Study to Assess Efficacy and Safety of Nilotinib 300mg Twice Daily in Patients With Philadelphia Positive Chronic Myeloid Leukaemia (CML) in Chronic Phase Who Are Intolerant to Prior Tyrosine Kinase Inhibitors.

Study Overview
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Brief Summary
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The purpose of this Australian study was to assess the efficacy and safety of nilotinib 300mg twice daily in patients with chronic myeloid leukemia chronic phase who were intolerant but responsive to 1st line treatment with imatinib or dasatinib. Eligible patients have been previously treated with imatinib or dasatinib for at least 3 months and are experiencing non-hematologic toxicity whilst having documented responses that meet PBS authority for 1st line treatment of CML without current MR4.5.

Detailed Description
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The study was planned to enroll 130 patients to achieve the sample size requirement for a meaning full conclusion. Study got terminated with 20 patients because of slow recruitment. Therefore, due to small sample size, the results cannot be considered clinical significant.

Official Title
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A Multicenter, Single Arm Study to Assess Efficacy and Safety of Nilotinib 300mg Twice Daily in Patients With Philadelphia Positive Chronic Myeloid Leukemia in Chronic Phase (Ph+ CML-CP) Who Are Intolerant to Prior Tyrosine Kinase Inhibitors (TKIs).

Conditions
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Philidelphia Positive Chronic Myeloid Leukaemia

Intervention / Treatment
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* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent prior to screening procedures Eastern Cooperative Oncology Grou (ECOG) Performance Status of 0, 1, or 2. Patient with diagnosis of Ph+ CML-CP associated with BCR-ABL quantifiable by RQ-PCR (IS). Patient has received a minimum of 3 months of imatinib or dasatinib treatment (any dose) since initial diagnosis with a documented response. Patient is eligible for Pharmaceutical Benefits Scheme (PBS) reimbursed 1st line TKI treatment. Patient has experienced non-hematological Adverse Events (AE(s)) of any grade, which persisted for at least 1 month despite supportive care or recurred at any grade at least once. Patients who, at the Investigator's discretion, require immediate discontinuation due to the severity of the adverse event are also eligible. No other current or planned anti-leukemia therapies. Adequate organ function. Potassium, Magnesium and Total Calcium above Lower limit of normal. life expectancy of more than 12 months in the absence of any intervention Key Exclusion Criteria: Prior treatment with nilotinib. Prior Accelerated Phase (AP), Blast Crisis (BC) or allogeneic-transplant (unless the patient received an autologous transplant and was in Chrionic Phase (CP) prior to transplant and never in AP or BC). Patient has documented Molecular Response (MR) 4.5 at the time of study entry Patients with atypical BCR-ABL transcript not quantifiable by standard RQ-PCR. Known impaired cardiac function. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug. Pregnant or breast feeding (lactating) women. Women of child-bearing potential unwilling or unable to use highly effective contraception.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>Nilotinib was administered orally at 300 mg BD at approximately 12 hour intervals which had to be taken without food. The capsules were to be swallowed whole with water and no food should have been consumed for at least 2 hours before and at least 1 hour after the dose was taken. Prior to the first dose of nilotinib, patients were required to have an imatinib or dasatinib washout period of at least 3 days. Therapy with nilotinib was to be continued for up to 24 months while on study. | Drug: Nilotinib<br>* Nilotinib 150mg hard gelatin capsules taken orally<br>* Other names: AMN107;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Deep Molecular Response (MR4.5) Rate: Percentage of Patients Who Have Achieved a 4.5-log Reduction in BCR-ABL Level Within 24 Month | Deep Molecular Response (MR4.5) rate is defined as the percentage of patients who have achieved a 4.5 -log reduction in Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels. BCR-ABL levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is < 0.1 X the baseline value, the patient were classified as achieving a 1 log reduction in BCR-ABL. | Baseline, 96 weeks (24 months) | 
| Molecular Response (MR4.0) Rate: Percentage of Patients Who Have Achieved a 4.0-log Reduction in BCR-ABL Level Within 12 Months and 24 Months | Molecular Response (MR4.0) rate is defined as the percentage of patients who have achieved a 4-log reduction in BCR-ABL levels at 12 months and 24 months following the commencement of nilotinib therapy. Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.0 corresponds to a BCR-ABL ratio 0.01% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is < 0.1 X the baseline value, the patients were classified as achieving a 1 log reduction in BCR-ABL. | Baseline, 48 weeks (12 months), 96 weeks (24 months) | 
| Major Molecular Response (MMR) Rate: Percentage of Patients Who Have Achieved a 3 Log Reduction in BCR-ABL Levels Within 12 Months and 24 Months | Major Molecular Response (MMR) rate is defined as the percentage of patients who have achieved a 3 log reduction in BCR-ABL levels at 12 months and at 24 months following the commencement of nilotinib therapy. Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood at the 12 and 24 months following the commencement of nilotinib therapy. MMR corresponds to a BCR-ABL ratio 0.1% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is < 0.1 * the baseline Value, the patient will be classified as achieving a 1 log drop. | Baseline, 48 weeks (12 months), 96 weeks (24 months) | 
| Duration of Prior TKI Therapy for Patients Based on MR4.5 Achievement Status Within 24 Months | Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. Deep molecular response (MR4.5) rate was defined as the percentage of patients who have achieved a 4.5-log reduction (MR4.5) in BCR-ABL levels during the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% IS using RQ-PCR. If a post-baseline value for BCR-ABL is < 0.1 X the baseline value, the patient were classified as achieving a 1 log reduction in BCR-ABL. | Baseline, 96 weeks (24 months) | 
| Number of Patients With MR4.5 Response by Baseline BCR-ABL Response Level Within 24 Months | Deep Molecular Response (MR4.5) rate is defined as the percentage of patients who have achieved a 4.5 -log reduction in Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels. BCR-ABL levels are measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% international scale (IS) using RQ-PCR. If a post-baseline value for BCR-ABL is < 0.1 X the baseline value, the patient were classified as achieving a 1 log reduction in BCR-ABL. | Baseline, 96 weeks (24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Kinetics of Molecular Response: Percentage of Patients With no Response Based on BCR-ABL Over Time After the Switch to Nilotinib | No response corresponds to a BCR-ABL ratio < 0.1% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR). | Baseline, week 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 | 
| Kinetics of Molecular Response: Percentage of Patients With MMR Based on BCR-ABL Over Time After the Switch to Nilotinib | MMR corresponds to a BCR-ABL ratio 0.1% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR). | Baseline, week 4, 8, 12, 24, 36, 48, 60, 72 and 96 | 
| Kinetics of Molecular Response: Percentage of Patients With MR4.0 Based on BCR-ABL Over Time After the Switch to Nilotinib | MR4.0 corresponds to a BCR-ABL ratio 0.01% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR). | Baseline, week 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 | 
| Kinetics of Molecular Response: Percentage of Patients With MR4.5 Based on BCR-ABL Over Time After the Switch to Nilotinib | MR4.5 corresponds to a BCR-ABL ratio 0.0032% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR). | Baseline, week 4, 8, 12, 24, 36, 48, 60, 72, 84, 96 | 
| Kaplan-Meier Estimates of Time to Deep Molecular Response (MR4.5) | Breakpoint cluster region - Abelson murine leukemia (BCR-ABL) levels is measured in patients by real-time quantitative polymerase chain reaction (RQ-PCR) testing of peripheral blood by the 24 months following the commencement of nilotinib therapy. MR4.5 corresponds to a BCR-ABL ratio 0.0032% IS using RQ-PCR. The derivation of time to molecular response for patients in the study was measured from the date of first nilotinib use, defined as follows: Days to MR4.5 = date of assessment where BCR-ABL ratio is 0.0032% IS - date of baseline + 1. | 96 weeks (24 months) | 
| Time to Progression-free Survival (PFS) | PFS was defined as the time from the date of baseline visit to the date of earliest progression-defining event: namely progression (or withdrawal due to progression to blast crisis (BC) or accelerated phase (AP) disease), or death from any cause. Patients who did not progress were censored at earliest of the following: the date of the 24-month visit; the date of loss to follow-up; the date of discontinuation of study treatment for any reason other than progression to BC, or AP disease, or death | 96 weeks (24 months) | 
| Time to Event Free Survival (EFS) | EFS was defined as the time from date of baseline visit to the first occurrence of any of the following: Disease progression, treatment failure or death from any cause, whichever was earlier. Patients who did not have an event of interest were censored at earliest of the following: the date of the 24-month visit; the date of loss to follow-up; the date of withdrawal from the study for any reason other than lack of efficacy/progressive disease, tolerance to reduced dose or death | 96 weeks (24 months) | 
| Number of Patients With Events Reported at Baseline That Have Shown an Improvement in Non-hematological AE Severity Compared to Week 12 Visit | The total number of patients that have showed improvement with respect to CTCAE grades at the time of the 12-week visit are reported. Improved is defined as prior to, or at the time of the 12-week visit, the AE has completely resolved. | Baseline, week 12 (month 3) | 
| Mean M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) | Quality of life was assessed using the M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) self-administered questionnaire for adult CML patients. The questionnaire consisted of 13 core questions in part I measuring the severity of symptoms, 6 questions in part 2 assessing the interference of symptoms on daily living. The CML component of the MDASI provided an additional 7 CML-specific symptom items: diarrhea, swelling, rash/skin change, muscle soreness/cramping, bruising/bleeding easily, malaise, and headache. In part I (13 questions) and the CML component (7 questions) each question was scored from 0 to 10 where 0 indicates a symptom is not present and 10 indicate the symptom is as bad as you can imagine. For part 1 the total score can therefore range from 0 to 130 and for CML 0 to 70. Part 2 is also recorded on a 0 to 10 scale, but 0 now indicates that the symptom did not interfere and 10 interfered completely. The total score can range from 0 to 60. | Baseline, week 12, 24, 48, 96 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CML, Ph-CML, leukaemia, leukemia, chronic myeloid leukemia, chronic myeloid leukaemia, TKI intolerance, tyrosine kinase inhibitor, tyrosine kinase inhibitor intolerance