| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adult patients with Ph+ chronic phase CML that have been treated with Imatinib for at least 2 years, are in CCyR, but have not achieved MR4.0 at study entry. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Adult patients with CML who have been treated with imatinib (Glivec) for at least two years and who have not achieved a certain level of molecular response at study entry. |
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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 | 19.0 |
| 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 |
|
| 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 assess the optimal duration of consolidation treatment with nilotinib 300 mg BID in order that patients remain in TFR (≥MR4.0) without molecular relapse 12 months after entering TFR phase.
|
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the proportion of patients who are eligible to suspend nilotinib therapy by achieving and maintaining a sustained ≥MR4.0 for at least 12 months during consolidation treatment with nilotinib 300 mg BID.
- To assess the achievement of MMR, MR4.0, and MR4.5 during induction/consolidation treatment with nilotinib 300 mg BID
- To assess the molecular response in patients during induction/consolidation treatment with nilotinib 300 mg BID
- To assess the proportion of patients in TFR at 3, 6, 12, 18 and 24 months after nilotinib cessation
- To assess the molecular response in patients after randomization
- To assess the kinetics of BCR-ABL transcript during induction/consolidation treatment with nilotinib 300 mg BID
- To assess the kinetics of BCR-ABL transcript during the TFR phase
- To assess the PFS, TFS, OS
- To assess the safety profile of nilotinib |
|
| 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 |
Optional Stem cells ENESTPath substudy:
The Stem cells ENESTPath substudy adds the determination of Ph+ stem cells in bone marrow for those patients consenting to participate in the substudy.
Objectives:
- To evaluate the presence and number of LSC and their progenitors in the bone marrow of all patients participating in this substudy before and after completing induction and first year of consolidation phase (at Visit 8);
- To evaluate if prolonging treatment re-initiationperiod of consolidation with nilotinib (patients in Arm 2 versus patients in Arm 1) induces a reduction in the percentage of patients presenting LSC and progenitor cells in bone marrow at the end of the second year of the consolidation phase
- To perform an exploratory analysis in order to evaluate whether relapse in patients during the TFR phase in either arm correlates with the presence of LSC and progenitor cells in bone marrow at the end of the consolidation phase and at the time of relapse during TFR.
"CML patients’ voice" Italian substudy:
The "CML patients’ voice" Italian substudy will evaluate the emotional aspects in patients participating to a nilotinib Treatment-free remission (TFR) trial. This substudy aims to examine patients’ psycho-emotional characteristics, quality of life and experiences of being involved in CAMN107AIC05 trial and its discontinuation using a qualitative-quantitative mixed method. The ‘CML patient’s voice’ Italian substudy will be conducted in Italy only [see Post-text Supplement 1]. |
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| E.3 | Principal inclusion criteria |
• Male or female patients, aged ≥ 18 years;
• Eastern Cooperative Oncology Group (ECOG) performance status of 0- 2;
• Documented confirmed diagnosis of chronic phase Ph+ and/or BCR-ABL+ CML. Documented chronic phase CML must meet all of the following criteria:
- < 15% blasts in peripheral blood and bone marrow
- < 30% blasts plus promyelocytes in peripheral blood and bone marrow
- < 20% basophils in the peripheral blood
- ≥ 100 x 109/L (≥ 100,000/mm3) platelets
- No evidence of extramedullary leukemic involvement, with the exception of hepato- and/or splenomegaly
• Previous first-line treatment with imatinib for a minimum of 24 months (even not continuously) in total and in imatinib treatment at time of enrollment;
• Patient in CCyR (a patient with MMR is considered to be in CCyR. Therefore, cytogenetic response (CgR) assessment has to be done if a patient has less than MMR in the local laboratory result and/or in the blood sample that was sent to the EUTOS standardized laboratory at the screening visit (patient will be considered screening failure if not in CCyR);
• Adequate end-organ function
• Patients must have the following electrolyte values within normal limits at screening analysis, or corrected to within normal limits with supplements prior to the first dose of study medication:
- Potassium
- Magnesium
- Total calcium
• Patients must have normal marrow function as defined below:
- Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L.
- Hemoglobin ≥9.0 g/dL
- Platelets ≥100 x 109/L
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures
• Written informed consent must be obtained prior to any screening procedures
For those patients consenting to participate in the optional Stem cells ENESTPath substudy or in the ‘CML patient’s voice’ Italian substudy, the same inclusion criteria for the ENESTPath study will be applicable, plus the following:
• Separate specific written informed consent for the Stem cells ENESTPath substudy or for the ‘CML patient’s voice’ Italian substudy must be obtained before starting any sub-study related assessment like but not limited to extraction of additional bone marrow samples for stem cells sub-study. |
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| E.4 | Principal exclusion criteria |
• Achievement of MR4.0 at study entry;
• Previous treatment with BCR-ABL inhibitors other than imatinib;
• Patients with detectable atypical BCR-ABL transcripts defined as absence of typical BCR-ABL transcripts for CML of the types b2(e13)-a2 or b3(e14)-a2 or both simultaneously documented at CML diagnosis or at any time before the screening procedure;
• Previous anticancer agents for CML except for imatinib, and/or cytoreduction after CML diagnosis, and/or interferon for less than 1 year;
• Known second chronic phase of CML after previous progression to AP/BC
• Known impaired cardiac function, including the following:
- Inability to determine the QT interval on ECG
- Complete left bundle branch block
- Right bundle branch block plus left anterior or posterior hemiblock
- Use of a ventricular paced pacemaker
- Long QT syndrome or a known family history of long QT syndrome
- History of or presence of clinically significant ventricular or atrial tachyarrhythmias
- Clinically significant resting bradycardia (<50 beats per minute)
- QTc >450 msec on the average of three serial baseline ECGs (using the QTcF formula). If QTcF >450msec and electrolytes are not within normal ranges, electrolytes should be corrected and the patient re-tested for the QTc
- History of clinically documented severe peripheral occlusive disease or severe ischemic cardiovascular disease (e.g. myocardial infarction, ischemic cerebral vascular disease) whenever in the opinion of the investigator other treatments could have a more favorable benefit/risk profile
- Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension)
• Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks or compromise compliance with the protocol;
• History of acute pancreatitis within 12 months of study entry, or a past medical history of chronic pancreatitis;
• Known presence of significant congenital or acquired bleeding disorder unrelated to cancer;
• History of other active malignancies within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer, or previous cervical carcinoma in situ treated curatively;
• Patients who have not recovered from prior surgery;
• Treatment with other investigational agents within 4 weeks of Day 1;
• Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers or medications that have the potential to prolong the QT interval that cannot be either discontinued or switched to a different medication prior to starting study drug;
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
• Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) female of childbearing potential unwilling to use highly effective contraceptive precautions (as detailed below) throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential);
• Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during dosing and for 14 days after the final dose of nilotinib or imatinib. Patients using an oral hormonal contraception method should complete their monthly treatment course.
• Patients not able to understand and comply with study instructions and requirements;
For those patients consenting to participate in the optional Stem cells ENESTPath substudy or in the ‘CML patient’s voice’ Italian substudy, the same exclusion criteria as for the ENESTPath study will apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is the number of patients who remain in TFR (≥MR4.0) without molecular relapse, at the end of 12 months in the TFR phase of the study, in the nilotinib 12 months consolidation treatment arm versus the nilotinib 24-month consolidation treatment arm. Molecular relapse during TFR is defined as the loss of MMR, or the confirmed loss of MR4.0 (defined by 3 consecutive tests less than MR4.0 assessed at 3 consecutive visits according to the visit schedule of the TFR phase) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| At the end of 12 months after in the TFR phase |
|
| E.5.2 | Secondary end point(s) |
- The proportion of patients who achieve a sustained ≥MR4.0 (defined as having 4 out of 5 quarterly assessments of ≥MR4.0 by a (EUTOS) standardized laboratory over the last 12 months and the last assessment before randomization is at least MR4.0) during the consolidation phase of the study.
- The proportion of patients who achieve MMR, MR4.0, or MR4.5 on the study at selected time points (every 3 months until Month 24 or Month 36 depending on the randomized arm) during the induction/consolidation phase of the study.
- The proportion of patients who are in MMR, MR4.0, or MR4.5 on the study at selected timepoints (every 3 months until Month 24 or Month 36 depending of the randomized arm) during the induction/consolidation phase of the study.
- The proportion of patients in TFR, i.e. with no confirmed loss of MR4.0, no loss of MMR and no restarting of nilotinib therapy within the first 3, 6, 12, 18, and 24 months following nilotinib cessation.
- The proportion of patients who are in MMR, MR4.0, or MR4.5 at selected time points (at Month 3, 6, 12, and every 3 months thereafter until Month 24 or Month 36 depending on the randomized arm) during the TFR phase in each one of the two treatment arms.
- BCR-ABL transcript levels (IS) during the induction/consolidation phase
- BCR-ABL transcript levels (IS) during the TFR phase
- BCR-ABL transcript levels (IS) during the nilotinib re-treatment phase
- PFS is defined as progression to AP/BC or death from any cause, where the “failure” event is the earliest occurrence of either of these events.
- TFS is defined as lack of any of the following events: loss of MMR, confirmed loss of MR4.0, re-start of nilotinib treatment for any reason, progression to AP/BC, or death from any cause.
- Overall survival is defined as the time from randomization to the time of death due to any cause.
- Safety will be monitored through assessment of Adverse Events, laboratory data, ECG, vital signs.
The following endpoints are applicable to all the objectives detailed for the optional Stem cells ENESTPath substudy:
- Proportion of patients with presence of Ph+ LSC in bone marrow (CD34+/CD38+ progenitor cells, CD34+/CD38− stem cells, and CD34+/CD56+ aberrant stem cells [the last ones only if detectable]) at screening and at Visit 8.
- Proportion of patients with presence of Ph+ LSC in bone marrow (CD34+/CD38+ progenitor cells, CD34+/CD38− stem cells, and CD34+/CD56+ aberrant stem cells [the last ones only if detectable]) at the end of consolidation arm (Visit 8 for Arm 1 and Visit 204 for Arm 2).
- Proportion of patients with or without molecular relapse in the first year of TFR in either arm by presence of LSC in bone marrow (CD34+/CD38+ progenitor cells, CD34+/CD38− stem cells, and CD34+/CD56+ aberrant stem cells [the last ones only if detectable]) at Visit 8 and at the time of relapse during TFR. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please see section 3 of the protocol; secondary endpoints. |
|
| 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 | No |
| 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 | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Evaluation of treatment free remission rate |
|
| 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 | No |
| 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) | No |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 251 |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
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