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: Active, not recruiting; 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)

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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

Description:

Participants will receive 6 cycles of Fludarabine + Cyclophosphamide + Rituximab (FCR) consisting of a single cycle of a single infusion of rituximab on Day 1 and fludarabine and cyclophosphamide infusions on Days 1-3 of each 28-day cycle or bendamustine (B) as infusions on Days 1 and 2 and a single cycle of rituximab on Day 1 of each 28-day cycle.

Treatment:

Drug: Cyclophosphamide

Drug: Fludarabine

Drug: Rituximab

Drug: Bendamustine