Clinical Trials /

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

NCT04285567

Description:

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).

Related Conditions:
  • Chronic Lymphocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • 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

Clinical Trial IDs

  • ORG STUDY ID: CO41685
  • SECONDARY ID: 2019-003327-37
  • NCT ID: NCT04285567

Conditions

  • Chronic Lymphocytic Leukemia (CLL)

Interventions

DrugSynonymsArms
ObinutuzumabGazyva, RO5072759, GA101VEN + G
VenetoclaxVenclexta, RO5537382, GDC-0199VEN + G
FludarabineFCR/BR
CyclophosphamideFCR/BR
RituximabFCR/BR
BendamustineFCR/BR

Purpose

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).

Trial Arms

NameTypeDescriptionInterventions
VEN + GExperimentalParticipants 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.
  • Obinutuzumab
  • Venetoclax
FCR/BRActive ComparatorParticipants 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.
  • Fludarabine
  • Cyclophosphamide
  • Rituximab
  • Bendamustine

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)

          -  Known central nervous system involvement

          -  Participants with a history of confirmed progressive multifocal leukoencephalopathy
             (PML)

          -  Detected del (17p) or TP53 mutation

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Minimal Residual Disease (MRD) Response Rate in the First 140 Participants Recruited
Time Frame:At Month 15
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression-free Survival (PFS)
Time Frame:Every year after disease progression until end of study (up to 46 months)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Objective Response Rate (ORR)
Time Frame:At Month 15
Safety Issue:
Description:
Measure:Complete Response (CR) Rate
Time Frame:At Month 15
Safety Issue:
Description:
Measure:MRD Response Rate in PB of Participant With a CR/CR With Incomplete Blood Count (CRi) at Month 15
Time Frame:At Month 15
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Duration of Objective Response (DOR)
Time Frame:Every year after disease progression until end of study (up to 46 months)
Safety Issue:
Description:
Measure:Best Overall Response
Time Frame:Up to and including the assessment at Month 15
Safety Issue:
Description:
Measure:Event-free Survival (EFS)
Time Frame:Every year after disease progression until end of study (up to 46 months)
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:Every year after disease progression until end of study (up to 46 months)
Safety Issue:
Description:
Measure: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)
Safety Issue:
Description: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".
Measure: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)
Safety Issue:
Description: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).
Measure: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)
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hoffmann-La Roche

Last Updated

March 25, 2020