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

Primary Purpose

Chronic Lymphocytic Leukemia

Status
Completed
Phase
Phase 3
Locations
Germany
Study Type
Interventional
Intervention
Ibrutinib
Placebo
Sponsored by
German CLL Study Group
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukemia focused on measuring CLL

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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)

Sites / Locations

  • German CLL Study Group

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

No Intervention

Placebo Comparator

Active Comparator

Arm Label

Watch & wait

Placebo 420 mg/d

Ibrutinib 420mg/d

Arm Description

Watch & wait

Placebo 420mg/d

Ibrutinib 420mg/d

Outcomes

Primary Outcome Measures

Event-free survival (EFS)
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.

Secondary Outcome Measures

Treatment-free survival
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)
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)
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
Overall survival (OS)
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

Full Information

First Posted
June 10, 2014
Last Updated
November 4, 2022
Sponsor
German CLL Study Group
Collaborators
Janssen-Cilag Ltd.
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1. Study Identification

Unique Protocol Identification Number
NCT02863718
Brief Title
Ibrutinib in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia With Risk of Disease Progression
Acronym
CLL12
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Completed
Study Start Date
April 30, 2014 (Actual)
Primary Completion Date
March 7, 2019 (Actual)
Study Completion Date
July 11, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
German CLL Study Group
Collaborators
Janssen-Cilag Ltd.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Lymphocytic Leukemia
Keywords
CLL

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
515 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Watch & wait
Arm Type
No Intervention
Arm Description
Watch & wait
Arm Title
Placebo 420 mg/d
Arm Type
Placebo Comparator
Arm Description
Placebo 420mg/d
Arm Title
Ibrutinib 420mg/d
Arm Type
Active Comparator
Arm Description
Ibrutinib 420mg/d
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Other Intervention Name(s)
Imbruvica
Intervention Description
Bruton's tyrosine kinase Inhibitor Ibrutinib 420mg daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo 420mg daily
Primary Outcome Measure Information:
Title
Event-free survival (EFS)
Description
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.
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
Secondary Outcome Measure Information:
Title
Treatment-free survival
Description
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
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
Title
Progression-free survival (PFS)
Description
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.
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
Title
Response rates (Overall response rate (ORR); Complete Remission (CR); Partial Remission (PR)
Description
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.
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
Title
rate of Treatment-related adverse events
Time Frame
randomization until 28 days after the last dose of study drug
Title
Overall survival (OS)
Description
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
Time Frame
date of randomization to the date of death for at least 60 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: 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) Serum total bilirubin > 1.5 ULN (with the exception of Gilbert's Syndrome) 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)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Petra Langerbeins, MD
Organizational Affiliation
German CLL Study Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
German CLL Study Group
City
Cologne
ZIP/Postal Code
50935
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
34758069
Citation
Langerbeins P, Zhang C, Robrecht S, Cramer P, Furstenau M, Al-Sawaf O, von Tresckow J, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Muller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. The CLL12 trial: ibrutinib vs placebo in treatment-naive, early-stage chronic lymphocytic leukemia. Blood. 2022 Jan 13;139(2):177-187. doi: 10.1182/blood.2021010845.
Results Reference
result
Links:
URL
http://www.dcllsg.de/en/trial/cll12/
Description
Click here for more information about this study: CLL12 (German CLL Study Group)

Learn more about this trial

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

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