Study of Nilotinib as First Line Treatment in Philadelphia Chromosome Positive(Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Study Overview
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Brief Summary
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The study was a local multicentric, open-label, non-randomized phase II study of nilotinib as a first line treatment in adult patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) and chronic phase myeloid leukemia (CML-CP).

Detailed Description
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This was a multicenter, open-label, single-arm, phase 2 study of nilotinib as a frontline treatment for patients with Ph+ CMLCP. All patients received oral nilotinib 300 mg twice daily for a planned treatment duration of 24 months or until early discontinuation. The primary efficacy end point was the cumulative rate of Major Molecular Response (MMR) in all participants by 12 months. Secondary efficacy end points included the rate of Complete Cytogenic Response (CCyR) at 6 and 12 months; cumulative rates of MMR up to 24 months; time to and durability of MMR; and cumulative rate of Complete Haematologic Response (CHR) by 12 months. Patient evaluations, including hematologic assessments, were conducted every 15 days during the first 3 months, monthly until month 12, and then every 3 months until the end of the study (24 months). All efficacy analyses were performed in the intent-to treat population.

Official Title
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A Phase II Multi-center, Open-label, Non-randomized Study of Nilotinib as First Line Treatment in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Conditions
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Chronic Myelogenous Leukemia

Intervention / Treatment
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* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 First cytogenetic diagnosis of CML-CP with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations within 6 months. Standard conventional cytogenetic analysis must be performed. Previously untreated for CML, except for hydroxyurea and/or anagrelide (except imatinib treatment for max. 31 days long) Adequate end organ function with following laboratory criteria: total bilirubin < 1.5 x upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN); creatinine < 1.5 x upper limit of normal (ULN); serum amylase and lipase ≤ 1.5 x upper limit of normal (ULN); alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN) unless considered tumor related Serum potassium, magnesium, and phosphorus levels are equal or above the lower limit of normal prior to the first dose of study medication Exclusion Criteria: Treatment with tyrosine kinase inhibitor(s) prior to study (in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of imatinib at any dose may be prescribed to the patient but for no longer than 31 days in duration) Known cytopathologically confirmed Central Nervous System CNS infiltration Impaired cardiac function Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection) Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention History of significant congenital or acquired bleeding disorder unrelated to cancer Previous radiotherapy to ≥25% of the bone marrow 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) Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon) Patients actively receiving therapy with strong Cytochrome P450 3A4 isoenzyme (CYP3A4) inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil) Patients actively receiving therapy with 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 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nilotinib<br>administered orally at a dose of 300 mg twice daily for 24 months | Drug: Nilotinib<br>* administered orally at a dose of 300 mg twice daily for 24 months<br>* Other names: Tasigna, AMN107;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months | Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months | Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders. | 3, 6, 9, 15, 18, 21 and 24 months | 
| Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 | CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase. | Month 6 and 12 | 
| Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 | A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved: WBC <10 x 109/L, thrombocyte <450 x 109/L, myelocyte + metamyelocyte <%5 in blood, no sign of blast and promyelocyte in blood, basophil <%5, and no sign of extramedullary involvement. | Month 3, 6, 9, 12, 18 and 24 | 
| Time to Major Molecular Response (MMR) | Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR. | 24 months | 
| Duration of Major Molecular Response (MMR) | MMR duration is defined as the time from the date of first documented MMR to the first time of the lost MMR, progression or death. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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First line treatment, newly diagnosed, Philadelphia chromosome positive, Chronic Myelogenous Leukemia, Ph+, CML-CP, major molecular response, Social risk