| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with previously untreated CLL requiring treatment |
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| E.1.1.1 | Medical condition in easily understood language |
Patients with previously untreated chronic lymphocytic leukaemia (blood cancer) in need of treatment
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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 | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008958 |
| E.1.2 | Term | Chronic lymphocytic leukaemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
| The primary objective of the study is to compare the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and fixed-duration ibrutinib plus venetoclax by measuring progression-free survival (PFS) in patients with previously untreated CLL. |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives of the study are the evaluation of the efficacy of continuous ibrutinib monotherapy with fixed-duration venetoclax plus obinutuzumab and with fixed-duration ibrutinib plus venetoclax by measuring for example MRD negativity in patients with previously untreated CLL. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented CLL requiring treatment according to iwCLL criteria.
2. Age at least 18 years.
3. Life expectancy ≥ 6 months.
4. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
5. Adequate bone marrow function independent of growth factor or transfusion support within 2 weeks of screening initiation as fol-lows, unless cytopenia is due to CLL:
a. Absolute neutrophil count ≥ 1.0 × 109/L
b. Platelet counts ≥ 30 × 109/L; in cases of thrombocytopenia clearly due to CLL (per the discretion of the investigator), platelet count should be ≥ 10 × 109/L
c. Total haemoglobin ≥ 9 g/dL (without transfusion support, unless anaemia is due to CLL)
6. GFR >30ml/min directly measured with 24hr urine collection, calculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 – age) x bodyweight)/ (72 x creatinine), for women x 0, 85) or an equally accurate method.
a. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated pa-tients with an estimated creatinine clearance less than 30 ml/min may be eligible if a repeat estimate after adequate hy-dration is > 30 ml/min.
7. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ ALT ≤ 2.5 x the institutional ULN value, unless directly attributable to the patient’s CLL or to Gilbert’s Syndrome.
8. 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 for study screening (i.e. PCR only required when serology was posi-tive).
9. Eastern Cooperative Oncology Group Performance Status (ECOG) performance status 0-2.
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| E.4 | Principal exclusion criteria |
1. Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention; within the last 10 days before start of study treatment, only dose equivalents up to 20 mg prednisolone are permitted).
2. Transformation of CLL (Richter transformation). When Richter transformation is suspected, PET-CT and/or biopsy should be performed to rule out transformation.
3. Patients with a history of PML.
4. An individual organ/ system impairment score of 4 as assessed by the CIRS definition limiting the ability to receive the study treatment or any other life-threatening illness, medical condition or organ system dysfunction that, in the investigator´s opinion, could compromise the patients’ safety or interfere with the absorption or metabolism of the study drugs (e.g. inability to swallow tablets or impaired resorption in the gastrointestinal tract).
5. Malignancies other than CLL currently requiring systemic therapies, not being treated with curative intent before (unless the malignant disease is in a stable remission due to the discretion of the treat-ing physician or showing signs of progression after curative treatment.
6. Uncontrolled or active infection.
7. Patients with known infection with human immunodeficiency virus (HIV).
8. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/ inducers (incl. up to 7 days prior to study treatment start).
9. Anticoagulant therapy with warfarin or phenprocoumon,
(alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib).
10. History of stroke or intracranial hemorrhage within 6 months prior to registration for study screening.
11. Known bleeding disorders
12. Child B / C liver cirrhosis
13. Use of investigational agents which might interfere with the study drug within 28 days prior to registration for study screening.
14. Vaccination with live vaccines 28 days prior to registration for study screening.
15. Major surgery less than 30 days before start of study treatment.
16. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
17. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
18. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 7 days before start of study treatment; further pregnancy testing will be performed monthly).
19. Fertile men or women of childbearing potential unless:
a. surgically sterile or ≥ 2 years after the onset of menopause
b. 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 18 months after the end of study treatment.
20. Legal incapacity.
21. Prisoners or subjects who are institutionalized by regulatory or court order.
22. Persons who are in dependence to the sponsor or an investigator.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Investigator-assessed PFS, defined as the time from randomization to the first occurrence of progression or relapse (determined using standard IWCLL guidelines), or death from any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The first analysis will be the interim PFS analysis and will take place after 65% of the total 212 events have been observed, i.e. 138 PFS events and a follow-up of at least 24 months after lasst patient enrolled will trigger the interim analysis. |
|
| E.5.2 | Secondary end point(s) |
• Rates of undetectable MRD (uMRD, i.e. <10-4) in peripheral blood (PB) and bone marrow (BM) at final restaging (RE), which will be at cycle 18 after start of treatment, and additional BM assessment approx. 12 months after RE
• MRD levels in PB at different time points (cycle 1 before start of ther-apy, start of cycle 7, start of cycle 13 [ end of VG treatment], start of cycle 16 [ end of VI treatment], final restaging [cycle 18], after-wards every 6 months to end of study)
• Duration of undetectable MRD (uMRD)
• Overall response rate (ORR; defined as rate of a response of CR, CRi, or PR) as per iwCLL guidelines at final restaging
• Complete response rate (CRR; defined as rate of a response of CR or CRi) at final restaging as per iwCLL guidelines
• Overall survival (OS)
• Event-free survival (EFS) (I vs VG and I vs VI)
• Time to next treatment (TTNT)
• PFS2 (i.e. PFS after second-line treatment)
Safety parameters:
• Type, frequency, and severity of
o adverse events (AEs) and
o adverse events of special interest (AESI)
o adverse events of particular interest (AEPI)
and their relationship to study treatment
• Tumour lysis syndrome (TLS) risk category after G or I lead-in (before venetoclax ramp up)
Exploratory analyses:
• Evaluation of relationship between various baseline markers and clini-cal outcome parameters (e.g. PFS, OS, ORR relative to del17p/TP53, IGHV, fitness, etc)
• MRD by methods other than flow cytometry
• Correlation between MRD in BM and PB
• Correlation between MRD in BM and PFS/ EFS/ OS
Correlation between MRD in PB and PFS/ EFS/ OS
• Health-related quality of life by EORTC QLQC30 and QLQ-CLL17 questionnaires
• Medical Resource Utilization
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| In terms of timely completion, the final PFS analysis will be conducted as soon as 212 events have occurred. This will trigger the time point of the analysis of secondary endpoints. Safety analyses are independent from primary and secondary efficacy analyses. |
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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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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) | No |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 152 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 152 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Denmark |
| Finland |
| Germany |
| Ireland |
| Israel |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| Switzerland |
|
| 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
|
The end of the clinical trial is defined as the time point 213 PFS events have been reached. This will take place approximately 80 months after first patient has been randomized (FPI).
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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 | 6 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
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