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

Chronic Lymphocytic Leukemia (CLL) Clinical Trial

— CRISTALLO  

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 Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04285567
• Other study ID #: CO41685
• Secondary ID: 2019-003327-3720
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: May 28, 2020
• Est. completion date: July 31, 2026

Study information

• Verified date: March 2024
• Source: Hoffmann-La Roche
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 166
• Est. completion date: July 31, 2026
• Est. primary completion date: March 19, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia (CLL)
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Obinutuzumab
Obinutuzumab 1000 milligrams (mg) will be administered IV on Days 1 (and 2), 8, and 15 of Cycle 1 and on Day 1 of Cycles 2-6.
• 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.
• Fludarabine
Fludarabine will be administered in a dosage of 25 milligram per meter squared (mg/m^2), IV, on days 1, 2, and 3 of Cycles 1-6.
• Cyclophosphamide
Cyclophosphamide will be administered in a dosage of 250 mg/m^2, IV, on Days 1, 2, and 3 Cycles 1-6.
• 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.
• Bendamustine
Bendamustine will be administered at a dose of 90 mg/m^2, IV, on 2 consecutive days of Cycles 1-6.

Locations

Country	Name	City	State
Australia	Canberra Hospital; Haematology Department	Canberra	Australian Capital Territory
Australia	The Northern Hospital	Epping	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Liverpool Hospital; Haematology	Liverpool	New South Wales
Australia	Monash Medical Centre; Haematology	Melbourne	Victoria
Australia	Peter MacCallum Cancer Centre; Department of Haematology	Melbourne	Victoria
Australia	Port Macquarie Base Hospital	Port Macquarie	New South Wales
Australia	Royal North Shore Hospital; Haematology Department	St. Leonards	New South Wales
France	CHU de Caen, Institut d'Hématologie de Basse-Normandie	Caen
France	Hopital Henri Mondor; Hematologie Clinique	Creteil
France	Clinique Victor Hugo- CCS du Mans	Le Mans
France	CHRU Lille - Hôpital Claude Huriez; Service des Maladies du Sang	Lille
France	Hopital Saint Jean : Pole Santé du Rousillon; Unité de Recherche clinique	Perpignan
France	Hopital De Haut Leveque; Hematologie Clinique	Pessac
France	Ch Lyon Sud; Hemato Secteur Jules Courmont	Pierre Benite
France	Hopital De La Miletrie; Hematologie Et Oncologie Medicale	Poitiers
France	Hopital Robert Debre; Hematologie Clinique	Reims
France	CHI de Toulon - Hôpital Sainte Musse	Toulon
France	Hopital Bretonneau; Hematologie Therapie Cellulaire	TOURS Cedex
Italy	Irccs Ist. Tumori Giovanni Paolo Ii; Dipartimento Oncologia Medica	Bari	Puglia
Italy	A.O. Universitaria S. Martino Di Genova; Ematologia 1	Genova	Liguria
Italy	Asl Le-Ospedale "Vito Fazzi";U.O. Ematologia	Lecce	Puglia
Italy	ASST GRANDE OSPEDALE METROPOLITANO NIGUARDA; Struttura Complessa di Ematologia	Milano	Lombardia
Italy	Ospedale Maggiore Di Milano; U.O. Ematologia I - Padiglione Marcora	Milano	Lombardia
Italy	Azienda Ospedaliero-Universitaria Policlinico di Modena Ematologia	Modena	Emilia-Romagna
Italy	SCDU Ematologia	Novara	Piemonte
Italy	Uni Cattolica; Divisione Di Ematologia	Roma	Lazio
Italy	Universita' Degli Studi La Sapienza-Ist.Di Ematologia; Dip Biot Cel e Ematol	Roma	Lazio
Italy	Azienda Ospedaliera Di Perugia Ospedale s. Maria Della Misericordia; Oncologia Medica	Sant'Andrea Delle Fratte (PG)	Umbria
Spain	Hospital Universitari Germans Trias i Pujol; Servicio de Hematologia	Badalona	Barcelona
Spain	Hospital Universitario de Canarias;servicio de Hematologia	La Laguna	Tenerife
Spain	Hospital Universitario la Paz; Servicio de Hematologia	Madrid
Spain	Hospital General Universitario J.M Morales Meseguer; Servicio de Hematología	Murcia
Spain	Hospital de Navarra, Servicio de Hematología	Pamplona	Navarra
Spain	Hospital Universitario Virgen del Rocio; Servicio de Hematologia	Sevilla
Spain	Hospital Universitario de Toledo	Toledo
United States	Texas Oncology West	Amarillo	Texas
United States	Medical Center of Aurora; Rocky Mountain Cancer Centers	Aurora	Colorado
United States	Southwest Regional Cancer Center	Austin	Texas
United States	Center For Cancer and Blood Disorders	Bethesda	Maryland
United States	St. Vincent Frontier Cancer Center	Billings	Montana
United States	Maryland Oncology Hematology, P.A.	Columbia	Maryland
United States	Texas Oncology-Denton South	Denton	Texas
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	South Texas Cancer Center - McAllen	McAllen	Texas
United States	Community Cancer Trials of Utah	Ogden	Utah
United States	Oncology & Hematolgy Associates of SW Va Inc. - Roanoke	Roanoke	Virginia
United States	Texas Oncology- Northeast Texas	Tyler	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Hoffmann-La Roche

Countries where clinical trial is conducted

United States,  Australia,  France,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Minimal Residual Disease (MRD) Response Rate Using Next-generation Sequencing (NGS)		At Month 15
Secondary	Progression-free Survival (PFS)		From randomization up to the first occurrence of disease progression (PD), or death from any cause (up to 74 months)
Secondary	MRD Response Rate in Peripheral Blood (PB) at the End of Treatment Response Visit		At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary	MRD Response Rate in Bone Marrow (BM) at the End of Treatment Response Visit		At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary	Objective Response Rate (ORR)		At Month 15
Secondary	Complete Response (CR) Rate		At Month 15
Secondary	MRD Response Rate in PB of Participant With a CR/CR With Incomplete Blood Count (CRi) at Month 15		At Month 15
Secondary	MRD Response Rate in the BM of Participants With a CR/CRi at the End of Treatment Visit		At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary	Duration of Objective Response (DOR)		From time of first response until PD, or death from any cause (up to 74 months)
Secondary	Best Overall Response		Up to and including the assessment at Month 15
Secondary	Event-free Survival (EFS)		From randomization up to PD /relapse, death, or start of a new anti-leukemic therapy (up to 74 months)
Secondary	Overall Survival (OS)		From randomization up to death due to any cause (up to 74 months)
Secondary	Arm VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate		At screening and Cycle 1 Day 22 (cycle length= 28 days)
Secondary	Arm VEN + G: Reduction in Mandatory Hospitalisations During Venetoclax Ramp-up		On Cycle 1 Day 22 (cycle length= 28 days)
Secondary	Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score	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".	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 74 months)
Secondary	Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30)	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).	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 74 months)
Secondary	Number of Participants With Adverse Events (AEs)		Up to 28 days after last dose of study drug or until initiation of another anti-cancer therapy (up to 74 months)