MACS1532: Trial to Evaluate the Improvement of Chronic Low-grade AEs in Patients With Ph+ CML With Optimal Response to Imatinib When Switched to Nilotinib

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02115386
• Collaborator: (none)
• Enrollment: 7
• Location: 1
• Arm: 1
• Actual Duration (Months): 10.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

Primary Objective for this study is to evaluate changes in chronic low grade non-hematological adverse events experienced by patients who have been treated with at least 6 months of imatinib and who have not responded to supportive measures, when they are switched to nilotinib (CTCAE grading system).

Condition or Disease	Intervention/Treatment	Phase
Philadelphia Positive (Ph+) Chronic Myeloid Leukemia	Drug: Nilotinib	Phase 3

Detailed Description

Study was terminated by Novartis

Study Design

• Study Type: Interventional
• Actual Enrollment: 7 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label Multicenter Trial to Evaluate the Improvement of Chronic Low-grade Adverse Events Experienced by Patients With Ph+ Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) With Optimal Response to Imatinib When Switched From Imatinib to Nilotinib Treatment
• Actual Study Start Date: Dec 17, 2015
• Actual Primary Completion Date: Oct 31, 2016
• Actual Study Completion Date: Oct 31, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Nilotinib Dosage was 300 mg BID daily taken orally without food.	Drug: Nilotinib; supplied in 150 mg capsules to be taken orally

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 6 Months [at 6 month after switching from imatinib to nilotinib]

   Improvement was defined as decreasing of grade of non-hematological toxicity from 2 to <2 or from 1 to <1. In case of multiple low-grade non-hematological toxicities improvement was defined as an improvement of at least one non-hematological AE and no worsening of any other persistent non-hematological AEs.

Secondary Outcome Measures

1. Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 3 Months [at 3 month after switching from imatinib to nilotinib]

   Improvement was defined as decreasing of grade of non-hematological toxicity from 2 to <2 or from 1 to <1. In case of multiple low-grade non-hematological toxicities improvement was defined as an improvement of at least one non-hematological AE and no worsening of any other persistent non-hematological AEs.

2. Number of Participants With Complete Cytogenetic Response (CCyR) [at months 6,12 and 24 after switching from imatinib to nilotinib]

   Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone marrow and is defined as the following: Complete (CCyR) - 0% Ph+ metaphases.

3. Number of Participants With a Major Molecular Response [Months 1, 3, 6, early termination]

   MMR was defined as a ≥ 3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤ 0.1 % BCR-ABL/ABL % by international scale as measured by RQ-PCR, confirmed by duplicate analysis of the same sample. Molecular response was described for all time points except screening where response was estimated.

4. Time to and Duration of CCyR and MMR After Switch From Imatinib to Nilotinib at 24 Months [at 24 Months]

   to evaluate time to achievement and duration of CCyR and MMR after switching from imatinib to nilotinib

5. Time to First Improvement of Persistant Chronic Low-grade Non-hematologic AEs at 24 Months After Switch From Imatinib to Nilotinib [first improvement of AEs after switch to 24 Months]

   Evaluate time to first improvement of low-grade non-hematologic adverse events, experienced by patients treated with imatinib and persistent despite of best supportive measures after switching to nilotinib therapy. Optimal improvement is defined as AE grade decreasing to 0.

6. Lisiting by Participant of EORTC-QLQ-C30 for Quality of Life [Screening, months 1, 3, 6, after switch to nilotinib]

   EORTC-QLQ-C30 was administered to evaluate quality of life changes after switching to nilotinib. Scores ranged from 1 (very poor) to 6 (excellent)

Eligibility Criteria

Criteria

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

Inclusion criteria:

Male or female patients ≥ 18 years of age 2. ECOG ≤ 2 3. Diagnosis of CML-CP < 15% blasts in peripheral blood and bone marrow

• < 30% blasts plus promyelocytes in peripheral blood and bone marrow

• < 20% basophiles in the peripheral blood

• ≥ 100 x 109 /L platelets

• No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly. 4. Minimal treatment duration before inclusion is 6 months. 5. Optimal response to imatinib at the time of inclusion according to LeukemiaNet 2009 criteria defined as:

• Patients treated with imatinib for ≥6 and <12 months must be in MCR Patients treated with imatinib for ≥12 and <18 months must be in CCR

• Patients treated with imatinib for ≥18 months must be in MMR (MMR response defined either as 3 log reduction of bcr-abl/abl ratio or as 0,1% by IS). 6. Initial treatment with 400mg imatinib with current treatment with imatinib 400 or 300 mg QD 7. Imatinib dose interruptions are allowed prior to inclusion but should not exceed 28 consecutive days 8. Persistent Grade 1- 2 non-hematological adverse events for at least 2 months despite best supportive care. Toxicity was to be evaluated by treating physician using CTCAE criteria. 9. In case of several types of non-hematological AEs no one can exceed grade 2 and at least one should last at least 2 months. 10. Adequate end organ function defined by:

• Total bilirubin < 1.5 x ULN

• AST and ALT < 2.5 x ULN

• Creatinine < 1.5 x ULN

• Serum amylase and lipase ≤ 1.5x ULN

• Alkaline phosphatase ≤ 2.5 x ULN unless considered tumor related 11. Serum potassium, magnesium, phosphorus and calcium values within normal range or corrected to within normal limits with supplements prior to first dose of study medication. 12. Patients must have an imatinib washout period of at least 3 days and not to exceed 7 days prior to the first dose of nilotinib. 13. Ability to provide written informed consent prior to any study related screening procedures being done

Exclusion criteria:

1. Patients who have experienced any Grade 3 or higher non-hematologic toxicity 30 days prior to screening

2. Loss of response (hematologic, cytogenetic, molecular) any time prior to inclusion

3. Prior accelerated phase or blast phase CML

4. Previously documented T315I mutation

5. Chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+.

6. Previous treatment with imatinib >400 mg any time prior to inclusion.

7. Previous treatment with any other tyrosine kinase inhibitors except for only imatinib

Impaired cardiac function including any of the following:

• LVEF < 45% as determined by echocardiogram reading or MUGA

• Complete left bundle branch block

• Long QT syndrome or a known family history of long QT syndrome

• History or presence of clinically significant ventricular or atrial tachyarrhythmias

• Clinically significant resting bradycardia (< 50 beats per minute)

• QTcF > 450 msec on baseline ECG. If QTcF > 450 and electrolytes are not within normal ranges, electrolytes were to be corrected and then the patient re-screened for QTcF

• Myocardial infarction within 1 year of starting study drug

• Other clinically significant heart disease (e.g., unstable angina, congestive heart failure, or uncontrolled hypertension) 9. Patients receiving therapy with inhibitors of CYP3A4 or medications that prolong the QT interval and cannot be either discontinued or switched to a different medication prior to starting study drug. 10. Treatment with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, St. John's Wort), that cannot be discontinued or switched to a different medication prior to starting study drug. 11. Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug. 12. History of acute pancreatitis within 1 year of study entry. 13. Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required). 14. Any other malignancy that is clinically significant or requires active intervention.

1. Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, active or uncontrolled infection). 16. Acute or chronic liver or severe renal disease considered unrelated to cancer.

2. History of significant congenital or acquired bleeding disorder unrelated to cancer.

3. Previous radiotherapy to ≥ 25% of the bone marrow. 19. Major surgery within 4 weeks prior to Day 1 of study or patients who have not recovered from prior surgery.

4. Treatment with other investigational agents within 30 days of Day 1. 21. History of non-compliance to medical regimens or inability to grant consent 22. Women who are pregnant, breast feeding, or of childbearing potential without a negative urinary test at baseline

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Moscow		Russian Federation	125167

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: NCT02115386
• Other Study ID Numbers: CAMN107ARU02
• First Posted: Apr 16, 2014
• Last Update Posted: Dec 10, 2019
• Last Verified: Dec 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Ph+ CML, chronic myeloid leukemia
• Additional relevant MeSH terms: Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Study Results

Participant Flow

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Period Title: Overall Study
STARTED	7
COMPLETED	0
NOT COMPLETED	7

Baseline Characteristics

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Overall Participants	7
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	47.0 (13.1)
Sex: Female, Male (Count of Participants)
Female	4 57.1%
Male	3 42.9%
Race/Ethnicity, Customized (participants) [Number]
Caucasian	7 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 6 Months
Description	Improvement was defined as decreasing of grade of non-hematological toxicity from 2 to <2 or from 1 to <1. In case of multiple low-grade non-hematological toxicities improvement was defined as an improvement of at least one non-hematological AE and no worsening of any other persistent non-hematological AEs.
Time Frame	at 6 month after switching from imatinib to nilotinib

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	7
Number [participants]	0 0%

2. Secondary Outcome

Title	Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 3 Months
Description	Improvement was defined as decreasing of grade of non-hematological toxicity from 2 to <2 or from 1 to <1. In case of multiple low-grade non-hematological toxicities improvement was defined as an improvement of at least one non-hematological AE and no worsening of any other persistent non-hematological AEs.
Time Frame	at 3 month after switching from imatinib to nilotinib

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	7
Number [participants]	0 0%

3. Secondary Outcome

Title	Number of Participants With Complete Cytogenetic Response (CCyR)
Description	Cytogenetic response will be assessed as the percentage of Ph+ metaphases in the bone marrow and is defined as the following: Complete (CCyR) - 0% Ph+ metaphases.
Time Frame	at months 6,12 and 24 after switching from imatinib to nilotinib

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	6
Number [participants]	0 0%

4. Secondary Outcome

Title	Number of Participants With a Major Molecular Response
Description	MMR was defined as a ≥ 3.0 log reduction in BCR-ABL transcripts compared to the standardized baseline or ≤ 0.1 % BCR-ABL/ABL % by international scale as measured by RQ-PCR, confirmed by duplicate analysis of the same sample. Molecular response was described for all time points except screening where response was estimated.
Time Frame	Months 1, 3, 6, early termination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	6
Month 1	5 71.4%
Month 3	6 85.7%
Month 6	6 85.7%
Early termination	5 71.4%

5. Secondary Outcome

Title	Time to and Duration of CCyR and MMR After Switch From Imatinib to Nilotinib at 24 Months
Description	to evaluate time to achievement and duration of CCyR and MMR after switching from imatinib to nilotinib
Time Frame	at 24 Months

Outcome Measure Data

Analysis Population Description

No data collected for this Outcome Measure, as no participants reached month 24

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	0

6. Secondary Outcome

Title	Time to First Improvement of Persistant Chronic Low-grade Non-hematologic AEs at 24 Months After Switch From Imatinib to Nilotinib
Description	Evaluate time to first improvement of low-grade non-hematologic adverse events, experienced by patients treated with imatinib and persistent despite of best supportive measures after switching to nilotinib therapy. Optimal improvement is defined as AE grade decreasing to 0.
Time Frame	first improvement of AEs after switch to 24 Months

Outcome Measure Data

Analysis Population Description

No data collected for this assessment, as no participants reached month 24

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	0

7. Secondary Outcome

Title	Lisiting by Participant of EORTC-QLQ-C30 for Quality of Life
Description	EORTC-QLQ-C30 was administered to evaluate quality of life changes after switching to nilotinib. Scores ranged from 1 (very poor) to 6 (excellent)
Time Frame	Screening, months 1, 3, 6, after switch to nilotinib

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Nilotinib
Arm/Group Description	Dosage was 300 mg BID daily taken orally without food.
Measure Participants	7
Patient A Screening	3
Patient A Month 1	3
Patient A Month 3	3
Patient A Month 6	3
Patient A early termination	3
Patient B screening	5
Patient B Month 1	5
Patient B Month 3	5
Patient B Month 6	5
Patient B early termination	5
Patient C screening	4
Patient C Month 1	4
Patient C Month 3	5
Patient C Month 6	5
Patient C early termination	5
Patient D screening	3
Patient D Month 1	3
Patient D Month 3	3
Patient D Month 6	3
Patient D early termination	4
Patient E screening	5
Patient E early termination	4
Patient F screening	4
Patient F Month 1	5
Patient F Month 3	5
Patient F Month 6	5
Patient F early termination	5
Patient G screening	5
Patient G Month 1	4
Patient G Month 3	5
Patient G Month 6	5
Patient G early termination	5

Adverse Events

Time Frame	Adverse Events and Serious Adverse Events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 9 months
Arm/Group Title	Nilotinib
Arm/Group Description	Nilotinib
All Cause Mortality
	Nilotinib
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Serious Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	0/7 (0%)
Other (Not Including Serious) Adverse Events
	Nilotinib
	Affected / at Risk (%)	# Events
Total	7/7 (100%)
Ear and labyrinth disorders
HYPOACUSIS	1/7 (14.3%)
TINNITUS	1/7 (14.3%)
Gastrointestinal disorders
CONSTIPATION	1/7 (14.3%)
DRY MOUTH	1/7 (14.3%)
HAEMORRHOIDS	1/7 (14.3%)
General disorders
ASTHENIA	1/7 (14.3%)
Hepatobiliary disorders
HYPERBILIRUBINAEMIA	1/7 (14.3%)
Infections and infestations
PHARYNGITIS	1/7 (14.3%)
Investigations
BILIRUBIN CONJUGATED INCREASED	1/7 (14.3%)
BLOOD CHOLESTEROL INCREASED	1/7 (14.3%)
LIPASE INCREASED	2/7 (28.6%)
Metabolism and nutrition disorders
HYPOPHOSPHATAEMIA	3/7 (42.9%)
Nervous system disorders
HEADACHE	1/7 (14.3%)
PAROSMIA	1/7 (14.3%)
Psychiatric disorders
NERVOUSNESS	1/7 (14.3%)
Respiratory, thoracic and mediastinal disorders
DYSPNOEA	1/7 (14.3%)
Skin and subcutaneous tissue disorders
PRURITUS	1/7 (14.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.