A Study That Switched Patients From Imatinib to Nilotinib and Then Was Followed by Treatment Cessation (ENESTgoal)

A Phase II Randomized, Multicenter Study of Treatment-free Remission in Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Patients Who Achieve and Sustain MR4.5 After Switching to Nilotinib

To evaluate molecular relapse free rates 6 months after stopping nilotinib therapy in patients who achieve MR4.5

Study Overview

• Status: Completed
• Conditions: CML
• Intervention / Treatment: Drug: nilotinib

Detailed Description

Study protocol included criteria for study termination that was met when > 2 patients lost CCyR during TFR phase (> 1% BCR-ABL); This study was terminated early as > 2 cases of confirmed loss of complete cytogenetic response were reported despite BCR-ABL monitoring during the TFR Phase. All cases achieved MR4.5 after Nilotinib treatment re-initiation and maintained until end of study; trial did not mandate re-initiation within 4 weeks after loss of MMR_ that was a requirement in other Nilotinib TFR trials Initial sample size was 300 patients with CML-CP; Amendment #2 in June 2015 reduced sample size to 59 due to recruitment challenges; Study endpoint analysis and interpretations of data were challenging due to small sample size for early study closure..

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama Comprehensive Cancer Center University of Alabama (8)
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center Banner MD Anderson (2)
    • Scottsdale, Arizona, United States, 85258
      • Scottsdale Healthcare/TGen Clinical Research Service SC
  • Arkansas
    • Fayetteville, Arkansas, United States, 72703
      • Highlands Oncology Group
  • California
    • Duarte, California, United States, 91010 3000
      • City of Hope National Medical Center Dept of Oncology
    • Fountain Valley, California, United States, 92708
      • Compassionate Care Research Group Inc CCCMG
    • La Jolla, California, United States, 92093-0987
      • UC San Diego UC San Diego Cancer Ctr
    • Multiple Locations, California, United States
      • Wilshire Oncology Medical Group Corona Cancer Center
    • Pleasant Hill, California, United States, 94523
      • Epic-Care
    • Sacramento, California, United States, 95816-5199
      • Sutter Institute for Medical Research Oncology/Hematology
    • Santa Rosa, California, United States, 94503
      • St Joseph Heritage Healthcare
  • Colorado
    • Boulder, Colorado, United States, 80304
      • Rocky Mountain Cancer Centers USOR
  • Florida
    • Fort Myers, Florida, United States, 33901
      • Florida Cancer Specialists DeptofFloridaCancerSpecialists
    • Orlando, Florida, United States, 32806
      • MD Anderson Cancer Center - Orlando Cancer Center
    • Tampa, Florida, United States, 33612
      • H Lee Moffitt Cancer Center and Research Institute H. Lee Moffitt Cancer Ctr (67)
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Chicago, Illinois, United States, 60612
      • Stroger Cook County Hospital Division of Hematology & Onc
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics Holden Comprehensive Cancer Ct
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Hospital and Medical Center Clinical Research Center
    • Wichita, Kansas, United States, 67214-3728
      • Cancer Center of Kansas
  • Louisiana
    • Shreveport, Louisiana, United States, 71101
      • CHRISTUS Schumpert Health System
  • Michigan
    • Lansing, Michigan, United States
      • Michigan State University / Breslin Cancer Center Breslin Cancer Center (3)
  • Montana
    • Billings Montana, Montana, United States, 59101
      • Billings Clinic Billings Clinic (8)
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center John Theurer Cancer Center
    • Morristown, New Jersey, United States, 07962
      • Hematology Oncology Associates of Northern New Jersey PA Dept of Hem-Onc of Northern NJ
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center Montefiore Medicial Center
    • New York, New York, United States, 10032
      • Columbia University Medical Center Herbert Irving Pavilion
    • New York, New York, United States, 10017
      • Memorial Sloan Kettering Memorial Sloan Kettering (63)
    • New York, New York, United States, 10021
      • Weill Cornell Medical Center Dept. of Oncology
    • Rochester, New York, United States, 14642
      • University of Rochester Medical Center
    • Valhalla, New York, United States, 10595
      • Westchester Medical Center NY Medical College
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center Duke University Med Ctr
    • Hickory, North Carolina, United States, 28602
      • Carolina Oncology Specialists, PC
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences Hematology and Oncology
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Comprehensive Cancer Center/James Cancer Hospital OSU Medical Center
  • Oregon
    • Portland, Oregon, United States, 97210
      • Northwest Cancer Specialists Compass Oncology -BKM
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • University of South Carolina-Hollings Cancer Center Medical University of SC
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Tennessee Oncology Dept. of Centennial Medical
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Univeristy Ingram Cancer Center (10)
  • Texas
    • Abilene, Texas, United States, 79601
      • Hendrick Cancer Center Hendricks Cancer Center
    • Dallas, Texas, United States, 75246
      • Texas Oncology Texas Oncology - McAllen
    • Dallas, Texas, United States, 75246
      • Texas Oncology Texas Oncology - Plano West
    • Dallas, Texas, United States, 75251
      • Texas Oncology P A Texas Oncology - Midland
    • Galveston, Texas, United States, 77555-1188
      • University of Texas Medical Branch SC
    • Houston, Texas, United States, 77024
      • Oncology Consultants Oncology Consultants, P.A.
    • Houston, Texas, United States, 77030
      • The Methodist Hospital Cornell University
    • McAllen, Texas, United States, 78503
      • South Texas Cancer Center- McAllen
    • San Antonio, Texas, United States, 78234
      • Brooke Army Medical Center Brooke Army Medical
    • Waco, Texas, United States, 76712
      • Waco Cancer and Research Center
  • Utah
    • Salt Lake City, Utah, United States, 84103
      • University of Utah / Huntsman Cancer Institute Huntsman Cancer Center
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia
  • Washington
    • Kennewick, Washington, United States, 99336
      • Kadlec Clinic Hematology and Oncology SC
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia University/ Mary Babb Randolph Cancer Center Mary Babb Randolph Cancer Ctr
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin Med College of WI

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:

• diagnosis of CML
• Treated with at least 1 year of imatinib
• Bcr-Abl level by PCR must be less than or equal to 0.1% and greater than 0.0032% by PCR reported on the International scale confirmed during screening
• Written informed consent obtained prior to any screening procedures performed

Exclusion Criteria:

• T315I mutation
• Prior imatinib failure or had accelerated phase or blast crisis CML
• Impaired cardiac function
• Pregnant or lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment Free Remission; Patients entered a monitoring phase for 2 years and received 300 mg nilotinib mg bid. Patients who achieved MR4.5 entered a Consolidation Phase and were treated with nilotinib for 2 years. If MR4.5 was sustained during the Consolidation phase, patients were eligible to stop taking niltoinib during the treatment-free remission (TFR) phase.	Drug: nilotinib; Nilotinib will be provided as 150 mg capsules. Patients will take nilotinib 300mg twice daily on study and dose modifications to 450mg once daily is permitted per protocol.; Other Names: AMN107

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Without Molecular Relapse Within 6 Months After Starting the TFR Phase	Percentage of particpants without confirmed loss of MMR within 6 months following nilotinib TFR is calculated by dividing the number of patients with no documented confirmed loss of MR4, in the first 6 months after starting nilotinib TFR phase by the number of patients who entered nilotinib TFR phase. Molecular relapse is defined as having a confirmed BCR-ABL ratio above MMR (2 consecutive BCR-ABL levels >0.1% IS taken approximately 4 weeks apart).	6 months after stopping nilotinib therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse Free Survival is Defined as Time From the Date of Nilotinib Treatment Discontinuation to the First Documented Molecular Relapse (Confirmed Loss of MR4.5).	Relapse-free survival after the start of the TFR phase was summarized using the product-limit (Kaplan-Meier) estimates. The median for the relapse free survival and its 95% confidence intervals were provided. This analysis was performed on the FAS. Patients who dropped out without relapse were treated as censored observations.	7 years
Percentage of Participants Without Molecular Relapse Within 12 and 24 Months After Starting the Treatment -Free Remission (TFR) Phase	The percentage of participants without confirmed loss of MRR at 12 and 24 months is calculated by dividing the number of patients with no documented confirmed loss of MR4 at 12 and 24 months after starting the nilotinib TFR phase by the number of patients who entered nilotinib TFR phase.	12 and 24 months after starting the TFR
Percentage of Participants Who Regained MR4.5 After Restarting Nilotinib Due to Molecular Relapse	The percentage of participants who regained MR4.5 after restarting nilotinib will be calculated as the number of patients who achieved MR4.5 after having lost MR4 divided by the number of patients who lost MR4.	Restart of nilotinib up to month 6, 12 and 24
Number of Participants Who Progressed to Accelerated Phase/Blastic Crisis (AP/BC) or Died From From Any Cause.	Progression to AP/BC and death where the "failure" event is the earliest occurrence of the following event: progression to AP/BC date.	Baseline up to approximately 5 years
Overall Survival (OS)	OS was defined as the time from the date of cessation of nilotinib therapy to the date of death from any cause.	Baseline up to approximately 5 years
Change in Symptom-burden Scores by the M.D. Anderson Symptom Inventory - Chronic Myeloid Leukemia (MDASI-CML) Assessment	The M.D. Anderson Symptom Inventory for CML patients (MDASI-CML) was used to assess the nature and impact of symptom burden on life. It consisted of 20 validated symptom items and 6 validated interference items. Each item was assessed on an 11 point scale with responses from 0-10, 0=not present and 10=as bad as you can imagine. Symptom score (SS) was calculated when a patient scored at least 8 items of the symptom items using the formula: (sum of scores for the items answered) / number of items answered. If a subject responded to < 8 symptom items, the score was considered missing. Interference score (IS) was calculated when a patient scored at least 4 items using the formula: (sum of scores for the items answered)/number of items answered. If a subject responded to < 4 interference items, the score was considered missing. The total symptom score was 0-200 and total interference score was 0-60. Mean change from baseline was summarized at all post-baseline time points	From baseline to time to when MR4.5 is confirmed, up to 24 months, and from end of Consolidation Phase to 6 and 12 months into the TFR Phase
Change in Health Utility Assessed by EuroQol Group-5D-3L (EQ-5D-3L) Visual Analogue - Safety Set	The EQ-5D-3L questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression and visual analog has a scale 0 to 100 (0=worst imaginable health state, 100=best imaginable health state).	From baseline to time to when MR4.5, up to 24 months, is confirmed and from end of Consolidation Phase to 6 and 12 months into the TFR Phase
Change in Observed Scores for Patient Quality of Life Assessed by SF-8 - Safety Set	The SF-8 questionnaire consisted of 8 items (general health, physical functioning, role physical, bodily pain, vitality, social functioning, role-emotional and mental health) and was used to assess the impact of nilotinib treatment discontinuation on the quality of life. Each item had a 1 to 5 or 1 to 6 point response range and the higher number in the raw scores indicated poorer quality of life. The physical and mental component summary measures were calculated using a norm-based scoring method given in the instrument guidelines. These norm-based scores were summarized at baseline and mean change from baseline for post-baseline time points. The norm-based scores (based on the US population) had a mean of 50 and standard deviation of 10. Higher norm-based summary scores indicated better health	From baseline to time to when MR4.5 is confirmed and from end of Consolidation Phase to 6 and 12 months into the TFR Phase
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 3 in Consolidation Phase - Safety Set	The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point	At month 3 in Consolidation Phase
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Consolidation Phase - Safety Set	The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point	Month 12 in Consolidation Phase
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 24 in Consolidation Phase - Safety Set	The EuroQol Five Dimensional Three-level (EQ-5D-3L) questionnaire comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point	Month 24 in Consolidation Phase
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 6 in Treatment Free Remission Phase - Safety Set	The EuroQol Five Dimensional Three-level questionnaire (EQ-5D-3L) comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point	Month 6 in in Treatment Free Remission Phase
Percentage of Participants' Scores at Each Level Assessed by EQ-5D-3L for Month 12 in Treatment Free Remission Phase - Safety Set	The EuroQol Five Dimensional Three-level questionnaire (EQ-5D-3L) comprises 5 items: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each item has 3 levels (no problems, some problems and extreme problems). The percentages of patients at each level of the five items of the EQ-5D-3L will be summarized at each time point	Month 12 in in Treatment Free Remission Phase

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): August 12, 2013
• Primary Completion (Actual): September 28, 2018
• Study Completion (Actual): September 29, 2018

Study Registration Dates

• First Submitted: December 5, 2012
• First Submitted That Met QC Criteria: December 6, 2012
• First Posted (Estimate): December 7, 2012

Study Record Updates

• Last Update Posted (Actual): March 10, 2020
• Last Update Submitted That Met QC Criteria: February 25, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: CML, chronic myeloid leukemia, stop, niotinib, discontinue, imatinib, switch, MR4.5, undetectable, bcr-abl
• Other Study ID Numbers: CAMN107AUS37

Plan for Individual participant data (IPD)

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

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect 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