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 (CRISTALLO)

Roche

Status and phase

Completed

Phase 3

Conditions

Chronic Lymphocytic Leukemia (CLL)

Treatments

Drug: Bendamustine

Drug: Rituximab

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Venetoclax

Drug: Obinutuzumab

Study type

Interventional

Funder types

Industry

Identifiers

NCT04285567

2019-003327-37 (EudraCT Number)

CO41685

2023-504036-17-00 (Other Identifier)

Details and patient eligibility

About

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).

Enrollment

166 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.

Trial design

Primary purpose

Treatment

Allocation

Randomized

Interventional model

Parallel Assignment

Masking

None (Open label)

166 participants in 2 patient groups

VEN + G

Experimental group

Description:

Participants will receive 12 cycles of treatment (each cycle is 28 days). Venetoclax (VEN) will be administered orally, daily, with a 5-week ramp-up period, starting on Cycle 1, Day 22 and administration will continue until the end of Cycle 12. Obinutuzumab (G) will be administered intravenously (IV) on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.

Treatment:

Drug: Obinutuzumab

Drug: Venetoclax

FCR/BR

Active Comparator group