Trial Outcomes & Findings for Randomized Phase Lll Study of Imatinib Dose Optimization vs Nilotinib in CML Patients With Suboptimal Response to Imatinib (NCT NCT00802841)
NCT ID: NCT00802841
Last Updated: 2015-11-16
Results Overview
CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.
Recruitment status
COMPLETED
Study phase
PHASE3
Target enrollment
191 participants
Primary outcome timeframe
6 months
Results posted on
2015-11-16
Participant Flow
Participants were randomized in 1:1 ratio to imatinib 600 mg QD or nilotinib 400 mg BID for a 2 year study period.
Cross-over from one arm to the other was allowed for intolerant patients anytime during treatment, patients who failed to achieve CCyR after 6 months of treatment, loss of response, loss of CHR, loss of best achieved cytogenetic response any time during treatment, or other reason approved by the Study Management Committee.
Participant milestones
| Measure |
Nilotinib
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Overall Study
STARTED
|
96
|
95
|
|
Overall Study
Full Analysis Set
|
96
|
95
|
|
Overall Study
Safety Set
|
96
|
93
|
|
Overall Study
Cross-over Set
|
13
|
56
|
|
Overall Study
COMPLETED
|
0
|
0
|
|
Overall Study
NOT COMPLETED
|
96
|
95
|
Reasons for withdrawal
| Measure |
Nilotinib
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Overall Study
Administrative problems
|
1
|
0
|
|
Overall Study
Lost to Follow-up
|
2
|
1
|
|
Overall Study
Death
|
1
|
2
|
|
Overall Study
Adverse Event
|
8
|
2
|
|
Overall Study
Disease progression
|
7
|
3
|
|
Overall Study
Withdrawal by Subject
|
9
|
5
|
|
Overall Study
Protocol deviation
|
2
|
6
|
|
Overall Study
Treatment duration completed
|
66
|
76
|
Baseline Characteristics
Randomized Phase Lll Study of Imatinib Dose Optimization vs Nilotinib in CML Patients With Suboptimal Response to Imatinib
Baseline characteristics by cohort
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
Total
n=191 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
|
44.6 Years
STANDARD_DEVIATION 14.47 • n=5 Participants
|
44.2 Years
STANDARD_DEVIATION 15.02 • n=7 Participants
|
44.4 Years
STANDARD_DEVIATION 14.75 • n=5 Participants
|
|
Sex: Female, Male
Female
|
42 Participants
n=5 Participants
|
37 Participants
n=7 Participants
|
79 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
54 Participants
n=5 Participants
|
58 Participants
n=7 Participants
|
112 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 6 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Percentage of Participants With Complete Cytogenetic Response (CCyR)
|
50.0 Percentage of participants
|
42.1 Percentage of participants
|
SECONDARY outcome
Timeframe: 12 and 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
MMR was defined as having a fusion gene of the Bcr and Abl genes of (BCR-ACL) less than or equal to 0.1% on the International Scale (IS).
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Percentage of Participants With Major Molecular Response (MMR)
12 months
|
36.5 Percentage of participants
|
25.3 Percentage of participants
|
|
Percentage of Participants With Major Molecular Response (MMR)
24 months
|
37.5 Percentage of participants
|
35.8 Percentage of participants
|
SECONDARY outcome
Timeframe: 12 and 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
CCyR was assessed from bone marrow samples. CCyr was defined as having 0% Philadelphia positive (Ph+) chromosome metaphases in bone marrow.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Percentage of Participants With CCyr
12 months
|
53.1 Percentage of participants
|
55.8 Percentage of participants
|
|
Percentage of Participants With CCyr
24 months
|
51.0 Percentage of participants
|
61.1 Percentage of participants
|
SECONDARY outcome
Timeframe: 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
Time to CCyR was defined as time from date of randomization to date of first documented CCyR.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Time to CCyR
|
5.55 Months
Interval 5.52 to 5.98
|
5.85 Months
Interval 5.59 to 11.04
|
SECONDARY outcome
Timeframe: 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
Duration of CCyR was defined as time from the date of ransomization to the date of first loss of CCyR or death, whichever came first.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Duration of CCyR
|
NA Months
The median duration of CCyr was not achieved because there were not enough number of events.
|
17.2 Months
Interval 17.2 to
There were not enough events to calculate the upper limit of the 95% Confidence Interval (CI).
|
SECONDARY outcome
Timeframe: 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
PFS was defined as the time from the date of randomization to the date of documented disease progression to accelerated phase or blast crisis (AP/BC), or death due to any cause.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Progression-Free Survival (PFS)
|
NA Months
The median PFS time was not achieved.
|
NA Months
The median PFS time was not achieved.
|
SECONDARY outcome
Timeframe: 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
EFS was defined as the time from the date of randomization to the date of the first occurrence of any of the following: loss of Complete Hematological Response (CHR), loss of Partial Cytogenetic Response (PCyR), loss of CCyR, death on treatment or progression to AP/BC.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Event-Free Survival (EFS)
|
NA Months
The median EFS time was not achieved..
|
24.3 Months
Interval 23.8 to
There were not enough events to calculate the upper limit of the 95% CI.
|
SECONDARY outcome
Timeframe: 24 monthsPopulation: Full Analysis Set: The FAS included all participants to whom study treatment had been assigned by randomization.
OS was defined as time from date of randomization to the date of the death.
Outcome measures
| Measure |
Nilotinib
n=96 Participants
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=95 Participants
Participants receievd 600 mg imatinib once daily (QD).
|
|---|---|---|
|
Overall Survival (OS)
|
NA Months
The median OS time was not achieved because there were not enough number of events.
|
25.7 Months
The median was estimated, but the standard error could not be estimated due to the limitation of the Kaplan Meier method where there were too few events and the last participant had a death. Therefore, the 95% CI could not be calculated.
|
Adverse Events
Nilotinib
Serious events: 11 serious events
Other events: 80 other events
Deaths: 0 deaths
Imatinib
Serious events: 9 serious events
Other events: 61 other events
Deaths: 0 deaths
Cross-over to Nilotinib
Serious events: 4 serious events
Other events: 44 other events
Deaths: 0 deaths
Cross-over to Imatinib
Serious events: 1 serious events
Other events: 11 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Nilotinib
n=96 participants at risk
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=93 participants at risk
Participants receievd 600 mg imatinib once daily (QD).
|
Cross-over to Nilotinib
n=56 participants at risk
Nilotinib 400 mg BID
|
Cross-over to Imatinib
n=13 participants at risk
600 mg QD
|
|---|---|---|---|---|
|
Blood and lymphatic system disorders
Anaemia
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Blood and lymphatic system disorders
Leukocytosis
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Blood and lymphatic system disorders
Lymphadenopathy
|
0.00%
0/96
|
0.00%
0/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
2.1%
2/96
|
1.1%
1/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Cardiac disorders
Acute coronary syndrome
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Cardiac disorders
Angina pectoris
|
2.1%
2/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Cardiac disorders
Angina unstable
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Cardiac disorders
Tachyarrhythmia
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Endocrine disorders
Autoimmune thyroiditis
|
1.0%
1/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Endocrine disorders
Hyperthyroidism
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Eye disorders
Retinal detachment
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Gastrointestinal disorders
Pancreatitis acute
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Hepatobiliary disorders
Cholecystitis chronic
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Infections and infestations
Appendicitis
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Infections and infestations
Hepatitis B
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Infections and infestations
Pneumonia
|
0.00%
0/96
|
0.00%
0/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Investigations
Haemoglobin decreased
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Investigations
Malaria antibody test positive
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Blast cell crisis
|
1.0%
1/96
|
1.1%
1/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Endometrial cancer
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Renal and urinary disorders
Renal failure acute
|
0.00%
0/96
|
1.1%
1/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Respiratory, thoracic and mediastinal disorders
Respiratory failure
|
0.00%
0/96
|
0.00%
0/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Skin and subcutaneous tissue disorders
Eczema
|
0.00%
0/96
|
1.1%
1/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Vascular disorders
Arterial occlusive disease
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
0.00%
0/13
|
Other adverse events
| Measure |
Nilotinib
n=96 participants at risk
Participants received 400 mg nilotinib twice daily (BID).
|
Imatinib
n=93 participants at risk
Participants receievd 600 mg imatinib once daily (QD).
|
Cross-over to Nilotinib
n=56 participants at risk
Nilotinib 400 mg BID
|
Cross-over to Imatinib
n=13 participants at risk
600 mg QD
|
|---|---|---|---|---|
|
Vascular disorders
Hypertension
|
5.2%
5/96
|
2.2%
2/93
|
3.6%
2/56
|
7.7%
1/13
|
|
Blood and lymphatic system disorders
Anaemia
|
11.5%
11/96
|
19.4%
18/93
|
17.9%
10/56
|
30.8%
4/13
|
|
Blood and lymphatic system disorders
Leukocytosis
|
1.0%
1/96
|
0.00%
0/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Blood and lymphatic system disorders
Leukopenia
|
10.4%
10/96
|
23.7%
22/93
|
16.1%
9/56
|
0.00%
0/13
|
|
Blood and lymphatic system disorders
Lymphopenia
|
3.1%
3/96
|
6.5%
6/93
|
5.4%
3/56
|
7.7%
1/13
|
|
Blood and lymphatic system disorders
Neutropenia
|
11.5%
11/96
|
24.7%
23/93
|
23.2%
13/56
|
7.7%
1/13
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
19.8%
19/96
|
25.8%
24/93
|
23.2%
13/56
|
23.1%
3/13
|
|
Cardiac disorders
Tachycardia
|
2.1%
2/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Eye disorders
Eyelid oedema
|
1.0%
1/96
|
10.8%
10/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Eye disorders
Papilloedema
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Eye disorders
Periorbital oedema
|
2.1%
2/96
|
2.2%
2/93
|
1.8%
1/56
|
15.4%
2/13
|
|
Gastrointestinal disorders
Abdominal pain
|
1.0%
1/96
|
2.2%
2/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Gastrointestinal disorders
Abdominal pain upper
|
6.2%
6/96
|
4.3%
4/93
|
0.00%
0/56
|
0.00%
0/13
|
|
Gastrointestinal disorders
Anal fissure
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Gastrointestinal disorders
Diarrhoea
|
6.2%
6/96
|
16.1%
15/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Gastrointestinal disorders
Dyspepsia
|
2.1%
2/96
|
2.2%
2/93
|
0.00%
0/56
|
15.4%
2/13
|
|
Gastrointestinal disorders
Nausea
|
5.2%
5/96
|
15.1%
14/93
|
7.1%
4/56
|
15.4%
2/13
|
|
Gastrointestinal disorders
Proctalgia
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Gastrointestinal disorders
Stomatitis
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Gastrointestinal disorders
Tongue haematoma
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Gastrointestinal disorders
Vomiting
|
4.2%
4/96
|
10.8%
10/93
|
8.9%
5/56
|
23.1%
3/13
|
|
General disorders
Fatigue
|
6.2%
6/96
|
3.2%
3/93
|
0.00%
0/56
|
0.00%
0/13
|
|
General disorders
Generalised oedema
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
General disorders
Influenza like illness
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
15.4%
2/13
|
|
General disorders
Oedema peripheral
|
5.2%
5/96
|
1.1%
1/93
|
1.8%
1/56
|
0.00%
0/13
|
|
General disorders
Pyrexia
|
12.5%
12/96
|
8.6%
8/93
|
10.7%
6/56
|
15.4%
2/13
|
|
Hepatobiliary disorders
Hyperbilirubinaemia
|
14.6%
14/96
|
1.1%
1/93
|
16.1%
9/56
|
0.00%
0/13
|
|
Infections and infestations
Influenza
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Infections and infestations
Upper respiratory tract infection
|
5.2%
5/96
|
5.4%
5/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Injury, poisoning and procedural complications
Animal bite
|
0.00%
0/96
|
0.00%
0/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Investigations
Alanine aminotransferase increased
|
20.8%
20/96
|
5.4%
5/93
|
16.1%
9/56
|
0.00%
0/13
|
|
Investigations
Aspartate aminotransferase increased
|
7.3%
7/96
|
3.2%
3/93
|
7.1%
4/56
|
0.00%
0/13
|
|
Investigations
Bilirubin conjugated increased
|
8.3%
8/96
|
1.1%
1/93
|
8.9%
5/56
|
0.00%
0/13
|
|
Investigations
Blood bilirubin increased
|
13.5%
13/96
|
1.1%
1/93
|
19.6%
11/56
|
0.00%
0/13
|
|
Investigations
Blood phosphorus decreased
|
1.0%
1/96
|
2.2%
2/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Investigations
Gamma-glutamyltransferase increased
|
8.3%
8/96
|
0.00%
0/93
|
5.4%
3/56
|
0.00%
0/13
|
|
Investigations
Haemoglobin decreased
|
3.1%
3/96
|
8.6%
8/93
|
5.4%
3/56
|
0.00%
0/13
|
|
Investigations
Platelet count decreased
|
2.1%
2/96
|
3.2%
3/93
|
7.1%
4/56
|
7.7%
1/13
|
|
Investigations
Weight increased
|
3.1%
3/96
|
3.2%
3/93
|
7.1%
4/56
|
7.7%
1/13
|
|
Investigations
White blood cell count increased
|
1.0%
1/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Metabolism and nutrition disorders
Hypercholesterolaemia
|
4.2%
4/96
|
0.00%
0/93
|
5.4%
3/56
|
0.00%
0/13
|
|
Metabolism and nutrition disorders
Hyperglycaemia
|
11.5%
11/96
|
2.2%
2/93
|
3.6%
2/56
|
0.00%
0/13
|
|
Metabolism and nutrition disorders
Hypocalcaemia
|
5.2%
5/96
|
3.2%
3/93
|
1.8%
1/56
|
0.00%
0/13
|
|
Metabolism and nutrition disorders
Hypokalaemia
|
1.0%
1/96
|
0.00%
0/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Metabolism and nutrition disorders
Hypophosphataemia
|
10.4%
10/96
|
3.2%
3/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
9.4%
9/96
|
3.2%
3/93
|
3.6%
2/56
|
7.7%
1/13
|
|
Musculoskeletal and connective tissue disorders
Myalgia
|
8.3%
8/96
|
1.1%
1/93
|
3.6%
2/56
|
0.00%
0/13
|
|
Musculoskeletal and connective tissue disorders
Pain in extremity
|
3.1%
3/96
|
1.1%
1/93
|
5.4%
3/56
|
0.00%
0/13
|
|
Nervous system disorders
Dizziness
|
3.1%
3/96
|
4.3%
4/93
|
5.4%
3/56
|
7.7%
1/13
|
|
Nervous system disorders
Headache
|
14.6%
14/96
|
6.5%
6/93
|
14.3%
8/56
|
30.8%
4/13
|
|
Psychiatric disorders
Anxiety
|
0.00%
0/96
|
0.00%
0/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
5.2%
5/96
|
2.2%
2/93
|
0.00%
0/56
|
7.7%
1/13
|
|
Respiratory, thoracic and mediastinal disorders
Oropharyngeal pain
|
3.1%
3/96
|
2.2%
2/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Skin and subcutaneous tissue disorders
Hyperhidrosis
|
0.00%
0/96
|
0.00%
0/93
|
1.8%
1/56
|
7.7%
1/13
|
|
Skin and subcutaneous tissue disorders
Pruritus
|
8.3%
8/96
|
0.00%
0/93
|
5.4%
3/56
|
0.00%
0/13
|
|
Skin and subcutaneous tissue disorders
Rash
|
22.9%
22/96
|
4.3%
4/93
|
16.1%
9/56
|
7.7%
1/13
|
Additional Information
Study Director
Novartis
Phone: 862-778-1873
Results disclosure agreements
- Principal investigator is a sponsor employee 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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.
- Publication restrictions are in place
Restriction type: OTHER