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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)

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ClinicalTrials.gov Identifier: NCT04285567
Recruitment Status : Active, not recruiting
First Posted : February 26, 2020
Last Update Posted : March 9, 2023
Sponsor:
Information provided by (Responsible Party):
Hoffmann-La Roche

Study Description
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Brief 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).

Condition or disease Intervention/treatment Phase
Chronic Lymphocytic Leukemia (CLL) Drug: Obinutuzumab Drug: Venetoclax Drug: Fludarabine Drug: Cyclophosphamide Drug: Rituximab Drug: Bendamustine Phase 3

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 165 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Prospective, Open-Label, Multicenter Randomized Phase III 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
Actual Study Start Date : May 28, 2020
Estimated Primary Completion Date : March 29, 2024
Estimated Study Completion Date : June 28, 2025

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Arms and Interventions
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Arm Intervention/treatment
Experimental: VEN + G
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.
 Drug: Obinutuzumab
Obinutuzumab 1000 mg will be administered IV on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.
Other Names:
  • Gazyva
  • RO5072759
  • GA101

Drug: Venetoclax
Venetoclax 20 mg will be administered orally, once daily starting on Day 22 of Cycle 1 for 7 days, then ramp up from 50 to 400 mg/day during Cycle 2 and continue at 400 mg/day from Day 1 of Cycle 3 till end of Cycle 12.
Other Names:
  • Venclexta
  • RO5537382
  • GDC-0199
Active Comparator: FCR/BR
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.
 Drug: Fludarabine
Fludarabine will be administered in a dosage of 25 mg/m^2 IV on days 1, 2, and 3 of Cycles 1-6.

Drug: Cyclophosphamide
Cyclophosphamide will be administered in a dosage of 250 mg/m^2 IV on Days 1, 2, and 3 Cycles 1-6.

Drug: Rituximab
Rituximab will be administered at a dose of 375 mg/m^2 IV on Cycle 1, Day 1 followed by 500 mg/m^2 on Day 1 of Cycles 2-6.

Drug: Bendamustine
Bendamustine will be administered at a dose of 90 mg/m^2 IV on 2 consecutive days of Cycles 1-6.


Outcome Measures
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Primary Outcome Measures :
  1. Minimal Residual Disease (MRD) Response Rate Using Next-generation Sequencing (NGS) in the First 140 Participants Recruited [ Time Frame: At Month 15 ]

Secondary Outcome Measures :
  1. Progression-free Survival (PFS) [ Time Frame: Every year after disease progression until end of study (up to 46 months) ]
  2. MRD Response Rate in Peripheral Blood (PB) at the End of Treatment Response Visit [ Time Frame: At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR ]
  3. MRD Response Rate in Bone Marrow (BM) at the End of Treatment Response Visit [ Time Frame: At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR ]
  4. Objective Response Rate (ORR) [ Time Frame: At Month 15 ]
  5. Complete Response (CR) Rate [ Time Frame: At Month 15 ]
  6. MRD Response Rate in PB of Participant With a CR/CR With Incomplete Blood Count (CRi) at Month 15 [ Time Frame: At Month 15 ]
  7. MRD Response Rate in the BM of Participants With a CR/CRi at the End of Treatment Visit [ Time Frame: At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR ]
  8. Duration of Objective Response (DOR) [ Time Frame: Every year after disease progression until end of study (up to 46 months) ]
  9. Best Overall Response [ Time Frame: Up to and including the assessment at Month 15 ]
  10. Event-free Survival (EFS) [ Time Frame: Every year after disease progression until end of study (up to 46 months) ]
  11. Overall Survival (OS) [ Time Frame: Every year after disease progression until end of study (up to 46 months) ]
  12. TLS Risk Reduction Rate [ Time Frame: Every year after disease progression until end of study (up to 46 months) ]
  13. Reduction in Mandatory Hospitalisations During Venetoclax Ramp-up [ Time Frame: Every year after disease progression until end of study (up to 46 months) ]
  14. Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score [ Time Frame: Arm VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 46 months) ]
    The MDASI-CLL is a questionnaire of 25 items related to CLL specific symptoms that a participant may have experienced in the past 24 hours. Participants were asked to rate the severity of 13 symptoms called mean core symptom severity (i.e., pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting, and numbness or tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fevers and chills, lymph node swelling, diarrhea, easy bruising or bleeding, and constipation) and 6 mean interference on life questions (i.e., general activity, walking, work, mood, relations with other people, and enjoyment of life) on a scale from 0 to 10 with 0 indicating that the symptom is "not present" or "did not interfere" with the participant's activities and 10 indicating "as bad as you can imagine" or "interfered completely".

  15. Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30) [ Time Frame: Arm VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; Arm FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 46 months) ]
    The EORTC QLQ-C30 is a validated and reliable self-report measure consisting of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional, and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), and a global health status/global quality-of-life scale. The remaining single items (dyspnea, appetite loss, sleep disturbance, constipation, and diarrhea) assess the additional symptoms experienced by patients with cancer and the perceived financial burden of treatment. The 28 function and symptom items were scored on a 4-point scale that ranged from "not at all" to "very much," and the 2 global health status/global quality-of-life items were scored on a 7-point scale that ranged from "very poor" to "excellent." Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e., higher functioning, higher symptom severity).

  16. Number of Participants With Adverse Events (AEs) [ Time Frame: Up to 28 days after last dose of study drug or until initiation of another anti-cancer therapy (up to 46 months) ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04285567


Locations
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Sponsors and Collaborators
Hoffmann-La Roche
Investigators
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Study Director: Clinical trial Hoffmann-La Roche
More Information
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Responsible Party: Hoffmann-La Roche
ClinicalTrials.gov Identifier: NCT04285567    
Other Study ID Numbers: CO41685
2019-003327-37 ( EudraCT Number )
First Posted: February 26, 2020    Key Record Dates
Last Update Posted: March 9, 2023
Last Verified: March 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description:

Qualified researchers may request access to individual patient level data through the request platform (www.vivli.org). Further details on Roche's criteria for eligible studies are available here (https://vivli.org/ourmember/roche/).

For further details on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents, see here (https://www.roche.com/innovation/process/clinical-trials/data-sharing).

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Lymphoid
Leukemia, Lymphocytic, Chronic, B-Cell
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Leukemia, B-Cell
Cyclophosphamide
Bendamustine Hydrochloride
Rituximab
 Fludarabine
Venetoclax
Obinutuzumab
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological