| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with previously untreated chronic lymphocytic leukemia with treatment requiring disease and at least one out of three risk factors (17p-deletion, TP53 mutation or Complex karyotype). |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with chronic lymphocytic leukaemia (blood cancer) in need of firstline treatment and at least one out of three risk factors. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 aims to show that 14 cycles of treatment with triple combination of acalabrutinib, venetoclax and obinutuzumab (GAVe) prolong progression free survival as compared to 12 cycles of treatment with Venetoclax-Obinutuzumab (GVe) in patients with high risk CLL (defined as having at least one of the following risk factors: 17p-deletion, TP53- mutation or complex karyotype). |
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| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are other efficacy endpoints and safety. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Documented CLL/SLL requiring treatment according to iwCLL criteria1.
2. Age at least 18 years.
3. At least one of the following risk factors: 17p- deletion, TP53 mutation, complex karyo-type (defined as defined as the presence of 3 or more chromosomal aberrations in 2 or more metaphases.
4. Life expectancy ≥ 6 months.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2.
6. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
7. 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).
8. GFR >30 ml/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 30 ml/min may be eligible if a repeat estimate after adequate hydration is > 30 ml/min.
9. Adequate liver function as indicated by a total bilirubin ≤ 2 x, AST/ALT ≤ 2.5 x the institu-tional 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; pa-tients 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.
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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‘s transformation).
3. Known central nervous system involvement.
4. An individual organ/system impairment score of 4 as assessed by the CIRS definition lim-iting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system (note that symptoms related to CLL should not be in-cluded in the patient’s screening CIRS score). Investigators should consult the General Rules for Severity Rating as well as the Organ-Specific Categories when assigning scores for certain conditions (i.e., pulmonary embolism) and consider the level of morbid-ity associated with a patient’s condition.
5. Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for hemolysis.
Prior treatment with rituximab also for other indications than CLL is not permitted.
6. Patients with a history of confirmed progressive multifocal leukoencephalopathy.
7. 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 treat-ment.
8. Patients with active infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrollment
9. Patients with known infection with human immunodeficiency virus (HIV).
10. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.
11. Anticoagulant therapy with warfarin or phenoprocoumon,
(alternative anticoagulation is allowed (e.g. DOACs), but patients must be properly in-formed about the potential risk of bleeding under treatment with acalabrutinib).
12. Requirement of treatment with a PPI (proton pump inhibitor). If treatment with an acid re-ducing agent is required, consider using an antacid (e.g., calcium carbonate) or an H2-receptor antagonist (e.g. ranitidine or famotidine) instead
13. History of stroke or intracranial hemorrhage within 6 months prior to registration.
14. Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
15. Vaccination with live vaccines 28 days prior to registration.
16. Major surgery less than 30 days before start of treatment.
17. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
18. Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.
19. Pregnant women and nursing mothers (a negative pregnancy test is required for all wom-en of childbearing potential within 7 days before start of treatment; further pregnancy test-ing will be performed regularly).
20. 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 con-traceptive method (Pearl Index <1) and one additional effective (barrier) method dur-ing study treatment and for 18 months after the end of study treatment.
21. Inability to swallow a large number of tablets:
22. Legal incapacity.
23. Prisoners or subjects who are institutionalized by regulatory or court order or 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) |
| The primary endpoint of the study is investigator assessed progression-free survival (PFS). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
One formal interim analysis will be performed for efficacy (i.e. superiority of GAVe as compared to GVe) after 77% of the total 48 investigator-assessed PFS events have been observed (i.e. 37 investi-gator-assessed PFS events). The interim analysis is not designed to assess futility. Giving a recruitment period of approximately 30 months and a study duration of approximately 62 months, the inter-im analysis is projected to occur at month 50.
Based on the study assumptions 48 PFS events are required for the final PFS analysis. Assuming linear accrual of 178 patients (89 patients for GAVe and 89 patients for GVe) over approximately 30 months, the 48 events will be reached approximately 62 months after the first patient has been randomized. |
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| E.5.2 | Secondary end point(s) |
Secondary endpoints:
• Minimal residual disease (MRD) levels in the peripheral blood (PB) and in the bone marrow (BM) at final restaging ((Staging 5) cycle 15 day 1 for patients in GVe study arm, cycle 14 day 14 for patients in GAVe study arm)
• MRD in PB at cycle 27 day 1 for all patients (end of maintenance for patients in GAVe study arm, who had detectable MRD levels after 14 cycles of GAVe-treatment)
• Overall response rate (ORR; as per iwCLL guidelines) at cycle 15
• Complete response rate (CRR; as per iwCLL guidelines) at cycle 15
• Overall Survival (OS)
• Event-free survival (EFS)
• Duration of response (DOR)
• Time to next treatment (TTNT)
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be analysed at the same time as the primary endpoint: Either when the results of the interim analysis support the decision to stop early for efficacy or with the final analysis. |
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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 | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 80 |
| 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 | No |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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