ACALABRUTINIB for Chronic lymphocytic leukaemia (CLL) (high-risk)

Inclusion criteria

• {"criterion_text":"- Documented CLL/SLL3 requiring treatment according to iwCLL criteria as of 2018.\n- 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 cycle until 12 months after last treatment cycle), negative testing for hepatitis C RNA within 6 weeks prior to registration.\n- Age at least 18 years.\n- 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), or an unmutated IGHV status.\n- Life expectancy ≥ 6 months.\n- Eastern Cooperative Oncology Group (ECOG) performance status of 0 -2.\n- Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.\n- 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).\n- 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.\n- 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."}

Exclusion criteria

• {"criterion_text":"- Any prior CLL-specific therapies (except corticosteroid treatment administered due to necessary immediate intervention (after start of study treatment only continuous treatment with dose equivalents up to 20 mg prednisolone is permitted) and short-termed treatment with Rituximab because of auto-immune cytopenia .\n- Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.\n- 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).\n- This exclusion criterion applies only as long as acalabrutinib capsules are used for study medication (for tablets please refer to section 8.2.2): Requirement of treatment with a PPI (proton pump inhibitor). If treatment with an acid reducing agent is required, consider us-ing an antacid (e.g. calcium carbonate) or an H2-receptor antagonist (e.g. ranitidine or fa-motidine) instead.\n- History of stroke or intracranial hemorrhage within 6 months prior to registration.\n- Use of investigational agents which might interfere with the study drug within 28 days prior to registration.\n- Vaccination with live vaccines 28 days prior to registration.\n- Major surgery less than 30 days before start of treatment.\n- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.\n- Known hypersensitivity to any active substance or to any of the excipients of one of the drugs used in the trial.\n- 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 see chapter 2.3.1.5).\n- Transformation of CLL (Richter‘s transformation).\n- 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.\n- Inability to swallow a large number of tablets.\n- Legal incapacity.\n- Prisoners or subjects who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator.\n- Known central nervous system involvement.\n- 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. Current life-threatening illness, medical condi-tion, or organ system dysfunction which, in the Investigator’s opinion, could compromise the subject’s safety or put the study at risk.\n- Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of prednisolone or intravenous immunoglobulins (IVIG) being administered for hemolysis.\n- Patients with a history of confirmed progressive multifocal leukoencephalopathy.\n- 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 dis-cretion of the treating physician) or showing signs of progression after curative treatment.\n- Patients with active infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrollment.\n- Patients with known infection with human immunodeficiency virus (HIV)."}

Primary endpoints

• {"endpoint_text":"- The primary endpoint of the study is investigator assessed progression-free survival (PFS). The study is designed to demonstrate that treatment with GAVe prolong PFS as compared to treatment with 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, and/or unmutated IGHV-status).","definition_or_measurement_approach":"Investigator-assessed progression-free survival (PFS) as defined in protocol; PFS assessed by investigators."}

Secondary endpoints

• {"endpoint_text":"- Measurable 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)","definition_or_measurement_approach":"MRD levels measured in peripheral blood and bone marrow at specified staging/timepoints (Staging 5; cycle-specific days as stated)."}
• {"endpoint_text":"- MRD in PB at cycle 27 day 1 for all patients (Staging 9, respectively end of maintenance for patients in GAVe study arm, who had detectable MRD levels after 14 cycles of GAVe-treatment)","definition_or_measurement_approach":"MRD in peripheral blood measured at cycle 27 day 1 (stated timepoint)."}
• {"endpoint_text":"- Overall response rate (ORR; as per iwCLL guidelines) at cycle 15","definition_or_measurement_approach":"ORR assessed according to iwCLL 2018 guidelines at cycle 15."}
• {"endpoint_text":"- Complete response rate (CRR; as per iwCLL guidelines) at cycle 15","definition_or_measurement_approach":"CRR assessed according to iwCLL 2018 guidelines at cycle 15."}
• {"endpoint_text":"- Overall Survival (OS)","definition_or_measurement_approach":"Overall survival measured from randomisation to death from any cause."}
• {"endpoint_text":"- Event-free survival (EFS)","definition_or_measurement_approach":"Event-free survival as defined in protocol (time to event as specified in protocol)."}
• {"endpoint_text":"- Duration of response (DOR)","definition_or_measurement_approach":"Duration of response according to response criteria (as per iwCLL guidelines where applicable)."}
• {"endpoint_text":"- Time to next treatment (TTNT)","definition_or_measurement_approach":"Time from randomisation (or end of response) to initiation of next line of anti-CLL therapy."}

Germany

Earliest CTIS Part Ii Submission Date

08-08-2024

Latest Decision Or Authorization Date

22-01-2026

Processing Time Days

532

Number Of Sites

68

Number Of Participants

187

Austria

Earliest CTIS Part Ii Submission Date

08-08-2024

Latest Decision Or Authorization Date

16-02-2026

Processing Time Days

557

Number Of Sites

6

Number Of Participants

15

Portugal

Earliest CTIS Part Ii Submission Date

16-12-2025

Latest Decision Or Authorization Date

12-02-2026

Processing Time Days

58

Number Of Sites

6

Number Of Participants

30

Primary sponsor

Full Name

University Of Cologne

Organisation Type

Educational Institution

Country Of Registered Address

Germany

Third parties

• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Ulm AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"1","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Heidelberg AöR","duties_or_roles":"14","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"10,11,12,13,14,2,5,6,8","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"Universitaetsklinikum Schleswig-Holstein AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Germany","full_name":"University Hospital Cologne AöR","duties_or_roles":"4","organisation_type":"Hospital/Clinic/Other health care facility"}