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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04285567




Registration number
NCT04285567
Ethics application status
Date submitted
25/02/2020
Date registered
26/02/2020

Titles & IDs
Public 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
Scientific 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
Secondary ID [1] 0 0
2019-003327-37
Secondary ID [2] 0 0
CO41685
Universal Trial Number (UTN)
Trial acronym
CRISTALLO
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia (CLL) 0 0
Condition category
Condition code
Cancer 0 0 0 0
Leukaemia - Acute leukaemia
Cancer 0 0 0 0
Leukaemia - Chronic leukaemia
Cancer 0 0 0 0
Children's - Leukaemia & Lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Obinutuzumab
Treatment: Drugs - Venetoclax
Treatment: Drugs - Fludarabine
Treatment: Drugs - Cyclophosphamide
Treatment: Drugs - Rituximab
Treatment: Drugs - Bendamustine

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.

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.


Treatment: Drugs: 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.

Treatment: Drugs: 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.

Treatment: Drugs: 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.

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

Treatment: Drugs: 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.

Treatment: Drugs: Bendamustine
Bendamustine will be administered at a dose of 90 mg/m\^2, IV, on 2 consecutive days of Cycles 1-6.
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Minimal Residual Disease (MRD) Response Rate Using Next-generation Sequencing (NGS)
Timepoint [1] 0 0
At Month 15
Secondary outcome [1] 0 0
Progression-free Survival (PFS)
Timepoint [1] 0 0
From randomization up to the first occurrence of disease progression (PD), or death from any cause (up to 74 months)
Secondary outcome [2] 0 0
MRD Response Rate in Peripheral Blood (PB) at the End of Treatment Response Visit
Timepoint [2] 0 0
At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary outcome [3] 0 0
MRD Response Rate in Bone Marrow (BM) at the End of Treatment Response Visit
Timepoint [3] 0 0
At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary outcome [4] 0 0
Objective Response Rate (ORR)
Timepoint [4] 0 0
At Month 15
Secondary outcome [5] 0 0
Complete Response (CR) Rate
Timepoint [5] 0 0
At Month 15
Secondary outcome [6] 0 0
MRD Response Rate in PB of Participant With a CR/CR With Incomplete Blood Count (CRi) at Month 15
Timepoint [6] 0 0
At Month 15
Secondary outcome [7] 0 0
MRD Response Rate in the BM of Participants With a CR/CRi at the End of Treatment Visit
Timepoint [7] 0 0
At end of treatment response visit (up to approximately 15 months in Arm VEN + G and 9 months in Arm FCR/BR
Secondary outcome [8] 0 0
Duration of Objective Response (DOR)
Timepoint [8] 0 0
From time of first response until PD, or death from any cause (up to 74 months)
Secondary outcome [9] 0 0
Best Overall Response
Timepoint [9] 0 0
Up to and including the assessment at Month 15
Secondary outcome [10] 0 0
Event-free Survival (EFS)
Timepoint [10] 0 0
From randomization up to PD /relapse, death, or start of a new anti-leukemic therapy (up to 74 months)
Secondary outcome [11] 0 0
Overall Survival (OS)
Timepoint [11] 0 0
From randomization up to death due to any cause (up to 74 months)
Secondary outcome [12] 0 0
Arm VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate
Timepoint [12] 0 0
At screening and Cycle 1 Day 22 (cycle length= 28 days)
Secondary outcome [13] 0 0
Arm VEN + G: Reduction in Mandatory Hospitalisations During Venetoclax Ramp-up
Timepoint [13] 0 0
On Cycle 1 Day 22 (cycle length= 28 days)
Secondary outcome [14] 0 0
Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score
Timepoint [14] 0 0
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 outcome [15] 0 0
Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30)
Timepoint [15] 0 0
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 outcome [16] 0 0
Number of Participants With Adverse Events (AEs)
Timepoint [16] 0 0
Up to 28 days after last dose of study drug or until initiation of another anti-cancer therapy (up to 74 months)

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
28/05/2020
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/07/2026
Actual
Sample size
Target
Accrual to date
Final
166
Recruitment in Australia
Recruitment state(s)
ACT,NSW,TAS,VIC
Recruitment hospital [1] 0 0
Canberra Hospital; Haematology Department - Canberra
Recruitment hospital [2] 0 0
Liverpool Hospital; Haematology - Liverpool
Recruitment hospital [3] 0 0
Port Macquarie Base Hospital - Port Macquarie
Recruitment hospital [4] 0 0
Royal North Shore Hospital; Haematology Department - St. Leonards
Recruitment hospital [5] 0 0
Royal Hobart Hospital - Hobart
Recruitment hospital [6] 0 0
The Northern Hospital - Epping
Recruitment hospital [7] 0 0
Peter MacCallum Cancer Centre; Department of Haematology - Melbourne
Recruitment hospital [8] 0 0
Monash Medical Centre; Haematology - Melbourne
Recruitment postcode(s) [1] 0 0
2605 - Canberra
Recruitment postcode(s) [2] 0 0
2170 - Liverpool
Recruitment postcode(s) [3] 0 0
2444 - Port Macquarie
Recruitment postcode(s) [4] 0 0
2065 - St. Leonards
Recruitment postcode(s) [5] 0 0
7000 - Hobart
Recruitment postcode(s) [6] 0 0
VIC 3076 - Epping
Recruitment postcode(s) [7] 0 0
3002 - Melbourne
Recruitment postcode(s) [8] 0 0
3168 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Maryland
Country [3] 0 0
United States of America
State/province [3] 0 0
Montana
Country [4] 0 0
United States of America
State/province [4] 0 0
Tennessee
Country [5] 0 0
United States of America
State/province [5] 0 0
Texas
Country [6] 0 0
United States of America
State/province [6] 0 0
Utah
Country [7] 0 0
United States of America
State/province [7] 0 0
Virginia
Country [8] 0 0
France
State/province [8] 0 0
Caen
Country [9] 0 0
France
State/province [9] 0 0
Creteil
Country [10] 0 0
France
State/province [10] 0 0
Le Mans
Country [11] 0 0
France
State/province [11] 0 0
Lille
Country [12] 0 0
France
State/province [12] 0 0
Perpignan
Country [13] 0 0
France
State/province [13] 0 0
Pessac
Country [14] 0 0
France
State/province [14] 0 0
Pierre Benite
Country [15] 0 0
France
State/province [15] 0 0
Poitiers
Country [16] 0 0
France
State/province [16] 0 0
Reims
Country [17] 0 0
France
State/province [17] 0 0
Toulon
Country [18] 0 0
France
State/province [18] 0 0
TOURS Cedex
Country [19] 0 0
Italy
State/province [19] 0 0
Emilia-Romagna
Country [20] 0 0
Italy
State/province [20] 0 0
Lazio
Country [21] 0 0
Italy
State/province [21] 0 0
Liguria
Country [22] 0 0
Italy
State/province [22] 0 0
Lombardia
Country [23] 0 0
Italy
State/province [23] 0 0
Piemonte
Country [24] 0 0
Italy
State/province [24] 0 0
Puglia
Country [25] 0 0
Italy
State/province [25] 0 0
Umbria
Country [26] 0 0
Spain
State/province [26] 0 0
Barcelona
Country [27] 0 0
Spain
State/province [27] 0 0
Navarra
Country [28] 0 0
Spain
State/province [28] 0 0
Tenerife
Country [29] 0 0
Spain
State/province [29] 0 0
Madrid
Country [30] 0 0
Spain
State/province [30] 0 0
Murcia
Country [31] 0 0
Spain
State/province [31] 0 0
Sevilla
Country [32] 0 0
Spain
State/province [32] 0 0
Toledo

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Hoffmann-La Roche
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Clinical trial
Address 0 0
Hoffmann-La Roche
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
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).
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT04285567