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Ibrutinib in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia With Risk of Disease Progression (CLL12)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02863718
Recruitment Status : Active, not recruiting
First Posted : August 11, 2016
Last Update Posted : June 7, 2019
Sponsor:
Collaborator:
Janssen-Cilag Ltd.
Information provided by (Responsible Party):
German CLL Study Group

Tracking Information
First Submitted Date  ICMJE June 10, 2014
First Posted Date  ICMJE August 11, 2016
Last Update Posted Date June 7, 2019
Actual Study Start Date  ICMJE April 30, 2014
Actual Primary Completion Date March 7, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 10, 2016)
Event-free survival (EFS) [ Time Frame: randomization until progression, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first, assessed for at at least 60 months ]
EFS is defined as the time between the date of completed registration and time point of symptomatic disease progression with treatment indication, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first. These will be counted as event for EFS.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02863718 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2016)
  • Treatment-free survival [ Time Frame: time of randomization until the date of initiation of subsequent treatment for CLL or death by any cause assessed for at at least 60 months ]
    The primary efficacy parameter is event-free survival (EFS) defined as the time of randomization until symptomatic disease progression with treatment indication, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first
  • Progression-free survival (PFS) [ Time Frame: the time of randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death by any cause, whichever occurs first, assessed for at at least 60 months ]
    PFS is defined by the time of randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death by any cause, whichever occurs first. These will be counted as event for PFS. Patients for whom no documented event for PFS is available at the time of analysis will be censored at the time point of last follow-up information they were assessed to be event-free.
  • Response rates (Overall response rate (ORR); Complete Remission (CR); Partial Remission (PR) [ Time Frame: Overall response rate (ORR) achieved during treatment or within 6 months of end of treatment, complete response (CR) and partial response (PR) rates will be evaluated for at least 60 months or Progression whichever occurs first ]
    ORR, CR- and PR- rates are defined by the proportion of patients having achieved a response (CR/CRi and nPR/PR), CR/CRi and nPR/PR as best response respectively based on the respective population.
  • rate of Treatment-related adverse events [ Time Frame: randomization until 28 days after the last dose of study drug ]
  • Overall survival (OS) [ Time Frame: date of randomization to the date of death for at least 60 months ]
    Respectively, for watch & wait- patients (study arm I) the date of completed registration will be used. Additionally, OS will also be calculated for the time period between first diagnosis of CLL and death due to any cause. Subjects who have not yet died at the time of analysis will be censored at the time of last follow-up information they were assessed to be alive. The exact cause of death will be recorded, with additional differentiation between CLL-related, treatment-related and other causes. Furthermore overall survival will be analyzed using a multivariate Cox regression model adjusted for risk category, study arm, and baseline prognostic factors
Original Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2016)
  • Treatment-free survival [ Time Frame: time of randomization until the date of initiation of subsequent treatment for CLL or death by any causeassessed for at at least 60 months ]
    The primary efficacy parameter is event-free survival (EFS) defined as the time of randomization until symptomatic disease progression with treatment indication, initiation of subsequent treatment for CLL or death by any cause, whichever occurs first
  • Progression-free survival (PFS) [ Time Frame: the time of randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death by any cause, whichever occurs first, assessed for at at least 60 months ]
    PFS is defined by the time of randomization until symptomatic disease progression (as defined by the updated iwCLL-guidelines) or death by any cause, whichever occurs first. These will be counted as event for PFS. Patients for whom no documented event for PFS is available at the time of analysis will be censored at the time point of last follow-up information they were assessed to be event-free.
  • Response rates (Overall response rate (ORR); Cemplete Remission (CR); Partial Remission (PR) [ Time Frame: Overall response rate (ORR) achieved during treatment or within 6 months of end of treatment, complete response (CR) and partial response (PR) rates will be evaluated for at least 60 months or Progression whichever occurs first ]
    ORR, CR- and PR- rates are defined by the proportion of patients having achieved a response (CR/CRi and nPR/PR), CR/CRi and nPR/PR as best response respectively based on the respective population.
  • rate of Treatment-related adverse events [ Time Frame: randomization until 28 days after the last dose of study drug ]
  • Overall survival (OS) [ Time Frame: date of randomization to the date of death for at least 60 months ]
    Respectively, for watch & wait- patients (study arm I) the date of completed registration will be used. Additionally, OS will also be calculated for the time period between first diagnosis of CLL and death due to any cause. Subjects who have not yet died at the time of analysis will be censored at the time of last follow-up information they were assessed to be alive. The exact cause of death will be recorded, with additional differentiation between CLL-related, treatment-related and other causes. Furthermore overall survival will be analyzed using a multivariate Cox regression model adjusted for risk category, study arm, and baseline prognostic factors
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ibrutinib in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia With Risk of Disease Progression
Official Title  ICMJE A Placebo-Controlled, Double-Blind, Randomized, Multicenter, Three Arm Phase III Trial to Compare the Efficacy and Safety of Ibrutinib vs. Placebo in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia Patients With Risk of Early Disease Progression
Brief Summary

This is a prospective, multicenter, randomized, placebo-controlled, double-blind phase III study that compares the efficacy and safety of oral ibrutinib in previously untreated Binet stage A CLL patients without treatment indication according to iwCLL guidelines but risk of early disease progression.

For event-free survival (EFS), an improvement from 24 months for untreated intermediate or (very) high risk CLL to 48 months for subjects treated with ibrutinib is considered clinically relevant. Ibrutinib / placebo is administered continuously orally until symptomatic disease progression, unacceptable toxicity, or voluntary treatment withdrawal, whichever occurs first.

Detailed Description

The primary objective of the study is to demonstrate superiority of ibrutinib over placebo in prolonging EFS for subjects with treatment-naïve CLL stage A and intermediate or (very) high risk of disease progression. All subjects with intermediate, (very) high risk randomized to the experimental treatment arm will be treated up to active progressive disease with treatment indication according to iwCLL-Guidelines with the objective to demonstrate prolongation of EFS for the ibrutinib arm. EFS is defined as the time between randomization until active progressive disease with treatment indication according to the iwCLL-Guidelines with subsequent treatment for CLL or death.

The secondary objectives are:

  • To evaluate the prolongation of overall survival of ibrutinib versus placebo
  • To evaluate the safety of ibrutinib versus placebo
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Chronic Lymphocytic Leukemia
Intervention  ICMJE
  • Drug: Ibrutinib
    Bruton's tyrosine kinase Inhibitor Ibrutinib 420mg daily
    Other Name: Imbruvica
  • Drug: Placebo
    Placebo 420mg daily
Study Arms  ICMJE
  • No Intervention: Watch & wait
    Watch & wait
  • Placebo Comparator: Placebo 420 mg/d
    Placebo 420mg/d
    Intervention: Drug: Placebo
  • Active Comparator: Ibrutinib 420mg/d
    Ibrutinib 420mg/d
    Intervention: Drug: Ibrutinib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: March 7, 2019)
515
Original Estimated Enrollment  ICMJE
 (submitted: August 10, 2016)
540
Estimated Study Completion Date  ICMJE April 2022
Actual Primary Completion Date March 7, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Previously untreated CLL
  • Stage Binet A without need for treatment
  • Age ≥ 18 years
  • Life expectancy ≥ 6 months
  • ECOG 0 - 2
  • Signed written informed consent
  • Patient in the experimental arm is willing to use a highly effective contraceptive method
  • Male subjects in the experimental treatment arm (placebo / ibrutinib) must:
  • Agree to not donate semen during study drug therapy and for a period after end of study drug therapy.
  • For males these restrictions apply for 3 months after the last dose of study medication.
  • Agree not to share study medication with another person.
  • Be counseled about pregnancy precautions and risks of fetal exposure.
  • Willingness to inform the general practitioner

Exclusion Criteria:

  • Any prior CLL specific therapy
  • Prior treatment with Ibrutinib or BTK inhibitors
  • Chronic use of steroids in excess of prednisone 20mg/day or its equivalent
  • Active infections requiring systemic antibiotics
  • An life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion could compromise the subject's safety, interfere with the absorption or metabolism of Ibrutinib capsules, or put the study outcomes at undue risk
  • Pregnant or lactating females
  • Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging. Subjects who have signs or symptoms suggestive of leukemic meningitis or a history of leukemic meningitis must have a lumbar puncture procedure performed within two weeks prior to randomization
  • Known second malignancy that limits survival to less than two years
  • Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV) and/or active Hepatitis C Virus (HCV) infection.
  • Any of the following laboratory abnormalities:

    1. Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) > 2.5 x upper limit of normal (ULN)
    2. Serum total bilirubin > 1.5 ULN (with the exception of Gilbert's Syndrome)
    3. Creatinine clearance < 30ml/min
  • Requires anticoagulant with warfarin or phenoprocoumon
  • Requires anticoagulant with oral direct Xa Inhibitors (rivaroxaban, apixaban, edoxaban)
  • History of stroke or intracranial hemorrhage within 6 months prior to randomization
  • Requires treatment with strong CYP3A4/5 Inhibitors
  • Participation in any clinical study for CLL or having taken any investigational therapy which would interfere with the study drug for a disease other than CLL within 28 days prior to initiating treatment.
  • Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator
  • Patients with uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia
  • For males these restrictions apply for 3 months after the last dose of study medication.
  • Agree not to share study medication with another person.
  • Be counseled about pregnancy precautions and risks of fetal exposure.
  • Willingness to inform the general practitioner
  • Requires anticoagulant with warfarin or phenoprocoumon
  • Requires anticoagulant with oral direct Xa inhibitors (rivaroxaban, apixaban, edoxaban)
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02863718
Other Study ID Numbers  ICMJE CLL12
2013-003211-22 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party German CLL Study Group
Study Sponsor  ICMJE German CLL Study Group
Collaborators  ICMJE Janssen-Cilag Ltd.
Investigators  ICMJE
Principal Investigator: Petra Langerbeins, MD German CLL Study Group
PRS Account German CLL Study Group
Verification Date June 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP