E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
fit patients with previously untreated CLL without del(17p) or TP53 mutation |
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E.1.1.1 | Medical condition in easily understood language |
patients with a special kind of blood cancer and without specified genetic risk factors |
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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 | 10008976 |
E.1.2 | Term | Chronic lymphocytic leukemia |
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 |
The primary objective of the study is to evaluate the efficacy of obinutuzumab (GA101) plus venetoclax (GVe) versus standard chemoimmunotherapy (BR/FCR) [concerning MRD negativity measured by flow cytometry in peripheral blood (PB) at month 15] and obinutuzumab plus ibrutinib plus venetoclax (GIVe) versus standard chemoimmunotherapy (BR/FCR) [concerning progression free survival (PFS)] in previously untreated, fit CLL patients without del(17p) or TP53 mutation. |
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E.2.2 | Secondary objectives of the trial |
Measurement of MRD-Level Secondary objectives of the study are the evaluation of the efficacy of rituximab plus venetoclax (RVe) versus standard chemoimmunotherapy (BR/FCR), GVe and GIVe [concerning MRD negativity measured by flow cytometry in PB at month 15 and PFS]. |
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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 criteria12. 2. Age at least 18 years. 3. Life expectancy ≥ 6 months. 4. Ability and willingness to provide written informed consent and to ad-here to the study visit schedule and other protocol requirements. 5. Adequate bone marrow function indicated by a platelet count >30 x10^9/l (unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy) 6. GFR ≥70ml/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. For patients with creatinine values within the normal range the calculation of the clearance is not necessary. Dehydrated patients with an estimated creatinine clearance less than 70 ml/min may be eligible if a repeat estimate after adequate hydration is > 70 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. 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 ad-ministered 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). 3. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite prednisolon or intravenous immunoglobulins (IVIG) being administered for hemolysis. 4. Prior treatment with rituximab even for other indications than CLL is not permitted. 5. Detected del(17p) or TP53 mutation. 6. Patients with a history of PML. 7. Any comorbidity or organ system impairment rated with a single CIRS (cumulative illness rating scale) score of 4 (excluding the eyes/ears/nose/throat/larynx organ system), a total CIRS score of more than 6 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 im-paired resorption in the gastrointestinal tract). 8. Urinary outflow obstruction. 9. 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 treating physician) or showing signs of progression after curative treatment. 10. Uncontrolled or active infection. 11. Patients with known infection with human immunodeficiency virus (HIV). 12. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibi-tors/inducers. 13. Anticoagulant therapy with warfarin or phenoprocoumon, ( alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly informed about the potential risk of bleeding under treatment with ibrutinib). 14. History of stroke or intracranial hemorrhage within 6 months prior to registration. 15. Use of investigational agents which might interfere with the study drug within 28 days prior to registration. 16. Vaccination with live vaccines 28 days prior to registration. 17. Major surgery less than 30 days before start of treatment. 18. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products. 19. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial. 20. 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). 21. 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. 22. Legal incapacity. 23. Prisoners or subjects who are institutionalized by regulatory or court order. 24. 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) |
• Negativity rate of minimal residual disease (MRD) in peripheral blood (PB) measured by flow cytometry at month (MO) 15 for the comparison [GVe versus standard chemoimmunotherapy (SCIT)]. • Progression free survival (PFS) for the comparison [GIVe versus SCIT]
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• MRD levels in PB at MO 15 (all other comparisons except for [GVe ver-sus SCIT]) • MRD levels in PB at different time points (MO 2, 9 and 13; MRD at later time points might be evaluated according to the discretion of the treating physician at local laboratories) • MRD levels measured in bone marrow (BM) at final restaging (RE, 2 month after the end of last treatment cycle) • PFS (all other comparisons except for [GIVe versus SCIT]) • Overall response rate (ORR) [MO 3, 9, 13, 15] • (Clinical) CR / CRi rate [Interim staging [IST], cycle 9 day 1 (or final re-staging (RE) for patients in the SCIT arm), IR (or three month after RE for patients in the SCIT arm respectively) and MO 15] (with regard to best response achieved) • Event-free survival (EFS) • Overall survival (OS) • Duration of response in patients with: o complete response (CR) or CR with incomplete recovery of the bone marrow (CRi), o partial response (PR) • Time to next CLL treatment • Safety parameters: Type, frequency, and severity of o adverse events (AEs) and o adverse events of special interest (AESI) and their relationship to study treatment • Health-related quality of life by MARS and EORTC QLQ-C30 and QLQ-CLL16 questionnaires • Exploratory evaluations of potential associations between biomarkers and subject characteristics or outcome measures
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 4 |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 130 |
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 |
Israel |
Austria |
Finland |
Sweden |
Netherlands |
Switzerland |
Germany |
Belgium |
Denmark |
Ireland |
Norway |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 7 |