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)

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

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).

Study Overview

• Status: Terminated
• Conditions: Philadelphia Positive (Ph+) Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Nilotinib

Detailed Description

Study was terminated by Novartis

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 3

Contacts and Locations

Study Locations

• Russian Federation
  • Moscow, Russian Federation, 125167
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

  15. 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.

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

  18. 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. 20. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Improvement of Grades of Persistent Non-hematological Adverse Event (AE) for Grade 1 and 2 at 3 Months	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.	at 3 month after switching from imatinib to nilotinib
Number of Participants With Complete Cytogenetic Response (CCyR)	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.	at months 6,12 and 24 after switching from imatinib to nilotinib
Number of Participants With a Major Molecular Response	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.	Months 1, 3, 6, early termination
Time to and Duration of CCyR and MMR After Switch From Imatinib to Nilotinib at 24 Months	to evaluate time to achievement and duration of CCyR and MMR after switching from imatinib to nilotinib	at 24 Months
Time to First Improvement of Persistant Chronic Low-grade Non-hematologic AEs at 24 Months After Switch From Imatinib to Nilotinib	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.	first improvement of AEs after switch to 24 Months
Lisiting by Participant of EORTC-QLQ-C30 for Quality of Life	EORTC-QLQ-C30 was administered to evaluate quality of life changes after switching to nilotinib. Scores ranged from 1 (very poor) to 6 (excellent)	Screening, months 1, 3, 6, after switch to nilotinib

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): December 17, 2015
• Primary Completion (Actual): October 31, 2016
• Study Completion (Actual): October 31, 2016

Study Registration Dates

• First Submitted: April 14, 2014
• First Submitted That Met QC Criteria: April 15, 2014
• First Posted (Estimate): April 16, 2014

Study Record Updates

• Last Update Posted (Actual): December 10, 2019
• Last Update Submitted That Met QC Criteria: December 9, 2019
• Last Verified: December 1, 2019

More Information

Terms related to this study

• Keywords: Ph+ CML, chronic myeloid leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Other Study ID Numbers: CAMN107ARU02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

IPD Plan Description

Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No