Chronic Lymphocytic LeukemiaPhase 3CLL12NCT02863718
Ibrutinib in Previously Untreated Binet Stage A Chronic Lymphocytic Leukemia With Risk of Disease Progression
A Phase 3 study testing Ibrutinib in people with Chronic Lymphocytic Leukemia, run by German CLL Study Group at 1 site in Germany.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Chronic Lymphocytic Leukemia
- What is being tested?
- Ibrutinib
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 515 participants
- Where
- 1 siteGermany
- Study dates
- 30 Apr 2014to 11 Jul 2022
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Previously untreated CLL
- Stage Binet A without need for treatment
- Age ≥ 18 years
- Life expectancy ≥ 6 months
- ECOG 0 - 2
- Signed written informed consent
Show all 13Show fewer
- 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
Who cannot join
- 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
Show all 26Show fewer
- 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)
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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
- Conditions
- Chronic Lymphocytic Leukemia
- Being tested
- Ibrutinib, Placebo
- Keywords
- CLL
- Medical subject headings
- Leukemia, Lymphocytic, Chronic, B-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
IbrutinibDrug
Also called Imbruvica
Bruton's tyrosine kinase Inhibitor Ibrutinib 420mg daily
PlaceboDrug
Placebo 420mg daily
| Study group | Role | What they receive |
|---|---|---|
| Watch & wait | No intervention | Watch \& wait |
| Placebo 420 mg/d | Placebo comparator | Placebo 420mg/d Receives: Drug: Placebo |
| Ibrutinib 420mg/d | Active comparator | Ibrutinib 420mg/d Receives: Drug: Ibrutinib |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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 outcomes (5)
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
Measured: 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
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.
Measured: 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
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.
Measured: 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
rate of Treatment-related adverse events
Measured: randomization until 28 days after the last dose of study drug
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
Measured: date of randomization to the date of death for at least 60 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Aug 2016 (estimated)
- Study start30 Apr 2014
- Primary completion7 Mar 2019
- Study completion11 Jul 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Chronic Lymphocytic LeukemiaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 515 participants (actual)
Sponsor and investigators
- Lead sponsor
- German CLL Study Group
- Sponsor type
- University, hospital or other
- Collaborators
- Janssen-Cilag Ltd.
- Responsible party
- Sponsor
- Investigators
- Petra Langerbeins, MD, Principal investigator, German CLL Study Group
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02863718
- Sponsor's protocol ID
- CLL12
- Other IDs
- 2013-003211-22
- Acronym
- CLL12
- Status last verified
- Nov 2022
- First submitted
- 10 Jun 2014
- Last updated
- 30 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
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.
PubMed 34758069Langerbeins P, Robrecht S, Nieper P, Cramer P, Furstenau M, Al-Sawaf O, Simon F, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Schneider C, Muller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Zahn MO, Dorfel S, Staib P, Behlendorf T, Hensel M, Hebart H, Klaproth H, Block A, Liersch R, Hauch U, Heinrich B, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial. J Clin Oncol. 2025 Feb;43(4):392-402. doi: 10.1200/JCO.24.00975. Epub 2024 Nov 27.
PubMed 39602678
Study at a glance
From the registry record, last updated by the sponsor on 30 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02863718
- Acronym / sponsor ID
- CLL12 / CLL12
- Conditions
- Chronic Lymphocytic Leukemia
- Keywords
- CLL
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 515 participants (actual)
- Lead sponsor
- German CLL Study GroupUniversity, hospital or other
- Collaborators
- Janssen-Cilag Ltd.
- Study start
- 30 Apr 2014 (actual)
- Primary completion
- 7 Mar 2019 (actual)
- Study completion
- 11 Jul 2022 (actual)
- First posted
- 11 Aug 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Watch & wait | No intervention | –Watch \& wait |
| Placebo 420 mg/d | Placebo comparator | Drug: PlaceboPlacebo 420mg/d |
| Ibrutinib 420mg/d | Active comparator | Drug: IbrutinibIbrutinib 420mg/d |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (13 listed)
- Previously untreated CLL
- Stage Binet A without need for treatment
- Age ≥ 18 years
- Life expectancy ≥ 6 months
- ECOG 0 - 2
Key exclusion criteria (26 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| IbrutinibAlso: ImbruvicaBruton's tyrosine kinase Inhibitor Ibrutinib 420mg daily | Drug | Ibrutinib 420mg/d |
| PlaceboPlacebo 420mg daily | Drug | Placebo 420 mg/d |
Primary outcome
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.
5 secondary outcomes
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
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
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 30 Dec 2024.
- Background: PubMed 34758069Langerbeins 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 publication: PubMed 39602678Langerbeins P, Robrecht S, Nieper P, Cramer P, Furstenau M, Al-Sawaf O, Simon F, Fink AM, Kreuzer KA, Vehling-Kaiser U, Tausch E, Schneider C, Muller L, Eckart MJ, Schlag R, Freier W, Gaska T, Balser C, Reiser M, Stauch M, Zahn MO, Dorfel S, Staib P, Behlendorf T, Hensel M, Hebart H, Klaproth H, Block A, Liersch R, Hauch U, Heinrich B, Wendtner CM, Fischer K, Stilgenbauer S, Eichhorst B, Hallek M. Ibrutinib in Early-Stage Chronic Lymphocytic Leukemia: The Randomized, Placebo-Controlled, Double-Blind, Phase III CLL12 Trial. J Clin Oncol. 2025 Feb;43(4):392-402. doi: 10.1200/JCO.24.00975. Epub 2024 Nov 27.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Petra Langerbeins, MD principal investigator
German CLL Study Group
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Ibrutinib in people with Chronic Lymphocytic Leukemia, run by German CLL Study Group at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 13 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 30 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02863718, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2024.