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

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02546674

Acronym

NILOdeepR

Enrollment

171

Registered

2015-09-11

Start date

2016-02-18

Completion date

2021-03-25

Last updated

2022-07-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Chronic Myeloid Leukemia

Keywords

Chronic Myeloid Leukemia, Nilotinib, Molecular Response, MR4.5

Brief summary

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

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.

Interventions

DRUGNilotinib

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.

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 120 Years

Healthy volunteers

Inclusion criteria

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/

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Deep Molecular Response MR4.5 at 24 Months of Study Treatment	Month 24 and Month 21 (if assessment at Month 24 was missing)	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.

Secondary

Measure	Time frame	Description
Percentage of Participants With Major Molecular Response (MMR) at 12 Months of Study Treatment	Month 12	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.
Percentage of Participants With Complete Cytogenetic Response (CCyR) at 6 Months of Study Treatment	Month 6	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.
Progression-free Survival	From date of start of treatment to first documented disease progression to AP/ BC or death, assessed up to 24 months	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)
Time to Progression to AP/BC	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	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)
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)	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Physical Functioning	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Role Functioning	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Emotional Functioning	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
Percentage of Participants With MR4 at 24 Months of Study Treatment.	Month 24	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.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Social Functioning	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
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	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
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	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
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	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
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	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
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	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
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	Baseline, month 3, month 6, month 12, month 18 and month 24	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.
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ-C30): Cognitive Functioning	Baseline, month 3, month 6, month 12, month 18 and month 24	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.

Countries

Germany

Participant flow

Recruitment details

The study was conducted across 73 centers in 1 country (Germany).

Pre-assignment details

A total of 179 participants were screened in this study of which 8 discontinued screening phase and 171 participants were enrolled in the study

Participants by arm

Arm	Count
Nilotinib Participants with newly diagnosed CML in chronic phase received nilotinib 300 mg BID	171
Total	171

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	19
Overall Study	Death	1
Overall Study	Lost to Follow-up	1
Overall Study	Physician Decision	13
Overall Study	Pregnancy	1
Overall Study	Progressive Disease	2
Overall Study	Protocol Deviation	2
Overall Study	Subject/Guardian Decision	6
Overall Study	Withdrawal of Informed Consent	3

Baseline characteristics

Characteristic	Nilotinib
Age, Continuous	55.2 Years STANDARD_DEVIATION 13.87
Race/Ethnicity, Customized Asian	1 Participants
Race/Ethnicity, Customized Caucasian	170 Participants
Sex: Female, Male Female	63 Participants
Sex: Female, Male Male	108 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	1 / 171
other Total, other adverse events	148 / 171
serious Total, serious adverse events	38 / 171

Outcome results

Primary

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.

Time frame: Month 24 and Month 21 (if assessment at Month 24 was missing)

Population: Full Analysis Set (FAS): all participants who entered study and received at least one dose of study drug and had at least one post-baseline assessment of the primary efficacy variable. Only participants in the FAS with typical BCR-ABL transcripts (b2a2 and/or b3a2) were included in the analysis. Participants with atypical transcripts were excluded from the analysis, because their transcripts could not be used for molecular response determination

Arm	Measure	Value (NUMBER)
Nilotinib	Percentage of Participants With Deep Molecular Response MR4.5 at 24 Months of Study Treatment	35.3 Percentage of participants

Secondary

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.