Safety and Efficacy of Nilotinib vs. Imatinib in the Treatment of Newly Diagnosed Chinese Ph+ CML-CP Patients

Study Overview
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Brief Summary
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The study will compare the efficacy and safety of Nilotinib versus Imatinib in newly diagnosed Chinese patients with CML-CP.

Official Title
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ENESTChina: A Phase III Multi-center, Open-label, Randomized Study of Nilotinib Versus Imatinib in Chinese Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Nilotinib
* Drug: Imatinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients of Chinese ethnicity greater than or equal to 18 years of age ECOG 0, 1, or 2. Patients with CML-CP (Ph+) within 6 months of diagnosis (date of initial diagnosis is the date of first cytogenetic analysis). Standard conventional cytogenetic analysis must be done on bone marrow. (FISH cannot be used) Diagnosis of chronic myelogenous leukemia in chronic phase with cytogenetic confirmation for the presence of Philadelphia chromosome of (9;22 translocation; less than 20 metaphases may be used for diagnosis Documented chronic phase CML will meet all the criteria defined by: < 15% blasts in peripheral blood and bone marrow < 30% blasts plus promyelocytes in peripheral blood and bone marrow < 20% basophils in the peripheral blood ≥ 100 x 109/L (≥ 100,000/mm3) platelets No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly Adequate organ function as defined by: Total bilirubin < 1.5 x ULN SGOT and SGPT < 2.5 x ULN Creatinine < 1.5 x ULN Serum amylase and lipase ≤ 1.5 x ULN Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related. Patients must have the following laboratory values (≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to the first dose of study medication.): Potassium ≥ LLN Magnesium ≥ LLN Phosphate ≥ LLN Total calcium (corrected for serum albumin) ≥ LLN. Ability to provide written informed consent prior to any study related screening procedures being performed. Exclusion Criteria: Patients with previously documented T315I mutations; Treatment with tyrosine kinase inhibitor(s) prior to study entry is not allowed, except in the following situation: in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of Gleevec/Glivec at any dose may be prescribed to the patient but for no longer than 2 weeks in duration. Treatment with IFN for more than 3 months. Impaired cardiac function including any one of the following: Complete left bundle branch block Long QT syndrome or a known family history of long QT syndrome. History of or presence of clinically significant ventricular or atrial tachyarrhythmias Clinically significant resting bradycardia (<50 beats per minute) QTc > 450 msec If QTcF >450 msec and electrolytes are not within normal ranges, electrolytes should be corrected and then the patient re-screened for QTc History of clinically documented myocardial infarction within past 12 months History of unstable angina (during the last 12 months) Other clinically significant heart disease (e.g., congestive heart failure or uncontrolled hypertension). Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required). Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection). History of significant congenital or acquired bleeding disorder unrelated to cancer. Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery. Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 30 days of Day 1. History of non-compliance to medical regimens or inability to grant consent. Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention Patients actively receiving therapy with strong CYP3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm or reference Protocol post text appendix 1. Patients actively receiving therapy with strong CYP3A4 inducers (e.g., dexamthasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbitol, St. John's Wort) and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. See link for complete list of these medications: http://medicine.iupui.edu/flockhart/table.htm or reference Protocol post text appendix 1. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery) History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis. Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease. Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a comprehensive list of agents that prolong the QT interval). Patients who are: (a) pregnant, (b) breast feeding, (c) of childbearing potential without a negative pregnancy test prior to baseline and (d) female of childbearing potential unwilling to use contraceptive precautions throughout the trial (post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential) Other protocol-defined inclusion/exclusion criteria may apply

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br> | Drug: Nilotinib<br> <br> |
| Active Comparator: Imatinib<br> | Drug: Imatinib<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Molecular Response (MMR) at 12 Months - With Imputation. | Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. This endpoint was calculated based on the 12 month analysis. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MMR Rate at Each Time Point | Major molecular response (MMR) was defined as a value of ≤ 0.1% of BCR-ABL ratio on the IS. The minimum number of control genes for a sample to be valid was 3000. For statistical comparison purpose, MMR was considered as a binary variable with patients achieving MMR grouped as 'responders' and patients not achieving MMR, patients with missing PCR evaluations or patients with atypical transcripts at baseline grouped as 'non-responders'. These time points including the 12 month data were calculated based on the final analysis after the end of the study. | Months 3,6,9,12,15, 18, 21, 24, 36 | 
| Best MMR by Each Timepoint | Best MMR rates by scheduled time point are cumulative response rates up to that time point. In this analysis, patients who had achieved MMR at or before the time point were counted as responders, no matter if they lost the response/discontinued or not. Therefore, this response rate represented the best observed response rate up to that specific time point. | Months 3,6,9,12,15, 18, 21, 24, 36 | 
| Kaplan-Meier Estimates of Time to First MMR | Time to first MMR (months) = (date of first MMR or censoring - date of randomization + 1) / 30.4375. | End of study (up to 40 months) | 
| Durable MMR Rate at 24 Months | The rate of durable MMR at 24 months, defined as the proportion of patients who have achieved MMR at 12 months, and also maintain continuous MMR until the 24 month time point (1 month = 28 days) without intervening loss of MMR in between 12 and 24 months | 24 months | 
| Kaplan-Meier Estimates of Duration of First MMR Among Patients Who Achieved MMR | Duration of first MMR (months) = (date of loss of MMR or censoring-date of first MMR + 1)/30.4375. | End of Study (Up to 40 months) | 
| Best Complete Cytogenic Response (CCyR) Rate by Each Time Point | CCyR is defined as 0% Ph+ metaphases based on at least 20 metaphases from bone marrow cytogenetics. | Months 6, 12, 18, 30, 24, 36 | 
| Kaplan-Meier Estimates of Time to First CCYR | Time to first CCyR (months) = (date of first CCyR - date of randomization + 1) / 30.4375. | End of study (up to 40 months) | 
| Kaplan-Meier Estimates of Duration of First CCyR Among Patients Who Achieved CCyR | Duration of CCyR (months) = (date of CCyR loss or censoring-date of first CCyR + 1)/30.4375 | End of Study (up to 40 months) | 
| Kaplan-Meier Estimates of Time to Progression to Accelerated Phase/Blast Crisis (AP/BC) on Treatment | Time to progression to AP/BC was defined as the time from the date of randomization to the date of event defined as the first disease progression to AP/BC or the date of CML-related death, whichever is earlier. This variable was analyzed in 2 ways: On-treatment: included progressions to AP/BC or CML-related deaths occurring on treatment in the study as events. The time was censored at the date of last on-treatment assessment (hematology, extramedullary disease, or cytogenetic evaluation) in the study for patients without event. On-study: included progressions to AP/BC or CML-related deaths occurring in the study or during the follow-up period after discontinuation of treatment as events. The time was censored at the last assessment date in the study for patients who were still being treated and at the date of last contact for patients who discontinued treatment | End of study (up to 40 months) | 
| Kaplan-Meier Estimates of Event-free Survival (EFS) on Treatment | Event-free survival was defined as the time from the date of randomization to the date of first occurrence of any of the following:-Death due to any cause, - Progression to AP or BC, Loss of partial cytogenetic response (PCyR), - Loss of CCyR, - Loss of CHR | End of Study (up to 40 months) | 
| Kaplan-Meier Estimates of Progression-free Survival (PFS) on Treatment | Progression-free survival was defined as the time from the date of randomization to the date of event defined as the first disease progression to AP/BC or the date of death from any cause, whichever is earlier. This variable was analyzed in 2 ways: On-treatment: included progressions to AP/BC or deaths occurring only on-treatment in the study as events. The time was censored at the date of last on-treatment assessment (hematology, extramedullary disease or cytogenetic evaluation) in the study before the cut-off date of the analysis for patients without event. On-study: included progressions to AP/BC or deaths occurring in the study or during the follow-up period after discontinuation of study treatment as events. The time was censored at the last assessment date in the study for patients who were still being treated and at the date of last contact for patients who discontinued treatment. | End of study (up to 40 months) | 
| Kaplan-Meier Estimates of Overall Survival (OS) on Treatment | Patients who discontinued study treatment early or completed the study protocol and did not enter into the extension protocol were to be followed for survival every 3 months for up to 2 calendar years from the date the last patient randomized received the first dose of study drug and every 6 months until Last Patient Last Visit. Overall survival (all deaths) was defined as the time between date of randomization and date of death due to any cause at any time during the study, including the follow-up period after discontinuation of treatment, i.e. overall survival on-study. The time was censored at the date of last assessment in the study for patients who are still being treated and at the date of last contact for patients who discontinued treatment. | End of Study (up to 40 months) | 
| Best Complete Hematologic Response (CHR) | CHR was defined as having all of the following criteria present at any assessment, which was confirmed by another assessment at least after 4 weeks: • WBC count < 10 x 10E9 /L • Platelet count < 450 x 10E9 /L • Basophils < 5% • No blasts and promyelocytes in peripheral blood • Myelocytes + metamyelocytes < 5 % in peripheral blood • No evidence of extramedullary involvement. The assessment was not considered CHR, if there were any values indicative of CML in AP or BC (i.e. by blasts in bone marrow). For confirmation of CHR, both the initial CHR as well as the confirming assessment (at least 4 weeks after the initial assessment) had to satisfy all criteria mentioned above, without any assessment in between which indicated 'No response'. | Months 1, 3, 4, 5, 6, 9,12, 15,18, 21, 24, 30, 36 | 
| Modified ELN2009 Criteria | Patients satisfying criteria for several modified ELN 2009 categories are presented once under the worst category (Optimal> Suboptimal > Treatment failure). Patients in the Discontinued category are those who discontinued before the time point considered without satisfying any of the ELN 2009 criteria. Patients in the Missing category are those ongoing in the trial at the time point considered but with only missing or non evaluable data for ELN 2009 criteria. | End of Study (up to 40 months) | 
| Actual Dose Intensity | Total dose/time on treatment (periods of zero dose were included). | End of Study (up to 40 months) | 
| Summary Statistics of Trough Imatinib and Major Metabolite CGP74588 of Imatinib and Nilotinib PK Concentration by Time Point | Pharmacokinetic Analysis Set | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly diagnosed,, Ph+ chronic myeloid leukemia,, CML-CP