MACS0254: Study of Molecular Response in Adult Patients on Nilotinib With Philadelphia Chromosome Positive Chronic Myelogenous Leukemia (Ph+ CML) in Chronic Phase and a Suboptimal Molecular Response to Imatinib

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00644878
• Collaborator: (none)
• Enrollment: 18
• Locations: 11
• Arm: 1
• Duration (Months): 41
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This exploratory study will evaluate the change in molecular response in chronic myelogenous leukemia - chronic phase patients with a complete cytogenetic response and have a suboptimal molecular response to imatinib

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelogenous Leukemia - Chronic Phase	Drug: Nilotinib	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open-label, Exploratory Study of Bcr-Abl Kinetics in Adult Patients on Nilotinib With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) and a Suboptimal Molecular Response to Imatinib
• Study Start Date: Oct 1, 2008
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nilotinib	Drug: Nilotinib; Nilotinib 300 mg is taken by mouth twice a day at 12 hour intervals. Nilotinib is to be taken with water on an empty stomach. No food two hours prior to the dose of nilotinib and for one hour following the dose.; Other Names: Tasigna AMN 107

Outcome Measures

Primary Outcome Measures

1. Log Change From Baseline in Breakpoint Cluster Region Gene (BCR) - Abelson Proto-oncogene (ABL) (Bcr-Abl) Transcript Levels [From Baseline up to 12 Months]

   The change on a logarithmic scale at 12 months from a standardized baseline value (100% on the international scale [IS]) in Bcr-Abl transcripts as assessed by peripheral blood Quantitative real-time polymerase chain reaction (RQ-PCR).

Secondary Outcome Measures

1. Number of Participants Who Achieved Major Molecular Response (MMR) [From Baseline up to 12 Months]

   Major Molecular Response (MMR) value at molecular MD is designated a percentage, which is equivalent to a 3-log reduction from a standardized baseline value from the International Randomized InteYesrferon versus STI571 (IRIS) study or 0.1 percent (%) per International Scale (IS).

2. Number of Participants Achieved Reduction From a Standardized Baseline Value in Bcr-Abl Transcript Levels up to Month 12 [From Baseline up to 12 Months]

   Number of participants experiencing either a greater than or equal to (>or=) 1, >or= 2, or >or= 3 log10 reduction in Bcr-Abl transcript levels from Baseline to End of Cycle (EOC) 45 (Day1219 - Day1302) were presented.

3. Median Time to Best Molecular Response [From Start of Study up to End of the Study (up to 41 Months)]

   The median time to best molecular response, defined as the time (in months) from the date of enrollment to the date when the maximum reduction in Bcr-Abl transcript level was observed.

4. Duration of Best Molecular Response [From Start of Study up to End of the Study (up to 41 Months)]

   Duration of best molecular response, defined as the time (in months) from the date of best molecular response to a date when an increase in >1 log10 was observed

5. Number of Participants With an Event-free Survival [From Start of Study up to End of the Study (up to 41 Months)]

   Event-free survival was defined as the number of participants from the date of enrollment to the date of first occurrence of any of the following: loss of complete hematological response (CHR), loss of Complete cytogenetic response (CCyR), >1 log increase in Bcr-Abl transcripts from the lowest recorded value, progression to accelerated or blast phase, and death.

6. Number of Participants With a Progression-free Survival [From Start of Study up to End of the Study (up to 41 Months)]

   Progression-free survival was defined as the number of participants from the date of enrollment to the date of first occurrence of progression to Accelerated phase (AP) or Blast crisis (BC) phase, chronic myelogenous leukemia (CML) or death. Participants who did not have an event or dropped out without an event are considered censored at the date of the last observed event.

7. Number of Participants With an Overall Survival [From Start of Study Enrollment up to End of the Study (up to 41 Months)]

   Overall survival was defined as the number of participants from enrollment to the date of death.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Select Inclusion Criteria:

• Male or female patients ≥ 18 years of age with a confirmed diagnosis of Ph+ CML-CP and CCyR

• A suboptimal molecular response to imatinib defined as:

• Group 1: Treated with 1 year of imatinib, complete cytogenetic response (CCyR) but no major molecular response (MMR) (Bcr-Abl levels >0.1%IS);

• Group 2: No specific duration of imatinib required, achieved CCyR but has >1 log increase in Bcr-Abl transcript levels

• Adequate end organ function

• Patients must have had an imatinib washout period of at least 3 days and not to exceed 7 days prior to the first dose of nilotinib. Group 1 patients must have been treated with imatinib for at least 1 year. There was no imatinib treatment duration requirement for Group 2 patients.

• For Group 1, patients were eligible for screening if they were treated with an imatinib dose of at least 400mg daily. Dose reduction could have occurred as long as the minimum dose was 300mg daily and the reduction lasted ≤ 28 days. The patient was required to be on 400 mg daily (or a higher dose) of imatinib for at least 6 consecutive months leading up to screening for this study.

• For Group 2 patients, dose reduction while on imatinib could have occurred as long as the minimum dose was 300 mg daily, and the reduction lasted ≤28 days.

Select Exclusion Criteria:

• Prior accelerated phase or blast crisis CML

• Patients achieving prior CCyR on imatinib who lost cytogenetic response prior to entering study

• Previously documented T315I mutations

• Prior therapy with any other tyrosine kinase inhibitor except imatinib

• Patients with contraindications to receiving nilotinib, including concomitant medications

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	USC Norris Cancer Center Jane Anne Nohl	Los Angeles	California	United States	90033
2	Georgia Health Sciences University Dept. of MCG	Augusta	Georgia	United States	30912
3	Indiana Blood and Marrow Institute	Beech Grove	Indiana	United States	46107
4	University of Iowa Hospitals & Clinics Univ of Iowa Hosp & Clinic	Iowa City	Iowa	United States	52242
5	LSU HEALTH SCIENCES CENTER/ LSU SCHOOL OF MEDICINE Feist-Weiller Cancer Center	New Orleans	Louisiana	United States	70115
6	St. Agnes Hospital	Baltimore	Maryland	United States	21229
7	Cancer Centers of the Carolinas	Greenville	South Carolina	United States	29615
8	South Texas Institute of Cancer	Corpus Christi	Texas	United States	78405
9	Baylor College of Medicine - Breast Care Dan L Duncan Cancer Ctr	Houston	Texas	United States	77030
10	Central Utah Clinic Central Utah Clinic (7)	Provo	Utah	United States	84604
11	Froedert Memorial Lutheran Hospital Dept.ofFroedert Memorial	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00644878
• Other Study ID Numbers: CAMN107AUS09
• First Posted: Mar 27, 2008
• Last Update Posted: Aug 18, 2021
• Last Verified: Jul 1, 2021

• Keywords provided by Novartis Pharmaceuticals: leukemia; chronic myelogenous leukemia; chronic phase; molecular response; nilotinib; ENABL
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Philadelphia Chromosome

Study Results

Participant Flow

Recruitment Details	The study was conducted at 12 centers in United States.
Pre-assignment Detail	A total of 18 participants was enrolled in this study. Due to slower than expected enrollment, the study was terminated on 31 March 2012.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 milligram (mg) dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules twice daily (BID) for 12 cycles (each cycle = 28 days).
Period Title: Overall Study
STARTED	18
COMPLETED	0
NOT COMPLETED	18

Baseline Characteristics

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Overall Participants	18
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45.7 (12.15)
Sex: Female, Male (Count of Participants)
Female	7 38.9%
Male	11 61.1%
Race/Ethnicity, Customized (Count of Participants)
Caucasian	14 77.8%
Black	0 0%
Asian	1 5.6%
Other	3 16.7%

Outcome Measures

1. Primary Outcome

Title	Log Change From Baseline in Breakpoint Cluster Region Gene (BCR) - Abelson Proto-oncogene (ABL) (Bcr-Abl) Transcript Levels
Description	The change on a logarithmic scale at 12 months from a standardized baseline value (100% on the international scale [IS]) in Bcr-Abl transcripts as assessed by peripheral blood Quantitative real-time polymerase chain reaction (RQ-PCR).
Time Frame	From Baseline up to 12 Months

Outcome Measure Data

Analysis Population Description

The analysis was performed in intent-to-treat (ITT) population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment. Here, number of participants analyzed refer to the number of participants evaluable for this outcome measure at specified time point.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	18
Baseline	2.229 (0.6165)
Month 12	3.612 (0.5689)

2. Secondary Outcome

Title	Number of Participants Who Achieved Major Molecular Response (MMR)
Description	Major Molecular Response (MMR) value at molecular MD is designated a percentage, which is equivalent to a 3-log reduction from a standardized baseline value from the International Randomized InteYesrferon versus STI571 (IRIS) study or 0.1 percent (%) per International Scale (IS).
Time Frame	From Baseline up to 12 Months

Outcome Measure Data

Analysis Population Description

The analysis was performed in ITT population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	18
Response: Yes	0 0%
Response: No	18 100%
Response: Missing	0 0%
Response: Yes	9 50%
Response: No	3 16.7%
Response: Missing	6 33.3%

3. Secondary Outcome

Title	Number of Participants Achieved Reduction From a Standardized Baseline Value in Bcr-Abl Transcript Levels up to Month 12
Description	Number of participants experiencing either a greater than or equal to (>or=) 1, >or= 2, or >or= 3 log10 reduction in Bcr-Abl transcript levels from Baseline to End of Cycle (EOC) 45 (Day1219 - Day1302) were presented.
Time Frame	From Baseline up to 12 Months

Outcome Measure Data

Analysis Population Description

The analysis was performed in ITT population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment. Here the number of participants analyzed signifies participants who were evaluable for this outcome measure.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	12
>or=1 log10 reduction	12 66.7%
>or= 2 log10 reduction	12 66.7%
>or= 3 log10	9 50%

4. Secondary Outcome

Title	Median Time to Best Molecular Response
Description	The median time to best molecular response, defined as the time (in months) from the date of enrollment to the date when the maximum reduction in Bcr-Abl transcript level was observed.
Time Frame	From Start of Study up to End of the Study (up to 41 Months)

Outcome Measure Data

Analysis Population Description

The analysis was performed in ITT population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	18
Median (95% Confidence Interval) [months]	13.8

5. Secondary Outcome

Title	Duration of Best Molecular Response
Description	Duration of best molecular response, defined as the time (in months) from the date of best molecular response to a date when an increase in >1 log10 was observed
Time Frame	From Start of Study up to End of the Study (up to 41 Months)

Outcome Measure Data

Analysis Population Description

Since only one participant met the criterion of losing response (that is [i.e.,] an increase in > 1 log10 is observed after the occurrence of best molecular response), the analysis was not performed. Hence data was not collected and reported.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	0

6. Secondary Outcome

Title	Number of Participants With an Event-free Survival
Description	Event-free survival was defined as the number of participants from the date of enrollment to the date of first occurrence of any of the following: loss of complete hematological response (CHR), loss of Complete cytogenetic response (CCyR), >1 log increase in Bcr-Abl transcripts from the lowest recorded value, progression to accelerated or blast phase, and death.
Time Frame	From Start of Study up to End of the Study (up to 41 Months)

Outcome Measure Data

Analysis Population Description

The analysis was performed in ITT population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment. Participants who did not have an event or dropped out without an event are considered censored at the date of the last observed event.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	18
Event	1 5.6%
Censor	17 94.4%

7. Secondary Outcome

Title	Number of Participants With a Progression-free Survival
Description	Progression-free survival was defined as the number of participants from the date of enrollment to the date of first occurrence of progression to Accelerated phase (AP) or Blast crisis (BC) phase, chronic myelogenous leukemia (CML) or death. Participants who did not have an event or dropped out without an event are considered censored at the date of the last observed event.
Time Frame	From Start of Study up to End of the Study (up to 41 Months)

Outcome Measure Data

Analysis Population Description

The analysis was performed in ITT population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	18
Censor	15 83.3%
Missing	3 16.7%

8. Secondary Outcome

Title	Number of Participants With an Overall Survival
Description	Overall survival was defined as the number of participants from enrollment to the date of death.
Time Frame	From Start of Study Enrollment up to End of the Study (up to 41 Months)

Outcome Measure Data

Analysis Population Description

The analysis was performed in ITT population, defined as all enrolled participants who received at least 1 dose of study drug and had at least 1 post-baseline assessment.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
Measure Participants	18
Count of Participants [Participants]	18 100%

Adverse Events

Time Frame	From Start of Study to End of the Study (up to 41 Months)
Adverse Event Reporting Description	The analysis was performed on safety set population defined as all participants who received study drug and had at least one post-baseline safety assessment.
Arm/Group Title	Nilotinib
Arm/Group Description	Participants orally received a total of 600 mg dose of Nilotinib as a as 50-mg and 200-mg hard gelatin capsules BID for 12 cycles (each cycle = 28 days).
All Cause Mortality
	Nilotinib
	Affected / at Risk (%)	# Events
Total	0/18 (0%)
Serious Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	3/18 (16.7%)
Cardiac disorders
Bradycardia	1/18 (5.6%)
Ear and labyrinth disorders
Vertigo	1/18 (5.6%)
Gastrointestinal disorders
Pancreatitis	1/18 (5.6%)
Infections and infestations
Pneumonia	1/18 (5.6%)
Sinusitis	1/18 (5.6%)
Other (Not Including Serious) Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	18/18 (100%)
Blood and lymphatic system disorders
Anaemia	1/18 (5.6%)
Cardiac disorders
Tachycardia	1/18 (5.6%)
Ear and labyrinth disorders
Ear pain	1/18 (5.6%)
Eye disorders
Dry eye	3/18 (16.7%)
Eye irritation	1/18 (5.6%)
Eye pruritus	1/18 (5.6%)
Macular degeneration	1/18 (5.6%)
Vision blurred	1/18 (5.6%)
Gastrointestinal disorders
Abdominal discomfort	1/18 (5.6%)
Abdominal tenderness	1/18 (5.6%)
Anal pruritus	1/18 (5.6%)
Colitis	1/18 (5.6%)
Constipation	3/18 (16.7%)
Diarrhoea	1/18 (5.6%)
Flatulence	1/18 (5.6%)
Gastrooesophageal reflux disease	1/18 (5.6%)
Gingival bleeding	1/18 (5.6%)
Gingival pain	1/18 (5.6%)
Nausea	4/18 (22.2%)
Proctalgia	1/18 (5.6%)
Toothache	1/18 (5.6%)
Vomiting	2/18 (11.1%)
General disorders
Asthenia	1/18 (5.6%)
Fatigue	6/18 (33.3%)
Irritability	1/18 (5.6%)
Swelling	1/18 (5.6%)
Hepatobiliary disorders
Hyperbilirubinaemia	2/18 (11.1%)
Immune system disorders
Seasonal allergy	1/18 (5.6%)
Infections and infestations
Bronchitis	1/18 (5.6%)
Cystitis	1/18 (5.6%)
Eye infection	1/18 (5.6%)
Folliculitis	1/18 (5.6%)
Genital herpes	1/18 (5.6%)
Nasopharyngitis	2/18 (11.1%)
Sinusitis	4/18 (22.2%)
Tinea infection	1/18 (5.6%)
Upper respiratory tract infection	4/18 (22.2%)
Urinary tract infection	1/18 (5.6%)
Injury, poisoning and procedural complications
Fall	1/18 (5.6%)
Ligament sprain	1/18 (5.6%)
Procedural pain	1/18 (5.6%)
Sunburn	1/18 (5.6%)
Investigations
Alanine aminotransferase increased	3/18 (16.7%)
Aspartate aminotransferase increased	2/18 (11.1%)
Blood bilirubin increased	1/18 (5.6%)
Blood glucose increased	1/18 (5.6%)
Blood magnesium increased	1/18 (5.6%)
Blood phosphorus decreased	1/18 (5.6%)
Blood potassium decreased	1/18 (5.6%)
Blood pressure increased	1/18 (5.6%)
Blood uric acid increased	1/18 (5.6%)
Platelet count decreased	1/18 (5.6%)
Weight decreased	2/18 (11.1%)
Weight increased	2/18 (11.1%)
Metabolism and nutrition disorders
Decreased appetite	1/18 (5.6%)
Hypercholesterolaemia	2/18 (11.1%)
Hyperglycaemia	2/18 (11.1%)
Hypertriglyceridaemia	2/18 (11.1%)
Hypokalaemia	1/18 (5.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/18 (27.8%)
Back pain	1/18 (5.6%)
Muscle fatigue	1/18 (5.6%)
Muscle spasms	3/18 (16.7%)
Musculoskeletal chest pain	1/18 (5.6%)
Myalgia	4/18 (22.2%)
Pain in extremity	2/18 (11.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Squamous cell carcinoma	1/18 (5.6%)
Nervous system disorders
Dizziness	2/18 (11.1%)
Headache	5/18 (27.8%)
Hyperaesthesia	2/18 (11.1%)
Neuropathy peripheral	1/18 (5.6%)
Paraesthesia	1/18 (5.6%)
Speech disorder	1/18 (5.6%)
Tremor	1/18 (5.6%)
Psychiatric disorders
Anxiety	1/18 (5.6%)
Confusional state	1/18 (5.6%)
Depression	1/18 (5.6%)
Insomnia	2/18 (11.1%)
Loss of libido	1/18 (5.6%)
Renal and urinary disorders
Bladder prolapse	1/18 (5.6%)
Micturition urgency	1/18 (5.6%)
Urinary retention	1/18 (5.6%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/18 (5.6%)
Breast tenderness	1/18 (5.6%)
Dysmenorrhoea	1/18 (5.6%)
Erectile dysfunction	1/18 (5.6%)
Sexual dysfunction	1/18 (5.6%)
Uterine prolapse	1/18 (5.6%)
Vulvovaginal pruritus	1/18 (5.6%)
Respiratory, thoracic and mediastinal disorders
Cough	4/18 (22.2%)
Dysphonia	1/18 (5.6%)
Dyspnoea	3/18 (16.7%)
Dyspnoea exertional	1/18 (5.6%)
Oropharyngeal pain	3/18 (16.7%)
Pharyngeal erythema	1/18 (5.6%)
Respiratory tract congestion	1/18 (5.6%)
Rhinorrhoea	1/18 (5.6%)
Skin and subcutaneous tissue disorders
Alopecia	2/18 (11.1%)
Dermatitis contact	1/18 (5.6%)
Eczema	1/18 (5.6%)
Night sweats	3/18 (16.7%)
Pain of skin	1/18 (5.6%)
Pruritus	2/18 (11.1%)
Rash	5/18 (27.8%)
Rash generalised	1/18 (5.6%)
Rash pruritic	2/18 (11.1%)
Vascular disorders
Hypertension	2/18 (11.1%)
Hypotension	1/18 (5.6%)

Limitations/Caveats

The study was terminated on 31 March 2012 due to slower than planned enrollment, resulting in a small sample size, no inferential analyses were conducted.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.