Study Assessing Deep Molecular Response in Adult Patients With CML in Chronic Phase Treated With Nilotinib Firstline.

Study Overview
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Brief Summary
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The main purpose of this study was to evaluate the rate of deep molecular response (MR4.5) after 24 months of therapy with nilotinib in newly diagnosed patients with chronic phase chronic myeloid leukemia (CML) using EUTOS (European Treatment and Outcome Study for CML)-standardized laboratories. All participants received nilotinib 300 mg twice daily (BID).

Detailed Description
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This was a Phase IV open-label, multi-center, single-arm study in participants with newly diagnosed Philadelphia chromosome positive (Ph+) CML in chronic phase for who nilotinib is the appropriate treatment at the discretion of the investigator. A screening period of 2 weeks was used to assess eligibility and to taper participants off disallowed medications. Participants whose eligibility was confirmed entered a 24 months treatment phase with nilotinib 300mg BID. Nilotinib was prescribed by the investigator according to the individual needs of the participants.

Official Title
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A Phase IV Single Arm, Multicenter, Open-label Study Assessing Deep Molecular Response in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive CML in Chronic Phase After Two Years of Treatment With Nilotinib 300mg BID

Conditions
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Chronic Myeloid Leukemia

Intervention / Treatment
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* Drug: Nilotinib


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Patients with newly diagnosed (within 6 months) Philadelphia chromosome positive CML in chronic phase Patients must be previously untreated for CML with the exception of 6 months treatment with hydroxyurea and a maximum of 6 weeks treatment with imatinib Adequate end organ function Normal serum levels ≥ lower limit of normal (LLN) of potassium, magnesium, total calcium corrected for serum albumin or phosphorus, or correctable to within normal limits with supplements, prior to the first dose of study medication. Key Exclusion Criteria: Known impaired cardiac function like long QT syndrome, history of myocardial infarction or unstable angina in the past 12 months. Patients who are pregnant or breast feeding. Other inclusion/exclusion criteria might apply

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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>Participants with newly diagnosed CML in chronic phase received nilotinib 300 mg BID for 24 months | Drug: Nilotinib<br>* A daily dose of 300 mg was given to all participants as two 150 mg capsules BID. The prescription of study drug was not study dependent and followed medical needs of the participant only. The study treatment was administered for 24 months.<br>* Other names: AMN107;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Deep Molecular Response MR4.5 at 24 Months of Study Treatment | Percentage of participants who were in deep molecular response MR4.5 (IS) at 24 months measured in a standardized EUTOS (European Treatment and Outcome Study for CML) MR4.5 laboratory. MR4.5 was defined as either (i) detectable disease ≤ 0.0032% BCR-ABL (fusion gene from breakpoint cluster region and Abelson genes) (IS) or (ii) undetectable disease in cDNA with 32000-99999 ABL1 transcripts or 77000-239999 glucuronidase beta (GUSB) transcripts. Responders: Participants with a MR4.5 at 24 months, or if the assessment at this time point was missing, with a MR4.5 at 21 months Non-responders: Participants dropping out early or not providing sufficient data for any other reason. Participants who achieved MR4.5 before 24 months, but was no longer in MR4.5 at 24 months or progressed (or was no longer in MR4.5 at 21 months if evaluation at 24 months was missing). Confidence intervals were calculated based on the Exact Clopper-Pearson method. | Month 24 and Month 21 (if assessment at Month 24 was missing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With MR4 at 24 Months of Study Treatment. | Percentage of participants with MR4 at 24 months of study treatment. MR4 (IS) is defined as either (i) detectable disease ≤0.01% BCR-ABL by IS or (ii) undetectable disease in cDNA with 10000 - 31999 ABL1 transcripts or 24000 - 76999 GUSB transcripts. Confidence intervals were calculated based on the Exact Clopper-Pearson method. | Month 24 | 
| Percentage of Participants With Major Molecular Response (MMR) at 12 Months of Study Treatment | Percentage of participants with MMR at 12 months of study treatment. MMR is defined as ≤ 0.1% BCR-ABL by IS, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline. Confidence intervals were calculated based on the Exact Clopper-Pearson method. | Month 12 | 
| Percentage of Participants With Complete Cytogenetic Response (CCyR) at 6 Months of Study Treatment | Percentage of participants with CCyR at 6 months of study treatment. Cytogenetic response was assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow (a review of a minimum of 20 metaphases was required). CCyR was defined as a value of 0% Ph+ metaphases in bone marrow. Confidence intervals were calculated based on the Exact Clopper-Pearson method. | Month 6 | 
| Progression-free Survival | Progression-free survival is defined as the time from the date of start of study treatment to the date of the first documented disease progression to accelerated phase (AP)/ blast crisis (BC) or death from any cause, whichever is earlier. AP is defined as: 15% blasts in the peripheral blood or one marrow aspirate, but <30% blasts in both the peripheral blood and bone marrow aspirate 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate 20% basophils in the peripheral blood or bone marrow Thrombocytopenia (<100 x 109/Liter) that is unrelated to therapy Evidence of clonal evolution BC is defined as: ≥ 30% blasts in peripheral blood or bone marrow aspirate Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy (i.e., chloroma) | From date of start of treatment to first documented disease progression to AP/ BC or death, assessed up to 24 months | 
| Time to Progression to AP/BC | Time to progression to AP/BC is defined as the time from the date of start of study treatment to the date of earliest transformation to AP/BC, or CML-related death. AP is defined as: 15% blasts in the peripheral blood or one marrow aspirate, but <30% blasts in both the peripheral blood and bone marrow aspirate 30% blasts plus promyelocytes in peripheral blood or bone marrow aspirate 20% basophils in the peripheral blood or bone marrow Thrombocytopenia (<100 x 109/L) that is unrelated to therapy Evidence of clonal evolution (with consensus of SC only) BC is defined as: ≥ 30% blasts in peripheral blood or bone marrow aspirate Appearance of extramedullary involvement other than hepatosplenomegaly proven by biopsy (i.e., chloroma) | From the date of start of study treatment to the date of earliest transformation to AP/BC or CML-related death, assessed up to 24 months | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Global Health Status (GHS)/Quality of Life (QoL) | The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a GHS/QoL scale. The GHS/QoL scale has 7 possible scores of responses (1=very poor to 7=excellent). Scores were averaged and transformed to 0 to 100. Higher scores indicate better quality of life. A positive change from Baseline indicates improvement. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Physical Functioning | The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the physical functioning scale, participants self-rated levels of difficulty in doing strenuous activities, taking a walk, how much they needed to stay in bed or a chair, or needed help with eating, dressing, bathing, using the toilet. The physical functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in physical functioning. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Role Functioning | The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the role functioning scale, participants self-rated how much they were limited in doing work or daily activities, or in pursuing hobbies or other leisure time activities during the past week. The role functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in role functioning. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Emotional Functioning | The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the emotional functioning scale, participants self-rated how much they felt tense, worried, irritable or depressed during the past week. The emotional functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in emotional functioning. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Cognitive Functioning | The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the cognitive functioning scale, participants self-rated the extent of difficulty in concentrating on things or remembering things during the past week. The cognitive functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in cognitive functioning. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Social Functioning | The EORTC QLQ-C30 is a patient completed 30 item questionnaire that is composed of both multi-item scales and single-item measures. These include five functional scales, three symptom scales, six single items and a global health status/QoL scale. For the social functioning scale, participants self-rated how much their physical condition or medical treatment interfered with their family life and social activities during the past week. The social functioning scale had 4 possible scores (1=not at all, 2=a little, 3=quite a bit, 4=very much). Scores were averaged and transformed to 0 to 100. Higher scores indicate better functioning. A positive change from baseline indicates improvement in social functioning. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chronic Myeloid Leukemia Specific 24 (EORTC QLQ-CML 24): Symptom Burden | The EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality of life questionnaire for CML patients. The questionnaire is composed of four multi-item scales and two single-item scales. The module consists of 24 items assessing symptoms burden (13 items), impact on worry/mood (4 items), impact on daily life (3 items), satisfaction with care and information (2 items) body image problems (1 item) and satisfaction with social life (1 item). The items were measured on four levels: 1=not at all, 2=a little, 3=quite a bit, 4=very much. For each domain, scores were averaged and transformed to 0 to 100. A higher score in symptom burden domain indicates a worse outcome. A negative change from baseline indicates improvement. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chronic Myeloid Leukemia Specific 24 (EORTC QLQ-CML 24): Impact on Worry/Mood | The EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality of life questionnaire for CML patients. The questionnaire is composed of four multi-item scales and two single-item scales. The module consists of 24 items assessing symptoms burden (13 items), impact on worry/mood (4 items), impact on daily life (3 items), satisfaction with care and information (2 items) body image problems (1 item) and satisfaction with social life (1 item). The items were measured on four levels: 1=not at all, 2=a little, 3=quite a bit, 4=very much. For each scale, scores were averaged and transformed to 0 to 100. A higher score in impact on worry/mood domain indicates a worse outcome. A negative change from baseline indicates improvement. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chronic Myeloid Leukemia Specific 24 (EORTC QLQ-CML 24): Impact on Daily Life | The EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality of life questionnaire for CML patients. The questionnaire is composed of four multi-item scales and two single-item scales. The module consists of 24 items assessing symptoms burden (13 items), impact on worry/mood (4 items), impact on daily life (3 items), satisfaction with care and information (2 items) body image problems (1 item) and satisfaction with social life (1 item). The items were measured on four levels: 1=not at all, 2=a little, 3=quite a bit, 4=very much. For each domain, scores were averaged and transformed to 0 to 100. A higher score in impact on daily life domain indicates a worse outcome. A negative change from baseline indicates improvement. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chronic Myeloid Leukemia Specific 24 (EORTC QLQ-CML 24): Satisfaction With Care and Information | The EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality of life questionnaire for CML patients. The questionnaire is composed of four multi-item scales and two single-item scales. The module consists of 24 items assessing symptoms burden (13 items), impact on worry/mood (4 items), impact on daily life (3 items), satisfaction with care and information (2 items) body image problems (1 item) and satisfaction with social life (1 item). The items were measured on four levels: 1=not at all, 2=a little, 3=quite a bit, 4=very much. For each domain, scores were averaged and transformed to 0 to 100. A higher score in satisfaction with care and information domain indicates a higher level of satisfaction. A positive change from baseline indicates increasing satisfaction. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chronic Myeloid Leukemia Specific 24 (EORTC QLQ-CML 24): Body Image Problems | The EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality of life questionnaire for CML patients. The questionnaire is composed of four multi-item scales and two single-item scales. The module consists of 24 items assessing symptoms burden (13 items), impact on worry/mood (4 items), impact on daily life (3 items), satisfaction with care and information (2 items) body image problems (1 item) and satisfaction with social life (1 item). The items were measured on four levels: 1=not at all, 2=a little, 3=quite a bit, 4=very much. For each domain, scores were averaged and transformed to 0 to 100. A higher score in body image problems domain indicates a worse outcome. A negative change from baseline indicates improvement. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 
| Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chronic Myeloid Leukemia Specific 24 (EORTC QLQ-CML 24): Satisfaction With Social Life | The EORTC QLQ-CML 24 is an internationally developed disease specific health-related quality of life questionnaire for CML patients. The questionnaire is composed of four multi-item scales and two single-item scales. The module consists of 24 items assessing symptoms burden (13 items), impact on worry/mood (4 items), impact on daily life (3 items), satisfaction with care and information (2 items) body image problems (1 item) and satisfaction with social life (1 item). The items were measured on four levels: 1=not at all, 2=a little, 3=quite a bit, 4=very much. For each domain, scores were averaged and transformed to 0 to 100. A higher score in satisfaction with social life domain indicates a higher level of satisfaction. A positive change from baseline indicates increasing satisfaction. | Baseline, month 3, month 6, month 12, month 18 and month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Myeloid Leukemia, Nilotinib, Molecular Response, MR4.5