Study of Nilotinib as First Line Treatment in Philadelphia Chromosome Positive(Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)
Study Details
Study Description
Brief Summary
The study was a local multicentric, open-label, non-randomized phase II study of nilotinib as a first line treatment in adult patients with newly-diagnosed Philadelphia chromosome-positive (Ph+) and chronic phase myeloid leukemia (CML-CP).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
Phase 2 |
Detailed Description
This was a multicenter, open-label, single-arm, phase 2 study of nilotinib as a frontline treatment for patients with Ph+ CMLCP. All patients received oral nilotinib 300 mg twice daily for a planned treatment duration of 24 months or until early discontinuation.
The primary efficacy end point was the cumulative rate of Major Molecular Response (MMR) in all participants by 12 months. Secondary efficacy end points included the rate of Complete Cytogenic Response (CCyR) at 6 and 12 months; cumulative rates of MMR up to 24 months; time to and durability of MMR; and cumulative rate of Complete Haematologic Response (CHR) by 12 months.
Patient evaluations, including hematologic assessments, were conducted every 15 days during the first 3 months, monthly until month 12, and then every 3 months until the end of the study (24 months). All efficacy analyses were performed in the intent-to treat population.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Experimental: Nilotinib administered orally at a dose of 300 mg twice daily for 24 months |
Drug: Nilotinib
administered orally at a dose of 300 mg twice daily for 24 months
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months [12 months]
Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.
Secondary Outcome Measures
- Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months [3, 6, 9, 15, 18, 21 and 24 months]
Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders.
- Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 [Month 6 and 12]
CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase.
- Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 [Month 3, 6, 9, 12, 18 and 24]
A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved: WBC <10 x 109/L, thrombocyte <450 x 109/L, myelocyte + metamyelocyte <%5 in blood, no sign of blast and promyelocyte in blood, basophil <%5, and no sign of extramedullary involvement.
- Time to Major Molecular Response (MMR) [24 months]
Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR.
- Duration of Major Molecular Response (MMR) [24 months]
MMR duration is defined as the time from the date of first documented MMR to the first time of the lost MMR, progression or death.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
-
First cytogenetic diagnosis of CML-CP with cytogenetic confirmation of Philadelphia chromosome of (9;22) translocations within 6 months. Standard conventional cytogenetic analysis must be performed.
-
Previously untreated for CML, except for hydroxyurea and/or anagrelide (except imatinib treatment for max. 31 days long)
-
Adequate end organ function with following laboratory criteria: total bilirubin < 1.5 x upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (ULN); creatinine < 1.5 x upper limit of normal (ULN); serum amylase and lipase ≤ 1.5 x upper limit of normal (ULN); alkaline phosphatase ≤ 2.5 x upper limit of normal (ULN) unless considered tumor related
-
Serum potassium, magnesium, and phosphorus levels are equal or above the lower limit of normal prior to the first dose of study medication
Exclusion Criteria:
-
Treatment with tyrosine kinase inhibitor(s) prior to study (in emergent cases where the patient requires disease management while awaiting study start, commercial supplies of imatinib at any dose may be prescribed to the patient but for no longer than 31 days in duration)
-
Known cytopathologically confirmed Central Nervous System CNS infiltration
-
Impaired cardiac function
-
Severe or uncontrolled medical conditions (i.e. uncontrolled diabetes, active or uncontrolled infection)
-
Acute or chronic liver, pancreatic or severe renal disease considered unrelated to disease
-
Patients with another primary malignancy except if the other primary malignancy is neither currently clinically significant or requiring active intervention
-
History of significant congenital or acquired bleeding disorder unrelated to cancer
-
Previous radiotherapy to ≥25% of the bone marrow
-
Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
-
Use of therapeutic coumarin derivatives (i.e. warfarin, acenocoumarol, phenprocoumon)
-
Patients actively receiving therapy with strong Cytochrome P450 3A4 isoenzyme (CYP3A4) inhibitors (e.g, erythromycin, ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir, mibefradil)
-
Patients actively receiving therapy with medications that have the potential to prolong the QT interval and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug
Other protocol-defined inclusion/exclusion criteria may apply
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Novartis Investigative Site | Eskisehir | Meselik | Turkey | 26480 |
2 | Novartis Investigative Site | Istanbul | TUR | Turkey | 34098 |
3 | Novartis Investigative Site | Adana | Turkey | 01330 | |
4 | Novartis Investigative Site | Ankara | Turkey | 06100 | |
5 | Novartis Investigative Site | Bursa | Turkey | 16059 | |
6 | Novartis Investigative Site | Diyarbakir | Turkey | 21000 | |
7 | Novartis Investigative Site | Gaziantep | Turkey | 27310 | |
8 | Novartis Investigative Site | Istanbul | Turkey | 34093 | |
9 | Novartis Investigative Site | Izmir | Turkey | 35040 | |
10 | Novartis Investigative Site | Izmir | Turkey | 35340 | |
11 | Novartis Investigative Site | Okmeydani | Turkey | 34370 | |
12 | Novartis Investigative Site | Talas / Kayseri | Turkey | 38039 | |
13 | Novartis Investigative Site | Trabzon | Turkey | 61080 |
Sponsors and Collaborators
- Novartis Pharmaceuticals
Investigators
- Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals
Study Documents (Full-Text)
More Information
Publications
None provided.- CAMN107ETR02
Study Results
Participant Flow
Recruitment Details | A total of 112 participants were enrolled into the study from the 15 sites in Turkey. |
---|---|
Pre-assignment Detail | This was an open-label study with one treatment arm. The study did not involve a reference treatment. |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Period Title: Overall Study | |
STARTED | 112 |
COMPLETED | 92 |
NOT COMPLETED | 20 |
Baseline Characteristics
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Overall Participants | 112 |
Age (years) [Median (Full Range) ] | |
Median (Full Range) [years] |
47
|
Sex: Female, Male (Count of Participants) | |
Female |
49
43.8%
|
Male |
63
56.3%
|
Race and Ethnicity Not Collected (Count of Participants) |
Outcome Measures
Title | Percentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months |
---|---|
Description | Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders. |
Time Frame | 12 months |
Outcome Measure Data
Analysis Population Description |
---|
Intent-to-treat (ITT) analysis set |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Measure Participants | 112 |
Count of Participants [Participants] |
74
66.1%
|
Title | Percentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months |
---|---|
Description | Major Molecular Response (MMR) was defined as BCR-ABL1^IS ≤0.1%, on the International Scale [BCR-ABL1IS]) by 12 months. BCR is the Breakpoint Cluster Region gene / BCR gene product and ABL is the Abelson proto-oncogene. BCR-ABL is the Fusion gene from BCR and ABL/Protein product from BCR-ABL. Participants who withdrew prematurely or those who failed to provide data for the study for other reasons were designated as premature withdrawal or inevaluable, respectively, and were included in the ITT analysis as non-responders. |
Time Frame | 3, 6, 9, 15, 18, 21 and 24 months |
Outcome Measure Data
Analysis Population Description |
---|
ITT analysis set |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Measure Participants | 112 |
3 months |
28
25%
|
6 months |
57
50.9%
|
9 months |
67
59.8%
|
15 months |
84
75%
|
18 months |
92
82.1%
|
21 months |
93
83%
|
24 months |
93
83%
|
Title | Percentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12 |
---|---|
Description | CCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase. |
Time Frame | Month 6 and 12 |
Outcome Measure Data
Analysis Population Description |
---|
ITT analysis set included only the participants who had measurements i.e. excluding drop outs. |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Measure Participants | 112 |
Month 6 |
89
79.5%
|
Month 12 |
84
75%
|
Title | Percentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24 |
---|---|
Description | A confirmed complete hematological response (CHR) is defined when all of the following criteria are achieved: WBC <10 x 109/L, thrombocyte <450 x 109/L, myelocyte + metamyelocyte <%5 in blood, no sign of blast and promyelocyte in blood, basophil <%5, and no sign of extramedullary involvement. |
Time Frame | Month 3, 6, 9, 12, 18 and 24 |
Outcome Measure Data
Analysis Population Description |
---|
ITT analysis set included only the participants who had measurements i.e. excluding drop outs. |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Measure Participants | 112 |
Month 3 |
104
92.9%
|
Month 6 |
102
91.1%
|
Month 9 |
100
89.3%
|
Month 12 |
96
85.7%
|
Month 18 |
93
83%
|
Month 24 |
92
82.1%
|
Title | Time to Major Molecular Response (MMR) |
---|---|
Description | Time to MMR is defined as the time period from the date of first dose intake until the first documented MMR. |
Time Frame | 24 months |
Outcome Measure Data
Analysis Population Description |
---|
ITT analysis set. Only participants with a MMR were included in the analysis |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Measure Participants | 93 |
Mean (Standard Deviation) [days] |
252.38
(153.22)
|
Title | Duration of Major Molecular Response (MMR) |
---|---|
Description | MMR duration is defined as the time from the date of first documented MMR to the first time of the lost MMR, progression or death. |
Time Frame | 24 months |
Outcome Measure Data
Analysis Population Description |
---|
ITT analysis set. Only participants with a MMR and subsequent loss of MMR were included in the analysis |
Arm/Group Title | Nilotinib |
---|---|
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months |
Measure Participants | 12 |
Mean (Standard Deviation) [days] |
91
(4.22)
|
Adverse Events
Time Frame | Adverse events were collected from the start of the treatment to end of the treatment i.e 24 months. | |
---|---|---|
Adverse Event Reporting Description | ||
Arm/Group Title | Nilotinib | |
Arm/Group Description | administered orally at a dose of 300 mg twice daily for 24 months | |
All Cause Mortality |
||
Nilotinib | ||
Affected / at Risk (%) | # Events | |
Total | 2/112 (1.8%) | |
Serious Adverse Events |
||
Nilotinib | ||
Affected / at Risk (%) | # Events | |
Total | 43/112 (38.4%) | |
Blood and lymphatic system disorders | ||
Acute leukaemia | 1/112 (0.9%) | |
Neutropenia | 2/112 (1.8%) | |
Thrombocytopenia | 4/112 (3.6%) | |
Cardiac disorders | ||
Chest Pain | 3/112 (2.7%) | |
Acute myocardial infarction | 2/112 (1.8%) | |
Angina unstable | 1/112 (0.9%) | |
Bradycardia | 1/112 (0.9%) | |
Myocardial ischaemia | 1/112 (0.9%) | |
Paroxysmal arrhythmia | 1/112 (0.9%) | |
Eye disorders | ||
Conjunctivitis allergic | 1/112 (0.9%) | |
Gastrointestinal disorders | ||
Abdominal pain | 2/112 (1.8%) | |
Oral disorder | 1/112 (0.9%) | |
Pancreatitis acute | 1/112 (0.9%) | |
General disorders | ||
Asthenia | 1/112 (0.9%) | |
Pyrexia | 1/112 (0.9%) | |
Hepatobiliary disorders | ||
Hepatitis toxic | 1/112 (0.9%) | |
Immune system disorders | ||
Hypersensitivity | 1/112 (0.9%) | |
Infections and infestations | ||
Periorbital cellulitis | 1/112 (0.9%) | |
Investigations | ||
Alanine aminotransferase increased | 1/112 (0.9%) | |
Arteriogram coronary | 3/112 (2.7%) | |
Lipase increased | 2/112 (1.8%) | |
Weight decreased | 1/112 (0.9%) | |
Musculoskeletal and connective tissue disorders | ||
Lumbar vertebral fracture | 1/112 (0.9%) | |
Pain in extremity | 1/112 (0.9%) | |
Upper limb fracture | 1/112 (0.9%) | |
Nervous system disorders | ||
Brain neoplasm | 1/112 (0.9%) | |
Pregnancy, puerperium and perinatal conditions | ||
Pregnancy | 1/112 (0.9%) | |
Skin and subcutaneous tissue disorders | ||
Alopecia | 1/112 (0.9%) | |
Pruritus | 1/112 (0.9%) | |
Rash | 1/112 (0.9%) | |
Surgical and medical procedures | ||
Skin neoplasm excision | 1/112 (0.9%) | |
Uterine dilation and curettage | 1/112 (0.9%) | |
Other (Not Including Serious) Adverse Events |
||
Nilotinib | ||
Affected / at Risk (%) | # Events | |
Total | 90/112 (80.4%) | |
Blood and lymphatic system disorders | ||
Leukopenia | 10/112 (8.9%) | |
Thrombocytopenia | 19/112 (17%) | |
Gastrointestinal disorders | ||
Abdominal pain upper | 6/112 (5.4%) | |
Constipation | 7/112 (6.3%) | |
Hepatobiliary disorders | ||
Hyperbilirubinaemia | 17/112 (15.2%) | |
Hypercholesterolaemia | 11/112 (9.8%) | |
Investigations | ||
Alanine aminotransferase increased | 12/112 (10.7%) | |
Amylase increased | 7/112 (6.3%) | |
Blood alkaline phosphatase increased | 10/112 (8.9%) | |
Blood phosphorus decreased | 7/112 (6.3%) | |
Blood triglycerides increased | 11/112 (9.8%) | |
Haemoglobin decreased | 7/112 (6.3%) | |
Lipase increased | 9/112 (8%) | |
Musculoskeletal and connective tissue disorders | ||
Myalgia | 7/112 (6.3%) | |
Pain in extremity | 7/112 (6.3%) | |
Respiratory, thoracic and mediastinal disorders | ||
Influenza | 13/112 (11.6%) | |
Upper respiratory tract infection | 8/112 (7.1%) | |
Skin and subcutaneous tissue disorders | ||
Alopecia | 6/112 (5.4%) | |
Pruritus | 16/112 (14.3%) | |
Rash | 13/112 (11.6%) |
Limitations/Caveats
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.
Results Point of Contact
Name/Title | Study Director |
---|---|
Organization | Novartis Pharmaceuticals |
Phone | 862-778-8300 |
Novartis.email@novartis.com |
- CAMN107ETR02