Primary Outcomes

Description: Determination of the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) of nilotinib in combination with LDE225

Measure: Incidence rate and category of dose limiting toxicities (DLTs) during the first two cycles of therapy

Time: 56 days (2 treatment cycles at 28 days each)

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Secondary Outcomes

Description: Assessment of the safety and tolerability profile of nilotinib in combination with LDE225

Measure: No of participants with Adverse drug reactions and serious adverse drug reactions, changes in hematology and blood chemistry values, assessments of physical examinations, vital signs and electrocardiograms

Time: 336 days (12 treatment cycles)

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Description: Assessment of the PK characteristics of nilotinib administered in combination with LDE225

Measure: Plasma concentration and basic pharmacokinetics (PK) parameters (as Cmax, Tmax, AUC)

Time: 50 days

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Description: Determination of the kinetics of major molecular response

Measure: Major molecular response (MMR) rates at 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

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Description: Determination of the kinetics of complete molecular response

Measure: Complete molecular response (CMR) rates at 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

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Description: Determination of major cytogenetic response rates

Measure: Major cytogenic response (MCyR) rates by 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

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Description: Determination of complete cytogenetic response rates

Measure: Complete cytogenic response (CCyR) rates by 3, 6 and 12 months

Time: 336 days (12 treatment cycles)

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Primary Outcomes

Measure: To confirm the patterns of resistance including point mutations which are newly expressed during the nilotinib treatment

Time: 5 years

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Secondary Outcomes

Measure: To analyze and evaluate the overall survival and disease free survival in the nilotinib treatment according to progression of the disease and types of point mutations

Time: 5 years

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Primary Outcomes

Description: TFR is defined as no confirmed loss of MR4 (Molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% IS. Loss of MMR does not require confirmationTFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 48 weeks after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.

Measure: Percentage of patients in Treatment Free Remission (TFR) within 48 weeks

Time: First 48 weeks following nilotinib cessation.

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Secondary Outcomes

Description: TFR is defined as no confirmed loss of MR4 (molecular response 4.0 log reduction from baseline) or loss of MMR (major molecular response) and no re-starting of nilotinib therapy within 12 months following cessation of nilotinib. Confirmed loss of MR4 is two consecutive BCR-ABL > 0.01% IS. Loss of MMR does not require confirmation.TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, no documented loss of MMR and no re-starting of nilotinib therapy in the first 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.

Measure: Percentage of patients in Treatment Free Remission (TFR) within 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years

Time: 96, 144, 192, 264 weeks and within 6,7,8,9 and 10 years following nilotinib cessation

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Description: Kaplan-Meier (KM) estimation of PFS. PFS is measured from the date of start of nilotinib TFR phase (cessation of nilotinib) to the date of the earliest of the event: progression to AP/BC, or death from any cause. Patients not known to have recurred or died on or before the cut-off date for the KM analysis will have their PFS interval right-censored at the earlier of the date of their last assessment (cytogenetic, hematology or extramedullary) for patients who are still on study and at the date of last contact for patients are in follow-up.

Measure: Progression free survival (PFS) to Accelerated phase/Blast crisis (AP/BC) or death

Time: nilotinib cessation up to approximately 580 weeks

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Description: TFS is measured from the date of the start of the nilotinib TFR phase to the date of the earliest of the following: loss of MMR, confirmed loss of MR4, re-start of nilotinib treatment, progression to AP/BC or death from any cause. Patients not known to have had any of the events or died on or before the cut-off date for the KM analysis will have their TFS interval right-censored at the earlier of the date of their last assessment (PCR, cytogenetic, hematology or extramedullary) for patients who are still on study and at the date of last contact for patients are in follow-up.

Measure: Treatment free survival (TFS)

Time: nilotinib cessation up to approximately 580 weeks

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Description: Kaplan-Meier (KM) estimation of OS. OS is measured from the date of start of nilotinib TFR phase to the date of death from any cause. If a patient is not known to have died, survival will be censored at the date of last contact.

Measure: Overall survival (OS)

Time: nilotinib cessation up to approximately 580 weeks

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Description: Descriptive statistics of BCR-ABL over time after re-start of nilotinib therapy. ABL= Abelson leukemia virus and BCR=Break point cluster region

Measure: Change in BCR-ABL (oncoprotein product of BCR-ABL fusion gene) transcripts after re-start of nilotinib therapy

Time: re-start of nilotinib up to approximately 48 weeks

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Description: Percentage of patients who are in stable MMR (stable MMR=BCR-ABL ≤ 0.1% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MMR any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MMR, irrespective of whether there is loss of MMR in between, by the number of patients who achieved MMR at any time during the nilotinib re-initiation phase

Measure: Percentage of patients with stable MMR in nilotinib re-initiation phase

Time: start of nilotinib in re-initiation phase up to approximately 432 weeks

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Description: Percentage of patients who are in stable MR4 (stable MR4=BCR-ABL ≤ 0.01% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MR4 any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MR4, irrespective of whether there is loss of MR4 in between, by the number of patients who achieved MR4 at any time during the nilotinib re-initiation phase

Measure: Percentage of patients with stable MR4 in nilotinib re-initiation phase

Time: start of nilotinib in re-initiation phase up to approximately 432 weeks

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Description: Percentage of patients who are in stable MR4.5 (stable MR4.5=BCR-ABL ≤ 0.0032% IS) at 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks after achievement of that response in the nilotinib re-initiation phase for 48, 96, 144, 192, 240,288 ,336, 384, and 432 weeks is calculated by dividing the number of patients achieving MR4.5 any time during the nilotinib re-initiation phase and having the same response at 48, 96, 144, 192, 240,288,336, 384, and 432 weeks after the first achievement of MR4.5, irrespective of whether there is loss of MR4.5 in between, by the number of patients who achieved MR4.5 at any time during the nilotinib re-initiation phase

Measure: Percentage of patients with stable MR4.5 in nilotinib re-initiation phase

Time: start of nilotinib in re-initiation phase up to approximately 432 weeks

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Primary Outcomes

Description: Maximum Tolerated Dose (MTD) of Ruxolitinib with fixed dose of Nilotinib. Dose escalation will follow a 3+3 study design. The CTCAE v4.03 criteria will be used. Grade 4 toxicity will be accounted as dose limiting toxicity (DLT).

Measure: Phase I: Maximum Tolerated Dose (MTD)

Time: Average of 6 months

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Description: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow from CML and ALL patients

Measure: Phase II: Major cytogenetic response

Time: Average of 6 months

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Secondary Outcomes

Description: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in CML patients in AP or BP, and patients with Ph+ ALL.

Measure: Phase I: complete hematologic response

Time: Average of 3 months

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Description: Major cytogenetic response defined by 35% or less of Philadelphia chromosomes by metaphase cytogenetics in marrow taken at 6 months.

Measure: Phase I: major cytogenetic response

Time: Average of 6 months

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Description: It will be defined by NCI Common Terminology Criteria for Adverse Events (CTCAE)version 4.03 for adverse event reporting.

Measure: Phase I: Safety and tolerability

Time: Average of 6 months

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Description: Complete hematologic response defined by CBC differential without any evidence of leukemia. It will be evaluated in the CML patients in AP or BP and in patients with Ph+ ALL.

Measure: Phase II: complete hematologic response

Time: Average of 3 months

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Other Outcomes

Description: Cmax will be measured for the maximum plasma concentration of nilotinib after oral administration.

Measure: Phase II (exploratory): pharmacokinetic profile of combination of Nilotinib with Ruxolitinib

Time: During first 24 hours of first dose

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Primary Outcomes

Description: Full Treatment-Free Remission (FTFR) is defined as patients with Major Molecular Response (MMR) or better, including those who have totally discontinued treatment during the Treatment-Free Remission (TFR) phase and those who are treated with half the standard dosage. Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase is calculated by dividing the number of patients with no loss of MMR-Major Molecular Response (BCR-ABL ≤ 0.1% (IS) after 96 weeks by the number of patients who entered the consolidation phase.

Measure: Percentage of patients in full treatment-free remission 96 weeks after the start of the consolidation phase.

Time: Baseline of consolidation phase up to 96 weeks

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Secondary Outcomes

Description: The percentage of patients in sustained DMR at the end of the consolidation phase (week 48). Sustained DMR: ≥ MR 4.0 (BCR-ABL level ≤0.01% IS) in all of the last 4 BCR-ABL RQ-PCR assessments. The proportion of patients in sustained DMR at the end of the consolidation phase (week 48) is calculated by dividing the number of patients in sustained DMR at week 48 by the number of patients who entered the consolidation phase.

Measure: Percentage of patients who remain in sustained Deep Molecular Response (DMR) at the end of the consolidation phase (week 48).

Time: Baseline of consolidation phase up to 48 weeks

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Description: The percentage of patients in deep molecular response is calculated by dividing the number of patients in DMR (≥ MR 4.0 (BCR-ABL level ≤0.01% IS in all of the last 4 BCR-ABL RQ-PCR assessments) 48, 96 and 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.

Measure: Percentage of patients who remain in DMR at the end of the consolidation phase (week 48), at 96 weeks and at 144 weeks after the start of the consolidation phase.

Time: Baseline of consolidation phase, week 48, 96 and 144

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Description: The percentage of patients in full treatment-free remission at week 144 is calculated by dividing the number of patients with no loss of MMR (BCR-ABL ≤ 0.1% (IS)) 144 weeks after the start of the consolidation phase by the number of patients who entered the consolidation phase.

Measure: Percentage of patients in full treatment-free remission 144 weeks after the start of the consolidation phase.

Time: Baseline of consolidation phase, week 144

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Description: The percentage of patients with MMR at week 48, 96 and 144 is calculated by dividing the number of patients with MMR at week 48, 96 and 144, regardless of whether they required re-initiation of treatment after the start the study, by the number of patients who entered the consolidation phase.

Measure: Percentage of patients with MMR or better at 48, 96, 144 weeks after starting the consolidation phase

Time: Baseline of consolidation phase, week 48, 96 and 144

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Description: Descriptive statistics of BCR-ABL levels (International scale), measured by quantitative Polymerase Chain Reaction (PCR), over time after re-start of nilotinib therapy up to 144 weeks in patient who failed Treatment Free Remission Phase.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript after re-start of nilotinib therapy in patients who failed Treatment Free Remission Phase.

Time: Restart of nilotinib therapy up to approximately 144 weeks

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Description: Descriptive statistics of BCR-ABL levels (IS), measured by quantitative PCR, over time after discontinuation of nilotinib therapy in Treatment Free Remission Phase up to 144 weeks.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript after discontinuation of nilotinib therapy in Treatment Free Remission Phase.

Time: Discontinuation of nilotinib therapy in patients in TFR phase up to approximately 144 weeks

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Description: Descriptive statistics of BCR-ABL levels (IS), measured by quantitative PCR, over time during the consolidation period to 48 weeks.

Measure: Change in Polymerase Chain Reaction (PCR) of BCR-ABL transcript during the consolidation period.

Time: Baseline of consolidation phase up to 48 weeks

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Description: FTFS: time from the start of the consolidation phase to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to accelerated phase (AP)/blast crisis (BC), or death due to any cause.

Measure: Full Treatment-Free Survival (FTFS)

Time: Baseline of consolidation phase up to 144 weeks

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Description: Percentage of patients in TFR at weeks 96 and week 144 is calculated by dividing the number of patients with no loss of MMR and no reinitiation of nilotinib after drug discontinuation at weeks 96 and week 144 by the number of patients who entered the TFR phase.

Measure: Proportion of patients among those who entered the TFR phase with no loss of MMR and no reinitiation of nilotinib after drug discontinuation

Time: Baseline of consolidation up to 96 and 144 weeks

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Description: TFS: time from the start of the TFR phase to the earliest occurrence of any of the following events: loss of MMR, reinitiation of treatment due to any cause, progression to AP/BC or death due to any cause.

Measure: Treatment-free survival (TFS)

Time: From the start of the TFR phase up to Week 144.

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Description: PFS: time from the start of the consolidation phase to progression to AP/BC or death due to any cause, whichever occurs first.

Measure: Progression-free survival (PFS) after the start of consolidation phase

Time: Baseline of consolidation phase up to 144 weeks

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Description: PFS: time from the start of the TFR phase to progression to AP/BC or death due to any cause, whichever occurs first.

Measure: Progression Free Survival (PFS) after the start of TFR phase

Time: From the start of the TFR phase up to week 144.

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Description: OS: time from start of the study to death due to any cause.

Measure: Overall Survival (OS)

Time: Baseline of consolidation phase up to 144 weeks

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Description: To assess safety during the nilotinib treatment consolidation phase, TFR phase and during reinitiation of treatment with nilotinib.

Measure: The number of patients with Adverse Events as measure of safety and tolerability

Time: From screening up to approximately week 144

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Description: Statistical correlation between clinical and laboratory correlates at diagnosis (e.g. Sokal Risk scale, demography, type of BCR-ABL transcript) or during previous treatment (e.g. Early Molecular Response=BCR-ABL transcript measured by quantitative PCR <10% after 3 months of first-line treatment with nilotinib at the dose of 300 mg BID) and the achievement of Full Treatment Free Remission and Treatment Free Remission at 96 weeks

Measure: Correlation between clinical and laboratory factors and clinical outcome

Time: Baseline of consolidation phase up to 96 weeks

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Primary Outcomes

Description: This variable is defined as the number of patients who have a maintained MMR and have not restarted TKI therapy in the first 52 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase.

Measure: Proportion of patients with a maintained MMR within 52 weeks following ponatinib Treatment-Free Remission (TFR)

Time: 52 weeks

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Secondary Outcomes

Description: The number and percentage of patients with treatment-emergent adverse events (new or worsening from baseline) will be summarized by system organ class (SOC) and/or preferred term (PT), severity (based on CTCAE grades), type of adverse event and relation to study treatment.

Measure: Evaluate the toxicity and safety profile of 15 mg/24h dose treatment of ponatinib combined with ASA.

Time: 104 weeks

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Description: The number and percentage of patients with thromboembolic events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate thromboembolic events for study period.

Time: 104 weeks

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Description: The number and percentage of patients with hemorrhagic events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate hemorrhagic events for study period.

Time: 104 weeks

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Description: The number and percentage of patients with hemolytic events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate hemolytic events for study period.

Time: 104 weeks

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Description: The number and percentage of patients with gastrointestinal events will be summarized by preferred term, severity (based on CTCAE grades), type of adverse event, relation to study treatment by the phases or subsets previously described.

Measure: Evaluate gastrointestinal events for study period.

Time: 104 weeks

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Description: Number of patients still in MR4 and have not restarted TKI therapy in the first 52 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase.

Measure: Evaluate the proportion of patients still in MR4 (BCR-ABL ≤ 0.01%) within 52 weeks following ponatinib therapy cessation.

Time: 52 weeks

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Description: The number of patients who still have a MMR and have not restarted TKI therapy in the first 24 weeks after starting ponatinib TFR phase divided by the number of patients who entered ponatinib TFR phase.

Measure: Evaluate the proportion of patients still in MMR within 24 weeks following ponatinib therapy cessation.

Time: 24 weeks

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Description: Time from start ponatinib treatment to the occurrence of progression to AP/BC, loss of MMR or death from any cause, the earliest of these events.

Measure: To estimate progression-free survival (PFS)

Time: 4 years

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Description: time from ponatinib cessation to the occurrence of loss of MMR, restart of TKI treatment, progression of AP/BC, or death from any cause, the earliest of these events.

Measure: Treatment-free survival (TFS)

Time: 104 weeks

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Other Outcomes

Description: The number of patients who achieve a MR 5 at ponatinib therapy cessation divided by the number of patients who entered ponatinib TFR phase.

Measure: Evaluate the proportion of patients who achieve a MR 5 at ponatinib therapy cessation.

Time: 104 weeks

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