Study of Nilotinib as First Line Treatment in Philadelphia Chromosome Positive(Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT01274351
Collaborator
(none)
112
Enrollment
13
Locations
1
Arm
102.2
Actual Duration (Months)
8.6
Patients Per Site
0.1
Patients Per Site Per Month

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 DiseaseIntervention/TreatmentPhase
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

Study Type:
Interventional
Actual Enrollment :
112 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Multi-center, Open-label, Non-randomized Study of Nilotinib as First Line Treatment in Adult Patients With Newly Diagnosed Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP)
Actual Study Start Date :
Jan 25, 2011
Actual Primary Completion Date :
Aug 1, 2019
Actual Study Completion Date :
Aug 1, 2019

Arms and Interventions

ArmIntervention/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:
  • Tasigna, AMN107
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. 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.

    4. 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.

    5. 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

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

    SiteCityStateCountryPostal Code
    1Novartis Investigative SiteEskisehirMeselikTurkey26480
    2Novartis Investigative SiteIstanbulTURTurkey34098
    3Novartis Investigative SiteAdanaTurkey01330
    4Novartis Investigative SiteAnkaraTurkey06100
    5Novartis Investigative SiteBursaTurkey16059
    6Novartis Investigative SiteDiyarbakirTurkey21000
    7Novartis Investigative SiteGaziantepTurkey27310
    8Novartis Investigative SiteIstanbulTurkey34093
    9Novartis Investigative SiteIzmirTurkey35040
    10Novartis Investigative SiteIzmirTurkey35340
    11Novartis Investigative SiteOkmeydaniTurkey34370
    12Novartis Investigative SiteTalas / KayseriTurkey38039
    13Novartis Investigative SiteTrabzonTurkey61080

    Sponsors and Collaborators

    • Novartis Pharmaceuticals

    Investigators

    • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01274351
    Other Study ID Numbers:
    • CAMN107ETR02
    First Posted:
    Jan 11, 2011
    Last Update Posted:
    Sep 1, 2020
    Last Verified:
    Aug 1, 2020
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    No
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Novartis Pharmaceuticals
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment DetailsA total of 112 participants were enrolled into the study from the 15 sites in Turkey.
    Pre-assignment DetailThis was an open-label study with one treatment arm. The study did not involve a reference treatment.
    Arm/Group TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Period Title: Overall Study
    STARTED112
    COMPLETED92
    NOT COMPLETED20

    Baseline Characteristics

    Arm/Group TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Overall Participants112
    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

    1. Primary Outcome
    TitlePercentage of Participants Who Achieved Major Molecular Response (MMR) During the First 12 Months
    DescriptionMajor 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 Frame12 months

    Outcome Measure Data

    Analysis Population Description
    Intent-to-treat (ITT) analysis set
    Arm/Group TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Measure Participants112
    Count of Participants [Participants]
    74
    66.1%
    2. Secondary Outcome
    TitlePercentage of Participants Who Achieved Major Molecular Response (MMR) up to 24 Months
    DescriptionMajor 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 Frame3, 6, 9, 15, 18, 21 and 24 months

    Outcome Measure Data

    Analysis Population Description
    ITT analysis set
    Arm/Group TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Measure Participants112
    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%
    3. Secondary Outcome
    TitlePercentage of Participants With Complete Cytogenetic Response (CCyR) at Month 6 and 12
    DescriptionCCyR rate is identified as the rate of patients who had 0% of Ph+ metaphase.
    Time FrameMonth 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 TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Measure Participants112
    Month 6
    89
    79.5%
    Month 12
    84
    75%
    4. Secondary Outcome
    TitlePercentage of Participants With Complete Hematologic Response (CHR) at Month 3, 6, 9, 12, 18 and 24
    DescriptionA 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 FrameMonth 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 TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Measure Participants112
    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%
    5. Secondary Outcome
    TitleTime to Major Molecular Response (MMR)
    DescriptionTime to MMR is defined as the time period from the date of first dose intake until the first documented MMR.
    Time Frame24 months

    Outcome Measure Data

    Analysis Population Description
    ITT analysis set. Only participants with a MMR were included in the analysis
    Arm/Group TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Measure Participants93
    Mean (Standard Deviation) [days]
    252.38
    (153.22)
    6. Secondary Outcome
    TitleDuration of Major Molecular Response (MMR)
    DescriptionMMR 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 Frame24 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 TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    Measure Participants12
    Mean (Standard Deviation) [days]
    91
    (4.22)

    Adverse Events

    Time FrameAdverse events were collected from the start of the treatment to end of the treatment i.e 24 months.
    Adverse Event Reporting Description
    Arm/Group TitleNilotinib
    Arm/Group Descriptionadministered orally at a dose of 300 mg twice daily for 24 months
    All Cause Mortality
    Nilotinib
    Affected / at Risk (%)# Events
    Total2/112 (1.8%)
    Serious Adverse Events
    Nilotinib
    Affected / at Risk (%)# Events
    Total43/112 (38.4%)
    Blood and lymphatic system disorders
    Acute leukaemia1/112 (0.9%)
    Neutropenia2/112 (1.8%)
    Thrombocytopenia4/112 (3.6%)
    Cardiac disorders
    Chest Pain3/112 (2.7%)
    Acute myocardial infarction2/112 (1.8%)
    Angina unstable1/112 (0.9%)
    Bradycardia1/112 (0.9%)
    Myocardial ischaemia1/112 (0.9%)
    Paroxysmal arrhythmia1/112 (0.9%)
    Eye disorders
    Conjunctivitis allergic1/112 (0.9%)
    Gastrointestinal disorders
    Abdominal pain2/112 (1.8%)
    Oral disorder1/112 (0.9%)
    Pancreatitis acute1/112 (0.9%)
    General disorders
    Asthenia1/112 (0.9%)
    Pyrexia1/112 (0.9%)
    Hepatobiliary disorders
    Hepatitis toxic1/112 (0.9%)
    Immune system disorders
    Hypersensitivity1/112 (0.9%)
    Infections and infestations
    Periorbital cellulitis1/112 (0.9%)
    Investigations
    Alanine aminotransferase increased1/112 (0.9%)
    Arteriogram coronary3/112 (2.7%)
    Lipase increased2/112 (1.8%)
    Weight decreased1/112 (0.9%)
    Musculoskeletal and connective tissue disorders
    Lumbar vertebral fracture1/112 (0.9%)
    Pain in extremity1/112 (0.9%)
    Upper limb fracture1/112 (0.9%)
    Nervous system disorders
    Brain neoplasm1/112 (0.9%)
    Pregnancy, puerperium and perinatal conditions
    Pregnancy1/112 (0.9%)
    Skin and subcutaneous tissue disorders
    Alopecia1/112 (0.9%)
    Pruritus1/112 (0.9%)
    Rash1/112 (0.9%)
    Surgical and medical procedures
    Skin neoplasm excision1/112 (0.9%)
    Uterine dilation and curettage1/112 (0.9%)
    Other (Not Including Serious) Adverse Events
    Nilotinib
    Affected / at Risk (%)# Events
    Total90/112 (80.4%)
    Blood and lymphatic system disorders
    Leukopenia10/112 (8.9%)
    Thrombocytopenia19/112 (17%)
    Gastrointestinal disorders
    Abdominal pain upper6/112 (5.4%)
    Constipation7/112 (6.3%)
    Hepatobiliary disorders
    Hyperbilirubinaemia17/112 (15.2%)
    Hypercholesterolaemia11/112 (9.8%)
    Investigations
    Alanine aminotransferase increased12/112 (10.7%)
    Amylase increased7/112 (6.3%)
    Blood alkaline phosphatase increased10/112 (8.9%)
    Blood phosphorus decreased7/112 (6.3%)
    Blood triglycerides increased11/112 (9.8%)
    Haemoglobin decreased7/112 (6.3%)
    Lipase increased9/112 (8%)
    Musculoskeletal and connective tissue disorders
    Myalgia7/112 (6.3%)
    Pain in extremity7/112 (6.3%)
    Respiratory, thoracic and mediastinal disorders
    Influenza13/112 (11.6%)
    Upper respiratory tract infection8/112 (7.1%)
    Skin and subcutaneous tissue disorders
    Alopecia6/112 (5.4%)
    Pruritus16/112 (14.3%)
    Rash13/112 (11.6%)

    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.

    Results Point of Contact

    Name/TitleStudy Director
    OrganizationNovartis Pharmaceuticals
    Phone862-778-8300
    EmailNovartis.email@novartis.com
    Responsible Party:
    Novartis Pharmaceuticals
    ClinicalTrials.gov Identifier:
    NCT01274351
    Other Study ID Numbers:
    • CAMN107ETR02
    First Posted:
    Jan 11, 2011
    Last Update Posted:
    Sep 1, 2020
    Last Verified:
    Aug 1, 2020