| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Lymphocytic Leukemia |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic cancer of white blood cells and bone marrow |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009310 |
| E.1.2 | Term | CLL |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary Objective phase 2 part:
Grade ≥3-Infection-free survival in the treatment arm compared to the observation arm 12 weeks after finishing treatment (24 weeks after treatment initiation). This is a non-inferiority analysis as detailed in the statistical analysis plan to assure safety of the combination treatment in this preemptive trial population.
Primary Objective optional phase 3 part:
Grade ≥3-infection free and CLL-treatment-free survival 2 years after enrollment
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
- Grade ≥3-infection free and CLL-treatment-free survival at end of treatment, 1 year and 2 years after enrollment
- Rate of overall survival (OS) and cause of death
- Treatment free survival
- Rate and CTCAE V5.0 grade of infections
- Response rate and duration according to IWCLL criteria
- Treatment related adverse events, type, frequency and severity during and for 2 years after treatment
- Immune function as assessed by immune phenotyping, functional TruCulture assays and measurements of cytokine levels
Exploratory Objectives:
- MRD levels in bone marrow and peripheral blood
- Quality of life during and for 2 years after treatment, QLQC30 and CLL17
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. CLL diagnosed according to IWCLL criteria within one year prior to randomization
2. High risk of infection and/or progressive treatment within 2 years according to CLL-TIM
3. IWCLL treatment indication not fulfilled
4. Life expectancy > 2 years
5. Age at least 18 years
6. Ability and willingness to provide written informed consent and adhere to study procedures and treatment
7. Adequate bone marrow function as indicated by platelets above 100 x 10E9, hemoglobin above 10 g/dL and neutrophils above 1 x 10E9
8. Creatinine clearance above 30 mL/min directly measured with 24hr urine collection or calculated according to the modified formula of Cockcroft and Gault
9. Adequate liver function as indicated by a total bilirubin≤ 2 x, AST or ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
10. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.
11. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
12. Woman of childbearing potential (WOCBP) who are sexually active must use highly effective methods of contraception during treatment and for 30 days after the last dose of investigational drugs.
13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information.
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| E.4 | Principal exclusion criteria |
1. Prior CLL treatment (including monoclonal antibodies, chemotherapy, small molecules, including CD20 antibodies, BTK inhibitors and bcl-2 inhibitors for any indication)
2. Transformation of CLL (Richter’s transformation)
3. Previous autoimmune disease as AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura) treated with immune suppression or uncontrolled AIHA or ITP
4. History of progressive multifocal leukoencephalopathy
5. HIV infection (a negative test is required)
6. Known active infection
7. Malignancies other than CLL requiring systemic therapies (except anti-hormonal therapies) or considered to impact survival
8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers or anticoagulant therapy with vitamin K antagonists
9. History of bleeding disorders or current platelet inhibitors or anticoagulant therapy
10. History of clinically significant cardiovascular disease such as arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) > 480 msec at screening.
11. History of stroke or intracranial hemorrhage within 6 months prior to registration.
12. Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
13. Vaccination with live vaccines within 28 days prior to registration.
14. Major surgery less than 30 days before start of treatment. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
15. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
16. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of treatment; further pregnancy testing will be performed regularly).
17. Fertile men or women of childbearing potential unless: surgically sterile or ≥ 2 years after the onset of menopause or willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 30 days after the end of study treatment
18. Legal incapacity
19. Persons who are in dependence to the sponsor or an investigator
20. Persons not considered fit for the trial by the investigator
21. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel that is likely to affect absorption, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
22. Prothrombin time/INR or aPTT (in the absence of Lupus anticoagulant) > 2x ULN.
23. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Grade ≥3-Infection-free survival in the treatment arm compared to the observation |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 24 weeks after treatment initiation |
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| E.5.2 | Secondary end point(s) |
• Grade ≥3-infection free and CLL-treatment-free survival at end of treatment, 1 year and 2 years after enrollment
• Rate of overall survival (OS) and cause of death
• Treatment free survival
• Rate and CTCAE V5.0 grade of infections
• Response rate and duration according to IWCLL criteria
• Treatment related adverse events, type, frequency and severity during and for 2 years after treatment
• Immune function as assessed by immune phenotyping, functional TruCulture assays and measurements of cytokine levels
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| End of treatment, 1 and 2 years after enrolment and continuously as rate |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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