a study to compare the efficacy and safety of a combined regimen of venetoclax and obinutuzumab versus fludarabine, cyclophosphamide, and rituximab (fcr)/ bendamustine and rituximab (br) in fit patients with previously untreated chronic lymphocytic leukemia (cll) without del (17p) or tp53 mutation

Conditions: Chronic Lymphocytic Leukemia (CLL)

Summary: this study will evaluate the efficacy and safety of venetoclax and obinutuzumab (ven + g) compared with fludarabine + cyclophosphamide + rituximab or bendamustine + rituximab (fcr/br) in fit participants (fit is defined by a cumulative illness rating scale \[cirs\]/score of ≤6 and a normal creatinine clearance of ≥70 ml/min) with previously untreated cll without del(17p) or tp53 mutation requiring treatment. eligible participants will be randomly assigned in a 1:1 ratio to receive either ven + g (arm a) or fcr/br (arm b).


Eligibility criteria:
inclusion criteria: * ability to comply with the study protocol, in the investigator's judgment * aged 18 years or older * have previously untreated documented chronic lymphocytic leukemia (cll) according to the international workshop on chronic lymphocytic leukemia (iwcll) criteria * cll requiring treatment according to the iwcll criteria * cumulative illness rating scale (cirs) score ≤ 6 and creatinine clearance (crcl) ≥ 70 ml/min * hematology values within the following limits, unless cytopenia is caused by the underlying disease (i.e., no evidence of additional bone marrow (bm) dysfunction; e.g., myelodysplastic syndrome, hypoplastic bm): * absolute neutrophil count ≥ 1.0 x 109/l, unless there is bm involvement * platelet count ≥ 75 x 109/l and more than 7 days since last transfusion, or ≥ 30 x 109/l if there is bm involvement * adequate liver function as indicated by a total bilirubin, aspartate aminotransferase, and alanine transaminase ≤ 2 times the institutional upper limit of normal (uln) value, unless directly attributable to the participant's cll * life expectancy \>6 months * for women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception and agreement to refrain from donating eggs * for men: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, and agreement to refrain from donating sperm exclusion criteria: * transformation of cll to aggressive non-hodgkin's lymphoma (nhl) * participants with small lymphocyclic lymphoma (sll) only * known central nervous system involvement * participants with a history of confirmed progressive multifocal leukoencephalopathy (pml) * detected del(17p) or tp53 mutation (valid test within 6-months from screening is required for randomisation) * an individual organ/system impairment score of 4 as assessed by the cumulative illness rating scale (cirs) definition limiting the ability to receive the treatment regimen of this trial with the exception of eyes, ears, nose, throat organ system * participants with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia * history of prior malignancy * participants with infections requiring iv treatment (grade 3 or 4) within the last 8 weeks prior to enrollment * evidence of other clinically significant uncontrolled conditions including but not limited to active or uncontrolled systemic infection (e.g., viral, bacterial, or fungal) * history of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies or known sensitivity or allergy to murine products * hypersensitivity to fludarabine, bendamustine, cyclophosphamide, rituximab, obinutuzumab, or venetoclax or to any of the excipients (e.g., trehalose) * pregnant women and nursing mothers * vaccination with a live vaccine ≤ 28 days prior to randomization * prisoners or participants who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator * history of illicit drug or alcohol abuse within 12 months prior to screening, in the investigator's judgment * positive test results for chronic hepatitis b virus (hbv) infection (defined as positive hepatitis b surface antigen \[hbsag\] serology) * positive test result for hepatitis c (hepatitis c virus \[hcv\] antibody serology testing) * participants with known infection with hiv or human t-cell leukemia virus 1 (htlv-1) * any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study * received any of the following agents within 28 days prior to the first dose of study treatment: * immunotherapy * radiotherapy * hormone therapy * any therapies intended for the treatment of lymphoma/leukemia whether approved or experimental * participants who have received the following agents: * strong and moderate cyp3a inhibitors/inducers within 7 days prior to the initiation of study treatment * steroid therapy for anti-neoplastic intent with the exception of inhaled steroids for asthma, topical steroids, or replacement/stress corticosteroids within 7 days prior to the first dose of study drug administration * consumed grapefruit, grapefruit products, seville oranges(including marmalade containing seville oranges), or star fruit within 3 days prior to the first dose of study drug and throughout venetoclax administration * inability to swallow a large number of tablets.