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

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.

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

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)