Neoplasms

Blood and Lymph Conditions

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Rare Diseases

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Neoplasms by Histologic Type

Hematologic Diseases

Myeloproliferative Disorders

Bone Marrow Diseases

Chronic Disease

Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

All Drugs and Chemicals

Antineoplastic Agents

Amino Acids

Nilotinib

Dasatinib

Tyrosine Kinase Inhibitors

Imatinib Mesylate

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

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.

Nilotinib 150mg hard gelatin capsules taken orally

Novartis Pharmaceuticals

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.

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.

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.

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).

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.

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.

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.

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.

No response corresponds to a BCR-ABL ratio \< 0.1% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR).

MMR corresponds to a BCR-ABL ratio 0.1% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR).

MR4.0 corresponds to a BCR-ABL ratio 0.01% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR).

MR4.5 corresponds to a BCR-ABL ratio 0.0032% international scale (IS) using Real-time quantitative polymerase chain reaction (RQ-PCR).

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.

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

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

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.

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.

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

Age, Continuous

Sex: Female, Male

The study was planned to enroll 130 patients. Study got terminated with 20 patients because of slow recruitment. Therefore, due to small sample size, the results cannot be considered clinical significant.

Study Director

The full analysis set (FAS) consists of all patients enrolled into the study.

Deep Molecular Response (MR4.5) Rate: Percentage of Patients Who Have Achieved a 4.5-log Reduction in BCR-ABL Level Within 24 Month

Within 12 months

Within 24 months

The full analysis set (FAS) consists of all patients enrolled into the study. Analysis of MR4.0 was undertaken on the subgroup of the FAS that was not at MR4.0 at baseline.

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

The full analysis set (FAS) consists of all patients enrolled into the study.Analysis of MMR was undertaken on the subgroup of the FAS that was not at MMR at baseline.

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

Achieved MR4.5

Did not achieve MR4.5

Duration of Prior TKI Therapy for Patients Based on MR4.5 Achievement Status Within 24 Months

MR4.5 achieved (n=10): No response at baseline

MR4.5 achieved : MMR at baseline

MR4.5 achieved : MR4.0 at baseline

MR4.5 achieved: MR4.5 at baseline

MR4.5 not achieved: No response at baseline

MR4.5 not achieved: MMR at baseline

MR4.5 not achieved: MR4.0 at baseline

MR4.5 not achieved: MR4.5 at baseline

The full analysis set (FAS) consists of all patients enrolled into the study. 'n' in categories indicates patients achieved or did not achieve MR4.5 during 24 months

Number of Patients With MR4.5 Response by Baseline BCR-ABL Response Level Within 24 Months

Baseline : No Response

Week 4: No response

Week 8: No response

Week 12: No response

Week 24: No response

Week 36: No response

Week 48: No response

Week 60: No response

Week 72: No response

Week 84: No response

Week 96/End of study: No response

Full analysis set. n = number of patients with evaluable data at the defined time point

Kinetics of Molecular Response: Percentage of Patients With no Response Based on BCR-ABL Over Time After the Switch to Nilotinib

Baseline : MMR

Week 4: MMR

Week 8: MMR

Week 12: MMR

Week 24: MMR

Week 36: MMR

Week 48: MMR

Week 60: MMR

Week 72: MMR

Week 84: MMR

Week 96/End of study: MMR

Kinetics of Molecular Response: Percentage of Patients With MMR Based on BCR-ABL Over Time After the Switch to Nilotinib

Baseline : MR4.0

Week 4: MR4.0

Week 8: MR4.0

Week 12: MR4.0

Week 24: MR4.0

Week 36: MR4.0

Week 48: MR4.0

Week 60: MR4.0

Week 72: MR4.0

Week 84: MR4.0

Week 96/End of study: MR4.0

Kinetics of Molecular Response: Percentage of Patients With MR4.0 Based on BCR-ABL Over Time After the Switch to Nilotinib

Baseline : MR4.5

Week 4: MR4.5

Week 8: MR4.5

Week 12: MR4.5

Week 24: MR4.5

Week 36: MR4.5

Week 48: MR4.5

Week 60: MR4.5

Week 72: MR4.5

Week 84: MR4.5

Week 96/End of study: MR4.5

Kinetics of Molecular Response: Percentage of Patients With MR4.5 Based on BCR-ABL Over Time After the Switch to Nilotinib

The full analysis set (FAS) consists of all patients enrolled into the study. N represents all patients in FAS who achieved MR4.5.

Kaplan-Meier Estimates of Time to Deep Molecular Response (MR4.5)

The FAS consists of all patients enrolled into the study. There were no withdrawals due to progression to BC or AP disease, and there were no recorded deaths during the study.

Time to Progression-free Survival (PFS)

There were no patients in the study who were recorded as experiencing treatment failure.

Time to Event Free Survival (EFS)

Improved : Yes

Improved: No

The Safety Set (SS) consisted of all patients in the FAS who received at least 1 dose of study drug and had at least 1 post-baseline safety assessment.

Number of Patients With Events Reported at Baseline That Have Shown an Improvement in Non-hematological AE Severity Compared to Week 12 Visit

Baseline: MDASI part 1

Week 12: MDASI part 1

Week 24: MDASI part 1

Week 48: MDASI part 1

Week 96: MDASI part 1

Baseline: MDASI part 2

Week 12: MDASI part 2

Week 24: MDASI part 2

Week 48: MDASI part 2

Week 96: MDASI part 2

Baseline: CMLcomponent

Week 12: CMLcomponent

Week 24: CMLcomponent

Week 48: CMLcomponent

Week 96 CMLcomponent

The full analysis set (FAS) consists of all patients enrolled into the study. 'n' in the categories represents the number of patients with evaluable data for MDASI part 1/MDASI part 2/CML component at different time points. Week 96 includes end of study results for patients that did not complete the study.

Mean M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML)

Overall Study

Spots Global Cancer Trial Database for philidelphia positive chronic myeloid leukaemia