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

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ClinicalTrials.gov Identifier: NCT02115386
Recruitment Status : Completed
First Posted : April 16, 2014
Last Update Posted : March 5, 2018
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

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:

Rationale for study was the fact that Nilotinib is approved for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (CML) in adult patients resistant to or intolerant to prior therapy that included imatinib (400 mg BID), and for new diagnosed patients with Ph+ CML in CP (300 mg BID). But the majority of CML patients treated with imatinib experience adverse reactions at some time. The most frequently reported drug-related adverse reactions were edema, nausea and vomiting, muscle cramps, musculoskeletal pain, diarrhea and rash. Although the majority of adverse events experienced on imatinib are mild to moderate in grade and most either resolve or diminish over time, low grade adverse events requiring chronic treatment do occur which may adversely impact a patient's quality of life. This study will examine changes in chronic low grade chronic adverse events, measured by CTCAE, when patients are switched from imatinib to nilotinib therapy. So, 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). Primary endpoint is: Changes of non-hematological AE grade at 3 months after switch to nilotinib. Secondary Objectives are: Rate of CCyR after switch to nilotinib (both newly achieved (if absent at baseline) or maintained) at months 1, 3, 6, 12, 18 and 24 after switch to nilotinib; Rate of MMR at 1, 3, 6, 9, 12, 18 and 24 months after switch; Time to and duration of CCyR and MMR after switch until study end; Time to first documented and optimal improvement of the non-hematological adverse event(s) associated with imatinib; Overall nilotinib safety profile; QOL changes after switch to nilotinib and within the study period - measure at baseline (for imatinib) and at 1, 3, 6, 12, and 24 months; Evaluation of patients' experience with switching from imatinib to nilotinib due to low-grade chronic toxicity (diary) Study Design: Open-label, single arm study assessing the changes in chronic low grade adverse events when CML-CP patients are switched from imatinib to nilotinib therapy. Patients must have been treated with starting imatinib dose of 400 mg and at least 300mg QD of imatinib for ≥ 6 months and experience ≤ Grade 2 adverse events which persist ≥ 2 months despite maximal supportive care. Patients have to be optimal responders to imatinib according to LeukemiaNet 2009 criteria at the study entrance.

Adverse events will be graded according to CTCAE guidelines at baseline and will be assessed throughout the trial at each visit. Patients will be treated with nilotinib 300mg BID on study and followed up to 2 years.

Number of patients & centers: 40 patients, 8 centers.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 7 participants
Allocation: Non-Randomized
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 : December 17, 2015
Actual Primary Completion Date : October 31, 2016
Actual Study Completion Date : October 31, 2016


Arm Intervention/treatment
Experimental: Nilotinib Drug: Nilotinib
300 mg




Primary Outcome Measures :
  1. improvement of grades of persistent non-hematological AE grade [ Time Frame: at 6 month after switching from imatinib to nilotinib ]
    To evaluate improvement in chronic low grade non-hematological adverse events, experienced by patients treated with imatinib and persistent despite best supportive measures, when patients are switched from imatinib to nilotinib at 6 months after switch


Secondary Outcome Measures :
  1. improvement of chronic low-grade non-hematologic AEs [ Time Frame: at 3 month after switching from imatinib to nilotinib ]
    to evaluate improvement of low-grade non-hematologic adverse events, experiences by patients treated with imatinib and persistent despite of best supportive measures after switching to nilotinib therapy

  2. rate of CCyR [ Time Frame: at months 6,12 and 24 after switching from imatinib to nilotinib ]
    to evaluate CCyR after switching (both newly achieved or maintained)

  3. rate of MMR [ Time Frame: at months 1,3, 6, 9, 12, 18 and 24 after switching from imatinib to nilotinib ]
    to evaluate MMR after switching

  4. time to and duration of CCyR and MMR [ Time Frame: 24 Months ]
    to evaluate time to achievement and duration of CCyR and MMR after switching

  5. time to first improvement of chronic low-grade non-hematologic AEs [ Time Frame: 24 Months ]
    to evaluate time to first improvement of low-grade non-hematologic adverse events, experiences 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. summary of biochemistry and hematology AE/SAEs reported [ Time Frame: 24 Months ]
    to evaluate overall nilotinib safety profile in study

  7. QOL changes [ Time Frame: at months 1,3,6,12 and 24 after switch to nilotinib ]
    to evaluate quality of life changes after switching to nilotinib



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients ≥ 18 years of age

    • ECOG ≤ 2
    • Diagnosis of CML-CP < 15% blasts in peripheral blood and bone marrow

      • < 30% blasts plus promyelocytes in peripheral blood and bone marrow
      • < 20% basophils in the peripheral blood
      • ≥ 100 x 109 /L platelets
      • No evidence of extramedullary leukemic involvement, with the exception of hepatosplenomegaly.
    • Optimal response to imatinib according to LeukamiaNet 2009 criteria defined as:

      • MCR 6 months after starting imatinib
      • CCR 12 months after starting imatinib
      • MMR 18 months after starting imatinib (MMR response defined either as 3 log reduction of bcr-abl/abl ratio or as 0,1% by IS).
    • Initial treatment with 400mg imatinib with current treatment with imatinib 400 mg or 300 QD.
    • Imatinib dose interruptions are allowed prior to inclusion but should not exceed 28 consecutive days
    • Persistent Grade 1- 2 non-hematological adverse events for at least 2 months despite supportive care. Toxicity will be evaluated by treating physician using CTCAE criteria.

In case of several types of non-hematological AEs

  • Adequate end organ function defined by

    • Total bilirubin < 1.5 x ULN
    • SGOT(AST) and SGPT (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
  • Serum potassium and magnesium values ≥ LLN (lower limit of normal) or corrected to within normal limits with supplements prior to first dose of study medication.
  • 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.
  • Ability to provide written informed consent prior to any study related screening procedures being done

    • minimal duration of imatinib therapy 6 months

Exclusion Criteria:

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

    • Prior accelerated phase or blast phase CML
    • Previously documented T315I mutation
    • Presence of chromosomal abnormalities (trisomy 8) and/or clonal evolution other than Ph+.
    • Any grade >2 non-hematological AEs at inclusion and within 30 days prior to inclusion.
    • Previous treatment with imatinib >400 mg anytime prior to inclusion.
    • Previous treatment with any other tyrosine kinase inhibitor except for imatinib.
    • Impaired cardiac function including any of the following:

      • LVEF < 45% as determined by echocardiogram reading or MUGA
      • Complete left bundle branch block
      • Use of a ventricular-paced pacemaker
      • Congenital 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 should 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)
      • Right bundle branch block plus left anterior hemiblock, bifascicular block
    • 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.
    • Treatment with strong CYP3A4 inducers (e.g. phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, St. John's Wort), and the treatment cannot be discontinued or switched to a different medication prior to starting study drug.
    • Impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug.
    • History of acute pancreatitis within 1 year of study entry or documented past medical history of chronic pancreatitis.
    • Known cytopathologically confirmed CNS infiltration (in absence of suspicion of CNS involvement, lumbar puncture not required).
    • Any other malignancy that is clinically significant or requires active intervention.
    • Severe or uncontrolled medical conditions (i.e., uncontrolled diabetes, active or uncontrolled infection).
    • Acute or chronic liver or severe renal disease considered unrelated to disease.
    • History of significant congenital or acquired bleeding disorder unrelated to cancer.
    • Previous radiotherapy to ≥ 25% of the bone marrow.
    • Major surgery within 4 weeks prior to Day 1 of study or who have not recovered from prior surgery.
    • Treatment with other investigational agents within 30 days of Day 1.
    • History of non-compliance to medical regimens or inability to grant consent.
    • 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 within 7 days of the first dose of nilotinib

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02115386


Locations
Russian Federation
Novartis Investigative Site
Moscow, Russian Federation, 125167
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals

Responsible Party: Novartis Pharmaceuticals
ClinicalTrials.gov Identifier: NCT02115386     History of Changes
Other Study ID Numbers: CAMN107ARU02
First Posted: April 16, 2014    Key Record Dates
Last Update Posted: March 5, 2018
Last Verified: March 2018

Keywords provided by Novartis ( Novartis Pharmaceuticals ):
Ph+ CML, chronic myeloid leukemia

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Neoplasms by Histologic Type
Neoplasms
Myeloproliferative Disorders
Bone Marrow Diseases
Hematologic Diseases
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action