| 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 | 16.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052065 |
| E.1.2 | Term | Chronic phase chronic myeloid leukaemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 study aims to see if treatment with imatinib is as good as treatment with nilotinib when patients in either group who are not doing so well switch to ponatinib. The response to treatment is measured in the blood and tests will look for leukaemic cells. |
|
| E.2.2 | Secondary objectives of the trial |
| We are looking at survival in the group of patients who start on imatinib compared to the group of patients who start on nilotinib five years after they first start treatment. We would like to know the numbers of patients who start on either imatinib or nilotinib who are able to reduce or stop treatment and maintain control of their leukaemia. The study also aims to see how cost effective the use of these particular drugs can be to the NHS. Imatinib will soon be available to the NHS at a much lower price than it is now and also in comparison to nilotinib it is likely to be much cheaper for a number of years to come. Ponatinib (which will be supplied free of charge to trial patients) may be used to help patients that started on imatinib or nilotinib to gain the best response possible and it might be that reducing the dose of any of these drugs to half or being able to permanently stop them will be of great long-term benefit to the NHS in terms of cost. We will look at safety |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. Male or female patients ≥ 18 years of age. 2. Patients must fulfill all of the following: i) be diagnosed with chronic phase CML confirmed by blood morphology and RT-PCR for BCR-ABL. ii) be enrolled within 3 months of initial diagnosis of chronic phase CML (date of RT-PCR confirming presence of BCR-ABL) iii) be in confirmed chronic phase ie: a) < 15% blasts in blood (manual differential) b) < 30% blasts plus promyelocytes in blood c) < 20 % basophils in blood d) ≥ 100 x 109 /L platelets e) no evidence of extramedullary leukaemic involvement, with the exception of hepatosplenomegaly 3.Written voluntary informed consent. |
|
| E.4 | Principal exclusion criteria |
| 1. Any prior treatment for CML with any TKI (eg imatinib, dasatinib, nilotinib, bosutinib, ponatinib); busulphan, IFN-alpha, homoharringtonine, cytosine arabinoside, any other investigational agents. 2. Patients who have received prior CML chemotherapy including regimens used in peripheral blood progenitor cells (PBPCs) mobilisation for haematopoietic progenitor-cell transplantation. (collection of unmobilised PBPCs is allowed at diagnosis). 3. Patients who have had any form of prior haematopoietic stem cell transplant (autograft or allograft). 4. Patients with an ECOG Performance Status Score ≥ 3 5. Patients with serum bilirubin, SGOT/AST, SGPT/ALT or creatinine concentrations > 2.0 x upper limit of normal (ULN) 6. Patients with serum amylase or lipase > 1.5 x ULN, history of acute pancreatitis within 1 year of study, history of chronic pancreatitis, or uncontrolled hypertriglyceridaemia (triglycerides > 450 mg/dL) 7. Patients with significant uncontrolled or active cardiovascular disease, specifically including, but not restricted to a) myocardial infarction, unstable angina and/or congestive heart failure within 6 months prior to study; and b) history of clinically significant atrial arrhythmia; or any ventricular arrhythmia. 8. Patients taking medications known to be associated with Torsade de Pointes (eg amiodarone, azithromycin, chloroquine, citalopram, domperidone, erythromycin, quinidine, sotalol, thioridazine) 9. Patients with known uncontrolled hypertension; systolic blood pressure > 140mm Hg and/or diastolic blood pressure > 90mm Hg 10. Patients with a known INR or PTT > 1.5 x ULN, with the exception of patients on treatment with oral anticoagulants, or patients with a known bleeding disorder. Baseline testing of INR is not required. 11. Patients with uncontrolled medical disease such as diabetes mellitus, thyroid dysfunction, neuropsychiatric disorders or infection. 12. Patients who have undergone major surgery within 4 weeks of starting trial IMP. 13. Patients who are: a) pregnant b) breast feeding c) of childbearing potential without a negative pregnancy test prior to starting trial IMP and d) male or female of childbearing potential unwilling to use barrier contraceptive precautions throughout the trial (postmenopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential). 14. Patients with a history of another malignancy either currently or within the past five years (with the exception of basal cell skin carcinoma in situ). 15. Patients with a history of non-compliance to medical regimens or patients who can envisage being unable to complete the study for any reason. 16. Patients unwilling to receive trial drug via a home delivery method. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is major molecular response (MMR, MR3) at 3 years on study in group I and group N. Group I is all patients who were initially randomised to imatinib and group N is all patients who were initially randomised to nilotinib (regardless of whether they subsequently switched to ponatinib). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Three years from start of participation in trial. |
|
| E.5.2 | Secondary end point(s) |
| Overall survival (OS), progression free survival (PFS) and event free survival (EFS) at 5 years in group I (started on imatinib) vs group N (started on nilotinib). Assessment of the number of patients at 5 years in group I (started on imatinib) vs group N (started on nilotinib) who are in the following categories (MR3 will include PCR undetectable): - No dose reduction at 3 years (stage 3); on full dose, not in MR3 - No dose reduction at 3 years (stage 3); on full dose, in (late) MR3 - Underwent unsuccessful dose reduction at 3 years (stage 3); on full dose, not in MR3 - Underwent successful dose reduction at 3 years (stage 3); on reduced dose in MR3 - Underwent successful dose reduction at 3 years (stage 3); off treatment in MR3 - PCR undetectable regardless of current therapy The incremental cost per quality-adjusted life-year gained (incremental cost effectiveness ratio or ICER) over 5 years in group I and group N and extrapolated over the estimated patient life time. Assessment of the costs to the NHS and personal social services of the alternative regimens over 5 years and extrapolated over the estimated patient life time. Treatment failure due to resistance or intolerance in group I and group N. To assess the safety and tolerability of imatinib, nilotinib and ponatinib. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall survival, progression free survival and event free survival will be assessed at 5 years. Secondary endpoints that focus on patients who have switched treatment to ponatinib will be assessed at 5 years, focussing on their status at 3 years of the trial. |
|
| 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 | 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 | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | Yes |
| 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.8.2.4 | 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 | 163 |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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