Chronic Lymphocytic Leukemia (CLL)
Conditions
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).
Interventions
DRUGObinutuzumab
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.
DRUGVenetoclax
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.
DRUGFludarabine
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.
DRUGCyclophosphamide
Cyclophosphamide will be administered in a dosage of 250 mg/m\^2, IV, on Days 1, 2, and 3 Cycles 1-6.
DRUGRituximab
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.
DRUGBendamustine
Bendamustine will be administered at a dose of 90 mg/m\^2, IV, on 2 consecutive days of Cycles 1-6.
Sponsors
Hoffmann-La Roche
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS) | At Month 15 | MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Up to approximately 56.4 months | PFS was defined as the time from randomization to the first occurrence of disease progression (PD), or death from any cause. PD was assessed by the investigators using the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. PD was defined as any one of the following: Appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 centimeters \[cm\]); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/litres (L) B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; post treatment: progression of any cytopenia, documented by a decrease of hemoglobin (Hb) ≥ 2 grams per deciliter (g/dL) or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment. Kaplan-Meier (K-M) method was used to determine PFS. |
| MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit | 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) | MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point. |
| Event-free Survival (EFS) | Up to approximately 56.4 months | EFS was defined as the time between the date of randomization and the date of PD/relapse, death, or the start of a new anti-leukemic therapy. PD was defined as any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment. K-M method was used to determine EFS. |
| MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit | 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) | MRD response rate=percentage of participants with MRD-negativity measured in BM using NGS (cutoff of \<10\^-4). MRD negativity=\<1 CLL cell in 10,000 leukocytes. MRD in BM was assessed for participants with complete response (CR)/CR with incomplete blood count recovery (CRi) \& partial response (PR). CR=PB lymphocytes \<4x10\^9 /L; Absence of significant lymphadenopathy (nodes \<1.5 cm in longest diameter); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi=fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR= ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy (sum of longest diameter of up to 6 largest lymph nodes by physical exam \& 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline. |
| Objective Response Rate (ORR) | At Month 15 | ORR was defined as the percentage of participants with overall response (OR) of CR, CRi, and PR as determined by the investigator according to the iwCLL guidelines. CR was defined as PB lymphocytes \<4x10\^9 /L; absence of significant lymphadenopathy (nodes \<1.5 cm in longest diameter \[LD\]); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR was defined as ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy sum of longest diameter of up to 6 largest lymph nodes by physical exam and 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline. |
| CR Rate | At Month 15 | CR rate was defined as the percentage of participants with CR or CRi. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes (evaluated by blood and differential count) below 4 x 10\^9 /L; absence of significant lymphadenopathy (nodes \< 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point. |
| MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit | At Month 15 | MRD response rate was determined as the percentage of participants (with a CR/CRi) with MRD-negativity measured in the PB using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10\^9 /L; absence of significant lymphadenopathy (nodes \< 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point. |
| MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit | 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) | MRD response rate was determined as the percentage of participants (with CR/CRi) with MRD-negativity measured in the BM using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10\^9 /L; absence of significant lymphadenopathy (nodes \< 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria with CR but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point. |
| Duration of Objective Response (DOR) | Up to approximately 56.4 months | DOR=time from first occurrence of a documented objective response (CR, CRi \& PR) to the time of PD as determined by the investigator, or death from any cause, whichever occurred first. CR, CRi, PR, \& PD were defined per the iwCLL guidelines. PD = any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment. CR, CRi \& PR were defined as outlined in the description for ORR outcome measure. K-M method was used to determine DOR. |
| Best Overall Response (BOR) | At Month 15 | BOR=percentage of participants with CR/CRi/PR/stable disease (SD)/PD per the investigator. Participants with best response as CR/CRi/PR were considered responders while those reaching SD/PD were non-responders. SD=participants who have not achieved a CR or a PR, or who have not exhibited PD. PD=any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment. CR, CRi and PR were defined as outlined in the description for ORR, OM number 5. |
| Overall Survival (OS) | Up to approximately 56.4 months | OS was defined as the time between the date of randomization and the date of death due to any cause. K-M method was used to determine OS. |
| VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate | Baseline up to Cycle 1 Day 22 (1 cycle=28 days) | TLS risk reduction rate in the VEN + G arm was defined as the reduction in the percentage of participants who were TLS high-risk after 3 doses of obinutuzumab compared to the percentage of participants who were TLS high-risk at baseline. Risk for developing TLS were categorised into: Low - All measurable lymph nodes with the LD \< 5 cm and \< 25x10\^9/L absolute lymphocyte count (ALC); Medium - Any measurable lymph node with the LD ≥5 cm but \<10 cm OR ≥25x10\^9/L ALC; High - Any measurable lymph node with the LD ≥10 cm or the presence of both ≥25x10\^9/L ALC and any measurable lymph node with the LD ≥5 cm but \<10 cm. Percentages have been rounded off to the nearest decimal point. |
| VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up | Cycle 1 Days 22-28 up to Cycle 2 Days 1-7 (1 cycle=28 days) | Reduction in mandatory hospitalizations during venetoclax ramp-up in the VEN + G arm participants was defined as the actual number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up period after 3 doses of obinutuzumab compared to the number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up expected at baseline. Ramp-up period for venetoclax was defined as period from Cycle 1, Days 22-28, and Cycle 2, Day 1-Day 7 where the 20 mg and 50 mg daily doses of venetoclax, were administered for participants at TLS-high risk requiring mandated hospitalizations (the hospitalizations at 100, 200 and 400 was only needed if the participant had a TLS event at one of the lower doses). Total number of hospitalizations in high-risk TLS participants at baseline (expected to be N=2 hospitalization) was compared with the number of protocol mandated hospitalizations during the first 2 doses of the ramp-up. |
| Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) | Up to approximately 56.4 months | An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE that meets any of the following criteria: is fatal; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; is a significant medical event in the investigator's judgment. |
| Number of Participants With Premature Withdrawals Due to AEs | Up to approximately 56.4 months | An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Participants who withdrew from the study due to AEs are being reported here. |
| Change From Baseline in Physical Functioning Assessed Using European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQC-30) | Baseline, Day 22 of Cycle 1; Days 1, 2, 3 & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; Follow-up (FU) at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days) | The EORTC QLQ-C30 consists of 30 questions incorporated into 5 functional scales (physical, role, cognitive, emotional and social scales), 3 symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global quality-of-life (GHS/QoL) scale, and 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning items were scored on a 4-point scale (1=Not at All to 4=Very Much). Raw average scale scores were linearly transformed to range from 0-100. Higher scores=higher response levels (i.e. higher functioning). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint. Time frame continued: Day 28 After Completion/Early Termination (ET) of Combination Therapy (VEN+G)/Day 28 After Treatment Completion (TC)/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months. |
| Change From Baseline in Role Functioning Assessed Using EORTC QLQC-30 | Baseline, Day 22 of Cycle 1; Days 1, 2, 3 & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days) | The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a GHS/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The functioning items were scored on a 4-point scale (1=Not at All to 4=Very Much). Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e. higher functioning). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a given timepoint. Time frame continued: Day 28 After Completion/ ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months. |
| Change From Baseline in GHS/QoL Assessed Using EORTC QLQC-30 | Baseline, Day 22 of Cycle 1; Days 1, 2, 3 & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days) | The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a GHS/QoL scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The 2 GHS/QoL items were scored on a 7-point scale (1= Very poor to 7=Excellent). Raw average scale scores were linearly transformed to range 0-100 with higher scores indicating higher response levels (i.e. better QoL). FAS. Overall number analyzed=participants with data available for analysis. Number analyzed is the number of participants with data available for analysis at a given timepoint. Time frame continued (TFC): Day 28 After Completion/ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approximately (approx) 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months. |
| Change From Baseline in Mean Core Symptom Severity Score as Measured by the M.D. Anderson Symptom Inventory (MDASI-CLL) | Baseline, Day 22 of Cycle 1; Days 1, 2, & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days) | MDASI-CLL=25 items over 3 scales assessing core cancer \& CLL-related symptom severity \&symptom interference that a participant may have experienced in past 24 hours. Participants rated severity of 13 symptoms called mean core symptom severity (pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting \& numbness/tingling) to assess mean core symptom severity score. Each symptom is scored from 0 (not present)-10 (as bad as you can imagine). Total score across all questions(0-130) was divided by number of questions. Mean score, ranged from 0-10. Lower scores=lower symptom severity. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint. TFC: Day 28 After Completion/ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approx 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approx11 months. |
| Change From Baseline in Mean Module Symptom Severity Score as Measured by MDASI-CLL | Baseline, Day 22 of Cycle 1; Days 1, 2, & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days) | MDASI-CLL=25 items over 3 scales that assess core cancer \& CLL-related symptom severity, as well as symptom interference a participant may have experienced in past 24 hours. Participants were asked to rate the severity of 6 disease-specific symptoms called mean module symptom severity (night sweats, fever \& chills, lymph node swelling, diarrhea, easy bruising/bleeding \& constipation). Each symptom is scored on scale from 0-10, where 0=not present \& 10=as bad as you can imagine. The total score across all questions (0 to 60) was divided by the number of questions. The mean score, therefore, ranged from 0-10. Higher scores indicated more symptom severity. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed includes all with data at a given timepoint. Time frame continued: Day 28 After Completion/ET of VEN+G/Day 28 After TC/ET (FCR/BR)=Up to approximately 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approximately 11 months. |
| Change From Baseline in Mean Interference Score as Measured by MDASI-CLL | Baseline, Day 22 of Cycle 1; Days 1, 2, & 22 of Cycle 2; Days 1 & 2 of Cycles 3, 4, 5; Day 1 of Cycles 6, 7, 8, 9, 10, 11 & 12; FU at Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36 (1 cycle = 28 days) | MDASI-CLL consists of 25 items over 3 scales that assess core cancer \& CLL-related symptom severity, and symptom interference that a participant may have experienced in past 24 hours. Participants rated 6 mean interference on life questions (general activity, walking, work, mood, relations with other people \& enjoyment of life) to derive the Mean Interference Score. These were scored on a scale from 0 (symptom did not interfere)-10 (symptom interfered completely). Total score across all questions (0 to 60) was divided by number of questions. Mean score, therefore, ranged from 0-10. Higher scores=higher symptom interference. FAS. Overall number analyzed=participants with data available for analysis. Number analyzed=participants with data available for analysis at a given timepoint. Time frame continued: Day 28 After Completion/ ET of Combination Therapy (VEN+G)/Day 28 After TC/ET (FCR/BR)=Up to approx 5.6 months; Change at Day 28 After TC/EC of Ven Monotherapy=Up to approx 11 months. |
Countries
Australia, France, Italy, Spain, United States
Contacts
STUDY_DIRECTORClinical trial
Hoffmann-La Roche
Participant flow
Recruitment details
A total of 166 participants with previously untreated chronic lymphocytic leukemia (CLL) without del (17p) or tumor protein p53 (TP53) mutation took part in the study at 38 investigative sites in France, Italy, Australia, Spain, and the United States from 28 May 2020 to 19 March 2025. The study is considered "Completed" because all the pre-planned study activities and analyses have been performed.
Pre-assignment details
Participants were randomized in a 1:1 ratio to receive either venetoclax + obinutuzumab (VEN+G) or fludarabine, cyclophosphamide, and rituximab/bendamustine and rituximab (FCR/BR). All participants in FCR/BR arm were eligible for treatment with BR, whereas only participants ≤ 65 years were eligible for FCR. The choice between FCR or BR was at the investigator's discretion.
Participants by arm
| Arm | Count |
|---|---|
| Arm A: VEN+G Participants received obinutuzumab, 1000 mg, as IV infusion on Days 1 (and 2), 8, and 15 of Cycle 1 and Day 1 of Cycles 2-6. Participants also received venetoclax, with a 5-week ramp-up period (20 mg \[Cycle 1 Days 22-28\], 50 mg \[Cycle 2 Days 1-7\], 100 mg \[Cycle 2 Days 8-14\], 200 mg \[Cycle 2 Days 15-21\], 400 mg \[Cycle 2 Days 22-28\]) administered orally, QD. After the 5-week ramp-up period, participants received venetoclax, 400 mg, orally, QD from Cycle 3 Day 1 until the end of Cycle 12. (1 cycle = 28 days). | 80 |
| Arm B: FCR/BR Participants received rituximab (375 mg/m\^2 in Cycle 1 and 500 mg/m\^2 in Cycles 2-6), on Day 1 of each cycle, plus fludarabine 25 mg/m\^2 and cyclophosphamide 250 mg/m\^2 on Days 1, 2, and 3 of each cycle as IV infusion up to Cycle 6. Participants alternatively received bendamustine 90 mg/m\^2 on Days 1 and 2 of Cycles 1-6 plus rituximab 375 mg/m\^2 on Day 1 of Cycle 1 and 500 mg/m\^2 on Day 1 of Cycles 2-6. (1 cycle = 28 days). | 86 |
| Total | 166 |
Baseline characteristics
| Characteristic | Arm B: FCR/BR | Total | Arm A: VEN+G |
|---|---|---|---|
| Age, Continuous | 61.0 years STANDARD_DEVIATION 8.6 | 61.2 years STANDARD_DEVIATION 8.8 | 61.5 years STANDARD_DEVIATION 9.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 10 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 112 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 19 Participants | 44 Participants | 25 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 31 Participants | 20 Participants |
| Race (NIH/OMB) White | 73 Participants | 131 Participants | 58 Participants |
| Sex: Female, Male Female | 29 Participants | 54 Participants | 25 Participants |
| Sex: Female, Male Male | 57 Participants | 112 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 80 | 3 / 86 |
| other Total, other adverse events | 76 / 77 | 81 / 85 |
| serious Total, serious adverse events | 46 / 77 | 42 / 85 |
Outcome results
Primary
Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS)
MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point.
Time frame: At Month 15
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS) | 81.3 percentage of participants |
| Arm B: FCR/BR | Minimal Residual Disease (MRD) Response Rate Measured in Peripheral Blood (PB) Using Next Generation Sequencing (NGS) | 54.7 percentage of participants |
Comparison: P-value estimated using Cochran-Mantel-Haenszel (CMH) test stratified by the IvRS randomization stratification factors.p-value: 0.000495% CI: [12.33, 40.87]Cochran-Mantel-Haenszel
Secondary
Best Overall Response (BOR)
BOR=percentage of participants with CR/CRi/PR/stable disease (SD)/PD per the investigator. Participants with best response as CR/CRi/PR were considered responders while those reaching SD/PD were non-responders. SD=participants who have not achieved a CR or a PR, or who have not exhibited PD. PD=any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment. CR, CRi and PR were defined as outlined in the description for ORR, OM number 5.
Time frame: At Month 15
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | Best Overall Response (BOR) | 93.8 percentage of participants |
| Arm B: FCR/BR | Best Overall Response (BOR) | 90.7 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: 0.419995% CI: [-5.73, 11.84]Cochran-Mantel-Haenszel
Secondary
Change From Baseline in M.D. Anderson Symptom Inventory-CLL (MDASI-CLL) Score
MDASI-CLL consists of 25 items over 3 scales that assess core cancer & CLL-related symptom severity, as well as symptom interference that a participant may have experienced in past 24 hours. Participants were asked to rate severity of 13 symptoms called mean core symptom severity (pain, fatigue, nausea, disturbed sleep, distressed, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sadness, vomiting & numbness/tingling), 6 disease-specific symptoms called mean module symptom severity (night sweats, fever & chills, lymph node swelling, diarrhea, easy bruising/bleeding & constipation) & 6 mean interference on life questions (general activity, walking, work, mood, relations with other people & enjoyment of life) on a scale from 0-10 with 0 indicating that symptom is not present or did not interfere with participant's activities & 10 indicating as bad as you can imagine or interfered completely. Lower scores indicated lower symptom severity/interference.
Time frame: 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)
Secondary
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)
The EORTC QLQ-C30 consists of 30 questions incorporated into five functional scales (physical, role, cognitive, emotional and social scales), three symptom scales (fatigue, pain, nausea, and vomiting scales), a global health status/global quality-of-life (GHS/QoL) scale, and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). 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 GHS/QoL 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).
Time frame: 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)
Secondary
CR Rate
CR rate was defined as the percentage of participants with CR or CRi. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes (evaluated by blood and differential count) below 4 x 10\^9 /L; absence of significant lymphadenopathy (nodes \< 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.
Time frame: At Month 15
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | CR Rate | 50.0 percentage of participants |
| Arm B: FCR/BR | CR Rate | 32.6 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: 0.015495% CI: [1.96, 32.93]Cochran-Mantel-Haenszel
Secondary
Duration of Objective Response (DOR)
DOR was defined as the time from the first occurrence of a documented OR (CR, CRi and PR) to the time of PD as determined by the investigator, or death from any cause, whichever occurs first. CR, CRi, PR, and PD were defined according to the iwCLL guidelines. PD was defined as any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment. CR, CRi and PR were defined as outlined in the description for ORR outcome measure (OM) number 5.
Time frame: Up to approximately 74 months
Secondary
Event-free Survival (EFS)
EFS was defined as the time between the date of randomization and the date of PD/relapse, death, or the start of a new anti-leukemic therapy. PD was defined as any one of the following: appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 cm); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/L B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of Hb ≥ 2 g/dL or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment.
Time frame: Up to approximately 74 months
Secondary
MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit
MRD response rate was determined as the percentage of participants (with CR/CRi) with MRD-negativity measured in the BM using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10\^9 /L; absence of significant lymphadenopathy (nodes \< 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria with CR but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.
Time frame: 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)
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized. Overall number analyzed is the number of participants with CR/CRi.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit | 87.5 percentage of participants |
| Arm B: FCR/BR | MRD Response Rate in BM of Participants With a CR/CRi at the End of Treatment Visit | 60.7 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: 0.003895% CI: [3.86, 49.72]Cochran-Mantel-Haenszel
Secondary
MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit
MRD response rate=percentage of participants with MRD-negativity measured in BM using NGS (cutoff of \<10\^-4). MRD negativity=\<1 CLL cell in 10,000 leukocytes. MRD in BM was assessed for participants with complete response (CR)/CR with incomplete blood count recovery (CRi) & partial response (PR). CR=PB lymphocytes \<4x10\^9 /L; Absence of significant lymphadenopathy (nodes \<1.5 cm in longest diameter); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi=fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR= ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy (sum of longest diameter of up to 6 largest lymph nodes by physical exam & 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline.
Time frame: 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)
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized. Percentages have been rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit | 70.0 percentage of participants |
| Arm B: FCR/BR | MRD Response Rate in Bone Marrow (BM) of FCR/BR Compared With VEN+G at the End of Treatment Response Visit | 38.4 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: <0.000195% CI: [16.55, 46.71]Cochran-Mantel-Haenszel
Secondary
MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit
MRD response rate was determined as the percentage of participants with MRD-negativity measured in the PB using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. Percentages have been rounded off to the nearest decimal point.
Time frame: 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)
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit | 81.3 percentage of participants |
| Arm B: FCR/BR | MRD Response Rate in PB of FCR/BR Compared With VEN+G at the End of Treatment Response Visit | 60.5 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: 0.005395% CI: [6.66, 34.9]Cochran-Mantel-Haenszel
Secondary
MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit
MRD response rate was determined as the percentage of participants (with a CR/CRi) with MRD-negativity measured in the PB using NGS using a cutoff of \< 10\^-4. MRD was considered negative if the result was \< 1 CLL cell in 10,000 leukocytes. CR/CRi were defined according to the iwCLL guidelines. CR was defined as one of the following: PB lymphocytes below 4 x 10\^9 /L; absence of significant lymphadenopathy (nodes \< 1.5 cm in LD or any extra nodal disease); no hepatomegaly; no splenomegaly; absence of disease or constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as participants fulfilling CR criteria but had persistent anemia, thrombocytopenia, or neutropenia. Percentages have been rounded off to the nearest decimal point.
Time frame: At Month 15
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized. Overall number analyzed is the number of participants with CR/CRi.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit | 97.5 percentage of participants |
| Arm B: FCR/BR | MRD Response Rate in PB of Participants With a CR/CRi at the End of Treatment Visit | 78.6 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: 0.005495% CI: [0.91, 36.95]Cochran-Mantel-Haenszel
Secondary
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE that meets any of the following criteria: is fatal; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; is a significant medical event in the investigator's judgment.
Time frame: 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)
Secondary
Number of Participants With Premature Withdrawals Due to AEs
An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product, regardless of causal attribution. An AE can be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE was any AE that meets any of the following criteria: is fatal; is life-threatening; requires or prolongs inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to study drug; is a significant medical event in the investigator's judgment.
Time frame: 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)
Secondary
Objective Response Rate (ORR)
ORR was defined as the percentage of participants with overall response (OR) of CR, CRi, and PR as determined by the investigator according to the iwCLL guidelines. CR was defined as PB lymphocytes \<4x10\^9 /L; absence of significant lymphadenopathy (nodes \<1.5 cm in longest diameter \[LD\]); no hepatomegaly/splenomegaly; absence of disease/constitutional symptoms; BM at least normocellular for age, ≤30% of nucleated cells being lymphocytes. CRi was defined as fulfilling CR criteria but with persistent anemia/thrombocytopenia/neutropenia. PR was defined as ≥50% decrease in PB lymphocyte count from pre-treatment value; ≥50% reduction in lymphadenopathy sum of longest diameter of up to 6 largest lymph nodes by physical exam and 50% reduction in the sum of product of the diameter of up to 6 largest lymph nodes); ≥50% reduction of liver/spleen enlargement/normalization in size, if enlarged at baseline.
Time frame: At Month 15
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized. Percentages have been rounded off to the nearest decimal point.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | Objective Response Rate (ORR) | 88.8 percentage of participants |
| Arm B: FCR/BR | Objective Response Rate (ORR) | 79.1 percentage of participants |
Comparison: P-value estimated using CMH test stratified by the IvRS randomization stratification factors.p-value: 0.111995% CI: [-2.05, 21.41]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS)
OS was defined as the time between the date of randomization and the date of death due to any cause.
Time frame: Up to approximately 74 months
Secondary
Progression-free Survival (PFS)
PFS was defined as the time from randomization to the first occurrence of disease progression (PD), or death from any cause. PD was assessed by the investigators using the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. PD was defined as any one of the following: Appearance of any new lesion such as enlarged lymph nodes (≥ 1.5 centimeters \[cm\]); increase by ≥ 50% in greatest diameter of any previous site (≥ 1.5 cm); increase in the spleen/liver size by ≥ 50% or de novo appearance of splenomegaly/hepatomegaly; increase in blood lymphocytes by 50% or more with at least 5x10\^9/litres (L) B lymphocytes; transformation to a more aggressive histology; occurrence of cytopenia; posttreatment: progression of any cytopenia, documented by a decrease of hemoglobin (Hb) ≥ 2 grams per deciliter (g/dL) or 10 g/dL, or by a decrease of platelet counts ≥ 50%/100x10\^9/L, which occurs at least 3 months after treatment.
Time frame: Up to approximately 74 months
Secondary
VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up
Reduction in mandatory hospitalizations during venetoclax ramp-up in the VEN + G arm participants was defined as the actual number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up period after 3 doses of obinutuzumab compared to the number of protocol-mandated hospitalizations for TLS monitoring during venetoclax ramp-up expected at baseline. Ramp-up period for venetoclax was defined as period from Cycle 1, Days 22-28, and Cycle 2, Day 1-Day 7 where the 20 mg and 50 mg daily doses of venetoclax, were administered for participants at TLS-high risk requiring mandated hospitalizations (the hospitalizations at 100, 200 and 400 was only needed if the participant had a TLS event at one of the lower doses). Total number of hospitalizations in high-risk TLS participants at baseline (expected to be N=2 hospitalization) was compared with the number of protocol mandated hospitalizations during the first 2 doses of the ramp-up.
Time frame: Cycle 1 Days 22-28 up to Cycle 2 Days 1-7 (1 cycle=28 days)
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: VEN+G | VEN + G: Reduction in Mandatory Hospitalizations During Venetoclax Ramp-up | 2 number of hospitalizations |
Secondary
VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate
TLS risk reduction rate in the VEN + G arm was defined as the reduction in the percentage of participants who were TLS high-risk after 3 doses of obinutuzumab compared to the percentage of participants who were TLS high-risk at baseline. Risk for developing TLS were categorised into: Low - All measurable lymph nodes with the LD \< 5 cm and \< 25x10\^9/L absolute lymphocyte count (ALC); Medium - Any measurable lymph node with the LD ≥5 cm but \<10 cm OR ≥25x10\^9/L ALC; High - Any measurable lymph node with the LD ≥10 cm or the presence of both ≥25x10\^9/L ALC and any measurable lymph node with the LD ≥5 cm but \<10 cm. Percentages have been rounded off to the nearest decimal point.
Time frame: Baseline up to Cycle 1 Day 22 (1 cycle=28 days)
Population: FAS included all randomized participants, analyzed according to the treatment to which they were randomized.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Arm A: VEN+G | VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate | High-risk at Baseline | 23.8 percentage of participants |
| Arm A: VEN+G | VEN + G: Tumor Lysis Syndrome (TLS) Risk Reduction Rate | High-risk at Cycle 1 Day 22 | 0 percentage of participants |