MACS0999: An Exploratory Trial to Assess the Improvement of Adverse Events in Chronic Myelogenous Leukemia Patients Treated With Imatinib When Switched to Nilotinib Treatment

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00980018
• Collaborator: (none)
• Enrollment: 52
• Locations: 23
• Arm: 1
• Duration (Months): 36
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this exploratory study will be to examine changes in chronic low grade chronic adverse events, measured by Common Terminology Criteria for Adverse Events (CTCAE) grading, when patients are switched from imatinib to nilotinib therapy.

Condition or Disease	Intervention/Treatment	Phase
Chronic Myelogenous Leukemia	Drug: Nilotinib	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Exploratory Trial to Assess the Improvement of Chronic Low-grade Non-hematologic Adverse Events Experienced by Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) Treated With Imatinib When Switched to Nilotinib Treatment
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Dec 1, 2012
• Actual Study Completion Date: Dec 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: nilotinib Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).	Drug: Nilotinib; Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).; Other Names: Tasigna, nilotinib, AMN107,

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3 [End of Cycles 1, 2, and 3]

   A patient was considered improved if 50% or more of the chronic imatinib-related chronic low grade nonhematologic AEs showed improvement (a decrease in CTCAE [Common Terminology Criteria for Adverse Events] grade or complete resolution).

Secondary Outcome Measures

1. Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline [Cycles 1, 2, 6, 9, and 12]

   Time to complete cytogenetic response is defined as time from baseline to first time of CCyR as documented by bone marrow cytogenetics. Cytogenetic response was assessed as applicable by bone marrow cytogenetics 6, 12, and 18 months after starting imatinib therapy. Assess CCyR by bone marrow cytogenics

2. Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline [Cycles 1,2,3,6,9,12]

   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 Interferon versus STI571 (IRIS) study or 0.1% per International Scale (IS). Time to MMR is defined as time from baseline to first time of MMR as documented by RQ-PCR

3. Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy [Cycles 1,2,3,6,9, and 12]

   Levels of BCR-ABL transcripts were determined by quantitative RQ-PCR testing of peripheral blood and analyzed at a central testing laboratory. Log reduction in BCR-ABL transcripts levels from the standardized baseline value will be calculated for each sample from the reported percent ratio of BCR-ABL transcripts versus control gene transcripts converted to a reference standard.

4. Duration of Complete Cytogenetic Response [18 months of follow up from the first documented response]

   Duration of Complete Cytogenetic Response is defined as the time from first CCyR to first loss of CCyR as documented by bone marrow cytogenetics, or by FISH assay, whichever is earlier. The duration of CCyR begins on the day of enrollment for patients reporting CCyR at baseline.

5. Time to Complete Cytogenetic Response in Participants Not Reporting at Baseline [Cycle 12]

   For time to CCyR, an event is defined as achievement of CCyR documented by bone marrow cytogenetics.

6. Duration of Major Molecular Response [18 months of follow up from the first documented response]

   Duration of Major Molecular Response is defined as the time from first MMR to first loss of MMR as documented by RQ-PCR. The duration of MMR begins on the day of enrollment for patients reporting MMR at baseline.

7. Time to Major Molecular Response (MMR) in Participants With MMR Absent at Baseline [Cycles 1,2,3,6,9,12]

   For time to MMR, an event is defined as achievement of MMR documented by RQ-PCR. Patients with MMR at the Screening RQ-PCR assay are counted as having time to MMR equal to 0.

8. Time to Optimal Imatinib-related Adverse Event Improvement [18 months of follow up from the date of the first dose of study drug to the time to maximum decrease in CTCAE grade of these events]

   Time to optimal improvement is defined as the time when the sum of the total CTCAE toxicity grades for a patient's chronic low-grade imatinib-related adverse events reaches its minimum value.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age

2. Eastern Cooperative Oncology Group (ECOG) 0, 1, or 2

3. Diagnosis of CML-CP associated with Bcr-Abl quantifiable by RQ-PCR (IS)

4. Patients must be an imatinib responder and achieved the following efficacy milestones as appropriate for the length of time on imatinib therapy as per protocol

5. CML-CP patients initiated on any dose of imatinib

6. Ability to provide written informed consent prior to any study related screening procedures being done

Exclusion Criteria:

1. Loss of CHR or cytogenetic response

2. Prior accelerated phase or blast phase CML

3. Previously documented T315I mutation

4. Presence of chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+.

5. Previous treatment with any other tyrosine kinase inhibitor except for imatinib.

6. Treatment with other investigational agents within 30 days of Day 1.

7. History of non-compliance to medical regimens or inability to grant consent.

8. Women who are pregnant, breast feeding, or of childbearing potential without a negative serum test at baseline. Male or female patients of childbearing potential unwilling to use contraceptive precautions throughout the trial and 3 months following discontinuation of study drug. Post-menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Women of childbearing potential must have a negative serum pregnancy test prior to the first dose of nilotinib.

Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Highlands Oncology Group	Fayetteville	Arkansas	United States	72703
2	Hematology Oncology Services of Arkansas SC	Little Rock	Arkansas	United States	72205
3	USC Norris Cancer Center LAC & USC Medical Center	Los Angeles	California	United States	90033
4	Southwest Cancer Care Murrieta	Poway	California	United States	92064
5	Rocky Mountain Cancer Centers RMCC - Aurora	Greenwood Village	Colorado	United States
6	Florida Cancer Institute	New Port Richey	Florida	United States	34655
7	Cancer Centers of Florida PA Cancer Centers of FL-Orlando-4	Ocoee	Florida	United States	*see dep*
8	Stroger Cook County Hospital John H. Stroger Hospital	Chicago	Illinois	United States	60612
9	St. Francis Hospital and Health Centers IndianaBlood&MarrowTransplantn	Beech Grove	Indiana	United States	46107
10	St. Agnes Hospital	Baltimore	Maryland	United States	21229
11	St. Louis University Cancer Center	Saint Louis	Missouri	United States	63110
12	Northwest Cancer Specialists Salmon Creek Office	Portland	Oregon	United States	97210
13	Oregon Health Sciences University	Portland	Oregon	United States	97239
14	The Jones Clinic	Germantown	Tennessee	United States	38138
15	Texas Oncology, P.A.	Bedford	Texas	United States	76022
16	Presbyterian Hospital of Dallas TexasOncology@PresbyterianHosp	Dallas	Texas	United States	75231
17	Texas Oncology Texas Oncology - Sugar Land	Dallas	Texas	United States	75246
18	MD Anderson Cancer Center/University of Texas	Houston	Texas	United States	77031
19	Cancer Care Centers of South Texas / HOAST CCC of So. TX- San Antonio(2)	San Antonio	Texas	United States	78229
20	Novartis Investigative Site	Brampton	Ontario	Canada	L6R 3J7
21	Novartis Investigative Site	Toronto	Ontario	Canada	M5G 2M9
22	Novartis Investigative Site	Montreal	Quebec	Canada	H1T 2M4
23	Novartis Investigative Site	Montreal	Quebec	Canada	H3A 1A1

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00980018
• Other Study ID Numbers: CAMN107AUS17
• First Posted: Sep 18, 2009
• Last Update Posted: Jul 1, 2021
• Last Verified: Jun 1, 2021

• Keywords provided by Novartis Pharmaceuticals: CML; Leukemia; Tasigna; nilotinib; AMN107; CML-CP; Chronic Phase
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Study Results

Participant Flow

Recruitment Details	The study was conducted at 15 centers in US and 4 centers in Canada from 10-December-2009 (first patient first visit) to 27-December-2012 (last patient last visit).
Pre-assignment Detail	A total of 68 patients were screened out of which 52 enrolled and 40 completed the full duration of treatment.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Period Title: Overall Study
STARTED	52
COMPLETED	40
NOT COMPLETED	12

Baseline Characteristics

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Overall Participants	52
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	51.7 (10.76)
Sex: Female, Male (Count of Participants)
Female	26 50%
Male	26 50%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Improvement in Imatinib Related Chronic Low Grade Non Hematologic Adverse Event (AE) After Switch to Treatment With Nilotinib at End of Cycle 3
Description	A patient was considered improved if 50% or more of the chronic imatinib-related chronic low grade nonhematologic AEs showed improvement (a decrease in CTCAE [Common Terminology Criteria for Adverse Events] grade or complete resolution).
Time Frame	End of Cycles 1, 2, and 3

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	52
End of Cycle 1	37 71.2%
End of Cycle 2	43 82.7%
End of Cycle 3	44 84.6%

2. Secondary Outcome

Title	Percentage of Participants Achieving Complete Cytogenetic Response (CCyR) After Switching to Nilotinib for Participants Not Reporting CCyR at Baseline
Description	Time to complete cytogenetic response is defined as time from baseline to first time of CCyR as documented by bone marrow cytogenetics. Cytogenetic response was assessed as applicable by bone marrow cytogenetics 6, 12, and 18 months after starting imatinib therapy. Assess CCyR by bone marrow cytogenics
Time Frame	Cycles 1, 2, 6, 9, and 12

Outcome Measure Data

Analysis Population Description

FAS : All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	7
Cycle 1	2 3.8%
Cycle 2	3 5.8%
Cycle 3	0 0%
Cycle 6	2 3.8%
Cycle 9	0 0%
Cycle 12	0 0%

3. Secondary Outcome

Title	Percentage of Participants Achieving Major Molecular Response (MMR) After the Switch in the Therapy for Participants Not Reporting MMR at Baseline
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 Interferon versus STI571 (IRIS) study or 0.1% per International Scale (IS). Time to MMR is defined as time from baseline to first time of MMR as documented by RQ-PCR
Time Frame	Cycles 1,2,3,6,9,12

Outcome Measure Data

Analysis Population Description

FAS : All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	18
Cycle 1	2 3.8%
Cycle 2	6 11.5%
Cycle 3	3 5.8%
Cycle 6	2 3.8%
Cycle 9	2 3.8%
Cycle 12	0 0%

4. Secondary Outcome

Title	Log Change in BCR-Abl Transcript Level From Baseline After the Switch Therapy
Description	Levels of BCR-ABL transcripts were determined by quantitative RQ-PCR testing of peripheral blood and analyzed at a central testing laboratory. Log reduction in BCR-ABL transcripts levels from the standardized baseline value will be calculated for each sample from the reported percent ratio of BCR-ABL transcripts versus control gene transcripts converted to a reference standard.
Time Frame	Cycles 1,2,3,6,9, and 12

Outcome Measure Data

Analysis Population Description

FAS: All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	52
Cycle 1	-0.177 (0.3665)
Cycle 2	-0.407 (0.5748)
Cycle 3	-0.540 (0.6960)
Cycle 6	-0.718 (0.9313)
Cycle 9	-0.844 (0.9130)
Cycle 12	-0.902 (0.9913)

5. Secondary Outcome

Title	Duration of Complete Cytogenetic Response
Description	Duration of Complete Cytogenetic Response is defined as the time from first CCyR to first loss of CCyR as documented by bone marrow cytogenetics, or by FISH assay, whichever is earlier. The duration of CCyR begins on the day of enrollment for patients reporting CCyR at baseline.
Time Frame	18 months of follow up from the first documented response

Outcome Measure Data

Analysis Population Description

FAS: All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	52
Participants with CCyR at baseline	319.7 (143.03)
Participants achieving CCyR on study	266.3 (86.73)

6. Secondary Outcome

Title	Time to Complete Cytogenetic Response in Participants Not Reporting at Baseline
Description	For time to CCyR, an event is defined as achievement of CCyR documented by bone marrow cytogenetics.
Time Frame	Cycle 12

Outcome Measure Data

Analysis Population Description

FAS: All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	7
Median (95% Confidence Interval) [months]	1.9

7. Secondary Outcome

Title	Duration of Major Molecular Response
Description	Duration of Major Molecular Response is defined as the time from first MMR to first loss of MMR as documented by RQ-PCR. The duration of MMR begins on the day of enrollment for patients reporting MMR at baseline.
Time Frame	18 months of follow up from the first documented response

Outcome Measure Data

Analysis Population Description

FAS : All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	49
Participants with MMR at baseline	277.6 (166.88)
Participants achieving MMR on study	208.3 (123.61)

8. Secondary Outcome

Title	Time to Major Molecular Response (MMR) in Participants With MMR Absent at Baseline
Description	For time to MMR, an event is defined as achievement of MMR documented by RQ-PCR. Patients with MMR at the Screening RQ-PCR assay are counted as having time to MMR equal to 0.
Time Frame	Cycles 1,2,3,6,9,12

Outcome Measure Data

Analysis Population Description

FAS : All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	18
Median (95% Confidence Interval) [months]	2.8

9. Secondary Outcome

Title	Time to Optimal Imatinib-related Adverse Event Improvement
Description	Time to optimal improvement is defined as the time when the sum of the total CTCAE toxicity grades for a patient's chronic low-grade imatinib-related adverse events reaches its minimum value.
Time Frame	18 months of follow up from the date of the first dose of study drug to the time to maximum decrease in CTCAE grade of these events

Outcome Measure Data

Analysis Population Description

FAS: All participants who received at least one dose of study drug.

Arm/Group Title	Nilotinib
Arm/Group Description	Participants received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
Measure Participants	52
Median (95% Confidence Interval) [months]	1.9

Adverse Events

Time Frame	18 months of follow up from the date of the first dose of study drug to the time to maximum decrease in CTCAE grade of these events
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 received two 150 [a total of 300 mg at each dosing] mg nilotinib capsules twice daily (bid) orally every morning and every evening approximately 12 hours apart and two 200 mg capsules [a total of 400 mg at each dosing] for patients enrolled prior to Protocol Amendment 1).
All Cause Mortality
	Nilotinib
	Affected / at Risk (%)	# Events
Total	0/52 (0%)
Serious Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	9/52 (17.3%)
Cardiac disorders
Cardiac arrest	1/52 (1.9%)
Coronary artery disease	1/52 (1.9%)
Gastrointestinal disorders
Pancreatitis	1/52 (1.9%)
Pancreatitis acute	1/52 (1.9%)
General disorders
Pain	1/52 (1.9%)
Hepatobiliary disorders
Cholecystitis acute	1/52 (1.9%)
Infections and infestations
Bronchitis	1/52 (1.9%)
Gastroenteritis	1/52 (1.9%)
Vulval cellulitis	1/52 (1.9%)
Wound infection bacterial	1/52 (1.9%)
Wound infection staphylococcal	1/52 (1.9%)
Injury, poisoning and procedural complications
Cartilage injury	1/52 (1.9%)
Scapula fracture	1/52 (1.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/52 (1.9%)
Nervous system disorders
Facial palsy	1/52 (1.9%)
Reproductive system and breast disorders
Ovarian torsion	1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Pleural effusion	1/52 (1.9%)
Vascular disorders
Arteriosclerosis	1/52 (1.9%)
Hypotension	1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	49/52 (94.2%)
Eye disorders
Dry eye	4/52 (7.7%)
Gastrointestinal disorders
Abdominal pain	8/52 (15.4%)
Constipation	14/52 (26.9%)
Diarrhoea	8/52 (15.4%)
Dry mouth	4/52 (7.7%)
Dyspepsia	6/52 (11.5%)
Nausea	11/52 (21.2%)
General disorders
Chest pain	3/52 (5.8%)
Chills	5/52 (9.6%)
Fatigue	17/52 (32.7%)
Pyrexia	3/52 (5.8%)
Infections and infestations
Sinusitis	3/52 (5.8%)
Upper respiratory tract infection	6/52 (11.5%)
Investigations
Lipase increased	3/52 (5.8%)
Weight decreased	5/52 (9.6%)
Metabolism and nutrition disorders
Anorexia	7/52 (13.5%)
Decreased appetite	3/52 (5.8%)
Hyperglycaemia	4/52 (7.7%)
Hypokalaemia	3/52 (5.8%)
Hypophosphataemia	3/52 (5.8%)
Musculoskeletal and connective tissue disorders
Arthralgia	12/52 (23.1%)
Bone pain	3/52 (5.8%)
Muscle spasms	8/52 (15.4%)
Myalgia	4/52 (7.7%)
Pain in extremity	5/52 (9.6%)
Nervous system disorders
Dizziness	4/52 (7.7%)
Headache	17/52 (32.7%)
Hypoaesthesia	3/52 (5.8%)
Psychiatric disorders
Depression	3/52 (5.8%)
Insomnia	6/52 (11.5%)
Respiratory, thoracic and mediastinal disorders
Cough	5/52 (9.6%)
Dysphonia	3/52 (5.8%)
Dyspnoea	9/52 (17.3%)
Skin and subcutaneous tissue disorders
Alopecia	7/52 (13.5%)
Dry skin	7/52 (13.5%)
Night sweats	5/52 (9.6%)
Pruritus	12/52 (23.1%)
Rash	17/52 (32.7%)
Skin lesion	4/52 (7.7%)
Vascular disorders
Hot flush	5/52 (9.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT 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.