Clinical trial NCT04285567: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Chronic Lymphocytic Leukemia (CLL)
Lead sponsor: Hoffmann-La Roche
Sponsor class: INDUSTRY
First posted: 2020-02-26
Enrollment: 166
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).


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.

Primary outcomes:
measure: Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS)
timeFrame: At Month 15
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Up to approximately 74 months
measure: MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit
timeFrame: VEN+G: From Cycle 1 Day 1 up to 15 months; FCR/BR: From Cycle 1 Day 1 up to 9 months (1 cycle=28 days)
measure: MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit
timeFrame: VEN+G: From Cycle 1 Day 1 up to 15 months; FCR/BR: From Cycle 1 Day 1 up to 9 months (1 cycle=28 days)
measure: Objective Response Rate (ORR)
timeFrame: At Month 15
measure: CR Rate
timeFrame: At Month 15
measure: MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit
timeFrame: At Month 15
measure: MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit
timeFrame: VEN+G: From Cycle 1 Day 1 up to 15 months; FCR/BR: From Cycle 1 Day 1 up to 9 months (1 cycle=28 days)
measure: Duration of Objective Response (DOR)
timeFrame: Up to approximately 74 months
measure: Best Overall Response (BOR)
timeFrame: At Month 15
measure: Event-free Survival (EFS)
timeFrame: Up to approximately 74 months
measure: Overall Survival (OS)
timeFrame: Up to approximately 74 months
measure: VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate
timeFrame: Baseline up to Cycle 1 Day 22 (1 cycle=28 days)
measure: VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up
timeFrame: Cycle 1 Days 22-28 up to Cycle 2 Days 1-7 (1 cycle=28 days)
measure: Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: From Day 1 until 28 days after the last dose of study drug, or until initiation of another anti-cancer therapy (up to 74 months)
measure: Number of Participants With Premature Withdrawals Due to AEs
timeFrame: From Day 1 until 28 days after the last dose of study drug, or until initiation of another anti-cancer therapy (up to 74 months)
measure: Change From Baseline in Physical Functioning, Role Functioning and Health-Related Quality of Life (HRQoL) Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30)
timeFrame: VEN + G: Day 1 of Cycle 1-12, Day 28 after treatment completion/early termination (TC/ET), follow up (FU) visits; FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to 74 months) (1 cycle=28 days)
measure: Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score
timeFrame: VEN + G: Day 1 of Cycle 1-12, Day 28 after TC/ET, FU visits; FCR/BR: Day 1 of Cycle 1-6, Day 28 after TC/ET, end of combination treatment response visit and FU visit (up to approximately 74 months) (1 cycle=28 days)
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Medical Center of Aurora
state: Colorado
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland, PA
state: Maryland
city: Knoxville
country: United States
facility: University of Tennessee Medical Center;Office of Clinical Trials
state: Tennessee
city: Roanoke
country: United States
facility: Oncology & Hematology Associates of Southwest Virginia, Inc._Goldschmidt
state: Virginia
city: Canberra
country: Australia
facility: Canberra Hospital
state: Australian Capital Territory
city: Liverpool
country: Australia
facility: Liverpool Hospital
state: New South Wales
city: Port Macquarie
country: Australia
facility: Port Macquarie - Mid North Coast Cancer Institute
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Clayton
country: Australia
facility: Monash Health;Haematology Research
state: Victoria
city: Melbourne
country: Australia
facility: Peter MacCallum Cancer Centre;Clinical Haematology
state: Victoria
city: Melbourne
country: Australia
facility: Northern Hospital;Oncology and/or Hematology
state: Victoria
city: Pessac
country: France
facility: Hopital Haut Leveque Chu de Bordeaux
state: Aquitaine
city: Tours
country: France
facility: Centre Hospitalier Régional Universitaire de Tours - Hôpital Bretonneau;Hématologie et Thérapie Cellulaire
state: Indre-et-Loire
city: Perpignan
country: France
facility: Centre Hospitalier de Pérpignan;hématologie
state: Languedoc-Roussillon
city: Lille
country: France
facility: Hopital Claude Huriez - CHU de Lille;service maladies appareil digestif
state: Nord
city: Toulon
country: France
facility: Centre Hospitalier intercommunal de Toulon La Seyne sur Mer
state: Provence-Alpes-Côte-d'Azur
city: Pierre-Bénite
country: France
facility: centre hospitalier lyon sud;Service Hématologie
state: Rhône
city: Créteil
country: France
facility: HENRI MONDOR HOSPITAL;Centre d'investigation clinique
state: Val-de-Marne
city: Caen
country: France
facility: Centre Hospitalier Universitaire de Caen Normandie
city: Le Mans
country: France
facility: Clinique Victor Hugo- CCS du Mans
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers
city: Reims
country: France
facility: Centre Hospitalier Universitaire de Reims - Hôpital Robert Debré;Hématologie Clinique
city: Modena
country: Italy
facility: Azienda Ospedaliero Universitaria;Ematologia
state: Emilia-Romagna
city: Roma
country: Italy
facility: Policlinico Umberto I
state: Lazio
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
state: Lazio
city: Genova
country: Italy
facility: Ospedale San Martino;U.O. Clinica Ematologica
state: Liguria
city: Milano
country: Italy
facility: Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico;U.O.C Ematologia
state: Lombardia
city: Milan
country: Italy
facility: ASST Grande Ospedale Metropolitano Niguarda;Ematologia
state: Lombardia
city: Novara
country: Italy
facility: Azienda Ospedaliero Universitaria Maggiore della Carità;SCDU Ematologia
state: Piemonte
city: Bari
country: Italy
facility: Instituto Tumori Giovanni Paolo II;ONCOLOGIA MEDICA
state: Puglia
city: Lecce
country: Italy
facility: Ospedale Vito Fazzi;U.O. Ematologia IV Piano Polo Oncologico
state: Puglia
city: Perugia
country: Italy
facility: AO Santa Maria della Misericordia
state: Umbria
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
state: Barcelona
city: Pamplona
country: Spain
facility: COMPLEJO HOSPITALARIO DE NAVARRA;Servicio de Hematología
state: Navarra
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebron;Hematology
city: Madrid
country: Spain
facility: Hospital Universitario La Paz;Hematología
city: Murcia
country: Spain
facility: Hospital General Universitario Morales Meseguer;Hematologia y Oncologia médica
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocío;Unidad Onco-Hematología Pediátrica
city: Toledo
country: Spain
facility: Hospital Universitario de Toledo
Study officials:
affiliation: Hoffmann-La Roche
name: Clinical trial
role: STUDY_DIRECTOR
References: