Nilotinib in Newly Diagnosed Adult Philadelphia Chromosome & /or BCR-ABL Positive Chronic Myeloid Leukaemia in Chronic Phase

Study Overview
=================
Brief Summary
-----------------
This study will assess the efficacy and safety of nilotinib in adult patients with newly diagnosed Philadelphia chromosome positive/BCR-ABL positive chronic myeloid leukaemia in chronic phase. The aim of the study is to confirm the rates of complete molecular remission (CMR) of nilotinib in newly diagnosed CML chronic phase patients in a pan-European population using the EUTOS standardized laboratories.

Official Title
-----------------
A Phase IIIb, Multicentre, Open-label Study of Nilotinib in Adult Patients With Newly Diagnosed Philadelphia Chromosome and/or BCR-ABL Positive CML in Chronic Phase

Conditions
-----------------
CML in Chronic Phase

Intervention / Treatment
-----------------
* Drug: Nilotinib


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients with diagnosis of CP-CML with cytogenetic confirmation of Philadelphia (Ph) chromosome Ph negative cases or patients with variant translocations who are BCR-ABL positive in multiplex PCR are also eligible WHO performance status 0-2 Laboratory assessments within normal limits Written informed consent prior to any study procedures being performed Exclusion Criteria: Known impaired cardiac function History of acute or chronic pancreatitis Impaired gastrointestinal function or disease that may alter the absorption of study drug Concomitant medications with potential QT prolongation, or known to interact with CYP450 isoenzymes (CYP3A4, CYP2C9, and CYP2C8) Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy Patients who are pregnant or breast feeding, or females of reproductive potential not employing an effective method of birth control. Female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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>This was a single-arm study; therefore all participants received nilotinib (AMN107) 300 mg bid given as two 150 mg capsules twice daily. | Drug: Nilotinib<br>* Nilotinib was supplied by Novartis as 150 mg hard gelatin capsules in bottles. Nilotinib was dosed on a flat scale and not dosed by body weight. This form of supply was continued for all participants entered into the core study.<br>* Other names: AMN107;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Molecular Response (MR4^0) at 18 Months | MR4^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts. | at 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Free From Progression to Accelerated Phase/Blast Crisis (AP/BC) at 12 and 24 Months | The following events were considered disease progression to AP/BC: Death due to disease under study; AP, as defined by any of the following: ≥ 15% blasts in the peripheral blood or bone marrow, but < 30% blasts in both the peripheral blood and bone marrow, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow, ≥ 20% basophils in the peripheral blood, Thrombocytopenia (< 100 × 109/L) that was unrelated to therapy, Evidence of clonal evolution, as determined by medical review with consensus of the SSMC/DMC. BC was defined as: ≥ 30% blasts in peripheral blood or bone marrow, Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy. | at 12 and 24 months | 
| Rate of Event Free Survival at 12 and 24 Months | EFS was defined as the time from the date of Day 1 (first treatment) + 1 day to the first occurrence of any of the following: Loss of complete hematologic response (CHR), Loss of CCyR, Death from any cause, Progression to the AP or BC of CML, Not achieving CHR up to 3 months (ie, 91 + 15 days), Not achieving CCyR up to 18 months (ie, 548 + 15 days), whichever is earlier. | at 12 and 24 months | 
| Percentage of Participants With Major Molecular Response (MMR) at, as Well as by, 12 and 24 Months | MMR was defined as BCR-ABL ratio (IS) ≤ 0.1% in a peripheral blood sample. BCR-ABL1 is an abnormal gene found in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). The chromosomal defect in the Philadelphia chromosome is a translocation, in which parts of two chromosomes, 9 and 22, swap places. The result is that a fusion gene is created by juxtapositioning the Abl1 gene on chromosome 9 to a part of the BCR (breakpoint cluster region) gene on chromosome 22. Depending upon the breakpoints on the BCR gene, there are several forms of fusion proteins. | 12 months, 24 months | 
| Percentage of Participants With Complete Cytogenetic Response (CCyR) at, as Well as by, 12 and 24 Months | CCyR parameters were defined as 0% Philadelphia positive (Ph+) metaphases. Loss of CCyR was defined as a patient exceeding the CCyR criteria (ie, > 0% Ph+ metaphases) at a subsequent visit after the patient had achieved CCyR. | 12 and 24 months | 
| Percentage of Participants With Major Cytogenetic Response (MCyR) at, as Well as by, 12 and 24 Months | Major cytogenetic response (MCyR) parameters were defined as 0 to 35% Philadelphia positive (Ph+) metaphases. | 12 and 24 months | 
| Percentage of Participants Free From Progression to AP/BC With MR4^0 at 12 Months | The following events were considered disease progression to AP/BC: Death due to disease under study; AP, as defined by any of the following: ≥ 15% blasts in the peripheral blood or bone marrow, but < 30% blasts in both the peripheral blood and bone marrow, ≥ 30% blasts plus promyelocytes in peripheral blood or bone marrow, ≥ 20% basophils in the peripheral blood, Thrombocytopenia (< 100 × 109/L) that was unrelated to therapy, Evidence of clonal evolution, as determined by medical review with consensus of the SSMC/DMC. BC was defined as: ≥ 30% blasts in peripheral blood or bone marrow, Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy. | at 12 months | 
| Percentage of Participants With Event Free Survival in Participants Achieving MR4^0 at 12 Months | EFS was defined as the time from the date of Day 1 (first treatment) + 1 day to the first occurrence of any of the following: Loss of complete hematologic response (CHR), Loss of CCyR, Death from any cause, Progression to the AP or BC of CML, Not achieving CHR up to 3 months (i.e. 91 + 15 days). | at 12 months | 
| Percentage of Participants With Progression Free Survival (PFS) at 12 and 24 Months | PFS was defined by the study protocol as the time from the date of start of study drug to the date of earliest progression to AP/BC, or the date of death from any cause. | 12 months, 24 months | 
| Rate of Molecular Response (MR4^0) at, as Well as by, 12 and 24 Months | MR4^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts. | 12 and 24 months | 
| Rate of Molecular Response (MR4^5) at, as Well as by, 12 and 24 Months | MR4^5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL ratio (IS) with mean ABL transcripts ≥ 32 000 or (ii) undetectable disease in cDNA with ≥ 32 000 ABL transcripts). | 12 and 24 months | 
| Rate of Complete Hematologic Response (CHR) at, as Well as by, 12 and 24 Months | CHR was defined as all of the following present for ≥ 4 weeks in the peripheral blood: WBC count < 10 x 109/L, Platelet count < 450 x 109/L, No circulating peripheral blood blasts, promyelocytes, myelocytes, or metamyelocytes in the peripheral blood, The presence of < 5% basophils, No evidence of disease-related symptoms and extramedullary disease, including spleen and liver. Loss of CHR was defined as the appearance of any of the following after having achieved a CHR confirmed by a second determination ≥ 4 weeks later (unless associated with progression to AP/BC or death, which was considered to be a confirmed loss of CHR event on its own): WBC count that increased to > 20.0 x 109/L, Platelet count that increased to ≥ 600 x 109/L, Any palpable spleen, defined as size of spleen below costal margin > 5 cm, Appearance of > 5% myelocytes plus metamyelocytes, or any promyelocytes or blasts in the peripheral blood. | 12 months, 24 months | 
| Percentage of Participants With Overall Survival at 12 and 24 Months | OS was defined as the time between the date of Day 1 (first treatment) and the date of death from any cause. Deaths which occurred after the 24-month time window and which were occasionally reported by some Investigators were excluded from the analysis. This is in agreement with the protocol stating that patients were to be followed for survival and progression to AP/BC up to 24 months after the participants treatment start. | 12 months, 24 months | 
| Rate of Molecular Response (MR4^0) by 18 Months | MR4^0 was defined as either (i) detectable disease ≤ 0.01% BCR-ABL ratio (international scale (IS)) with mean ABL transcripts ≥ 10 000 or (ii) undetectable disease in complementary deoxyribonucleic acid (cDNA) with ≥ 10 000 ABL transcripts. BCR = Breakpoint Cluster Region gene/BCR gene product BCR-ABL is fusion gene formed from the ABL gene from chromosome 9 fusing with the BCR gene on chromosome 22, the gene product is BCR-ABL tyrosine kinase | by 18 months | 
| Rate of Molecular Response (MR4^5) by 18 Months | MR4^5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL ratio (IS) with mean ABL transcripts ≥ 32 000 or (ii) undetectable disease in cDNA with ≥ 32 000 ABL transcripts). BCR = Breakpoint Cluster Region gene/BCR gene product BCR-ABL is fusion gene formed from the ABL gene from chromosome 9 fusing with the BCR gene on chromosome 22, the gene product is BCR-ABL tyrosine kinase | by 18 months | 
| Percentage of Participants With Progression Free Survival in Participants Achieving MR4^0 at 12 Months | PFS was defined by the study protocol as the time from the date of start of study drug to the date of earliest progression to AP/BC, or the date of death from any cause. | 12 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
myeloid, Leukemia, myelogenous, chronic BCR-ABL positive, Nilotinib, Philadelphia chromosome, CML in chronic phase