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.

Phase 3TerminatedNCT02108951

Novartis Pharmaceuticals20 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Philidelphia Positive Chronic Myeloid Leukaemia

Interventions

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Written informed consent prior to screening procedures 2. Eastern Cooperative Oncology Grou (ECOG) Performance Status of 0, 1, or 2. 3. Patient with diagnosis of Ph+ CML-CP associated with BCR-ABL quantifiable by RQ-PCR (IS). 4. Patient has received a minimum of 3 months of imatinib or dasatinib treatment (any dose) since initial diagnosis with a documented response. 5. Patient is eligible for Pharmaceutical Benefits Scheme (PBS) reimbursed 1st line TKI treatment. 6. 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. 7. No other current or planned anti-leukemia therapies. 8. Adequate organ function. 9. Potassium, Magnesium and Total Calcium above Lower limit of normal. 10. life expectancy of more than 12 months in the absence of any intervention Key Exclusion Criteria: 1. Prior treatment with nilotinib. 2. 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). 3. Patient has documented Molecular Response (MR) 4.5 at the time of study entry 4. Patients with atypical BCR-ABL transcript not quantifiable by standard RQ-PCR. 5. Known impaired cardiac function. 6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug. 7. Pregnant or breast feeding (lactating) women. 8. Women of child-bearing potential unwilling or unable to use highly effective contraception.

Locations (14)

Novartis Investigative Site

Canberra, Australian Capital Territory, Australia

Novartis Investigative Site

Kingswood, New South Wales, Australia

Novartis Investigative Site

Kogarah, New South Wales, Australia

Novartis Investigative Site

Liverpool, New South Wales, Australia

Novartis Investigative Site

St Leonards, New South Wales, Australia

Novartis Investigative Site

Douglas, Queensland, Australia

Novartis Investigative Site

Nambour, Queensland, Australia

Novartis Investigative Site

South Brisbane, Queensland, Australia

Novartis Investigative Site

Adelaide, South Australia, Australia

Novartis Investigative Site

Fitzroy, Victoria, Australia

...and 4 more locations

Outcomes

Primary Outcomes

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: Baseline, 96 weeks (24 months)

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

Time frame: Baseline, 96 weeks (24 months)

Secondary Outcomes

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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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.

Time frame: 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

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

Time frame: 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.

Time frame: 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.

Time frame: Baseline, week 12, 24, 48, 96