Chronic Lymphocytic Leukemia
Conditions
Keywords
Oncology, Chronic Lymphocytic Leukemia, 17p Deletion, TP53 Mutation, Relapsed, Refractory, B-Cell receptor inhibitor
Brief summary
The purpose of this study is to evaluate the efficacy of venetoclax monotherapy in participants with relapsed/refractory CLL with or without the 17p deletion or TP53 mutation, including those who have received prior treatment with a B-cell receptor inhibitor.
Detailed description
Following the Screening period, all eligible participants initiate venetoclax on a once daily (QD) dosing schedule. To mitigate the risk for tumor lysis syndrome (TLS), dosing will start with a 5-week dose titration phase. Participants may receive venetoclax for up to 2 years provided they continue to tolerate the drug, have no evidence of disease progression (based on investigator assessment), do not have unacceptable toxicity and do not meet any of the criteria for subject discontinuation. In countries where venetoclax is not commercially available, participants who continued to derive benefit after 2 years of treatment may extend their treatment for up to 2 additional years in an extended access phase. Participants in the extended access phase of this study who continue to derive benefit from venetoclax after the 2-year extension and are transferring to the venetoclax extension study, Study M19-388 (NCT03844048), may remain in Extended Access for up to 1 additional year or until the extension study is approved and initiated at the site, whichever is sooner.
Interventions
DRUGVenetoclax
Tablets for oral administration
Sponsors
AbbVie
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
Inclusion criteria
* Participant has Eastern Cooperative Oncology Group (ECOG) performance score of less than or equal to 2 * Participant has relapsed/refractory disease (received at least 1 prior therapy) * Participant has diagnosis of CLL that meets published 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute Working Group (IWCLL NCI-WG) Guidelines and: * has an indication for treatment according to the 2008 Modified IWCLL NCI-WG criteria * has clinically measurable disease (lymphocytosis greater than 5 × 10\^9/L and/or palpable and measurable nodes by physical exam and/or organomegaly assessed by physical exam) * In addition, participants: * with or without 17p deletion or TP53 mutation, assessed by a local laboratory in bone marrow or peripheral blood are eligible * may have been previously treated with a prior B-cell receptor inhibitor * Participant must have adequate bone marrow function, coagulation profile, renal, and hepatic function, per laboratory at Screening
Exclusion criteria
* Participant has developed Richter's transformation or Prolymphocytic leukemia * Participant has previously received venetoclax * History of active malignancies other than CLL within the past 2 years prior to first dose of venetoclax, with the exception of: * adequately treated in situ carcinoma of the cervix uteri * adequately treated basal cell carcinoma or localized squamous cell carcinoma of the skin * previous malignancy confined and surgically resected (or treated with other modalities) with curative intent * Participant has active and uncontrolled autoimmune cytopenias (for 2 weeks prior to Screening), including autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura despite low dose corticosteroids * Participant has undergone an allogeneic stem cell transplant * Treatment with any of the following within five half-lives or 14 days (if half-life unknown) as applicable prior to the first dose of venetoclax, or clinically significant adverse effect(s)/toxicity(s) of the previous therapy have not resolved to \< National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.03 Grade 2: * Any anti-cancer therapy including chemotherapy, or radiotherapy; * Investigational therapy, including targeted small molecule agents * Participant is human immunodeficiency virus (HIV) positive * Participant has known allergy to both xanthine oxidase inhibitors and rasburicase
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes. CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator. CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met: * 50% decrease in peripheral blood lymphocyte count from the Baseline value; * 50% reduction in lymphadenopathy; * 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy); In addition at least 1 of the following criteria must be met: * Neutrophils \> 1,500/μL or ≥ 50% improvement over Baseline; * Platelets \> 100,000/μL or ≥ 50% improvement over Baseline; * Hemoglobin \> 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors. PR must have been confirmed at least 7 weeks later. |
| Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity. |
| Duration of Overall Response (DOR) - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date. |
| Time to Progression (TTP) - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology. |
| Progression-Free Survival (PFS) - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology. |
| Overall Survival (OS) - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology. |
| Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Baseline and Weeks 48 and 108 | The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess health-related quality of life (HRQoL) and leukemia-specific symptoms using a core set of questions (Functional Assessment of Cancer Therapy-General; FACT-G), and a cancer site-specific leukemia subscale. Questions are scored on a scale from 0 (not at all) to 4 (very much). FACT-G consists of 27 general items divided into 4 primary HRQoL domains: Physical Well-being (PWB; 7 items; score range 0-28), Social/Family Well-being (SWB; 7 items; score range 0-28), Emotional Well-being (EWB; 6 items; score range 0-24), Functional Well-being (FWB; 7 items; score range 0-28). The leukemia subscale consists of 17 items (score range 0-68) that assess patient concerns relating to leukemia. Three summary scales were calculated: FACT-Trial Outcome Index composed of the PWB, FWB, and leukemia subscale (score range 0-124); FACT-G (score range 0-108) and the FACT-Leu Total (range 0-176). Higher scores reflect better HRQoL. |
| Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) | Baseline and Weeks 48 and 108 | The FACIT-Fatigue questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-Fatigue includes 13 items answered on a 5-point rating scale based on a 7-day recall period. Scores range from 0 to 52, with lower scores reflecting greater fatigue. |
| Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score | Baseline and Weeks 48 and 108 | The EQ-5D-5L is a generic measure of health status consisting of two parts: a descriptive system consisting of 5 items and a visual analog scale (VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant is asked to rate each dimension on 5 levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems). The scores for the 5 dimensions are used to compute a single health utility index score representing the general health status of the individual. The health index score ranges from zero (defined as a health state equivalent to being dead) to 1 (full health). |
| Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score | Baseline and Weeks 48 and 108 | The EQ-5D-5L is a generic measure of health status consisting of two parts, a descriptive system consisting of 5 items and a visual analog scale (VAS). The VAS assesses the participant's self-rated overall health on a scale from 0 (worst health imaginable) to 100 (best health imaginable). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator. CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met: * 50% decrease in peripheral blood lymphocyte count from the Baseline value; * 50% reduction in lymphadenopathy; * 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy); In addition at least 1 of the following criteria must be met: * Neutrophils \> 1,500/μL or ≥ 50% improvement over Baseline; * Platelets \> 100,000/μL or ≥ 50% improvement over Baseline; * Hemoglobin \> 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors. PR must have been confirmed at least 7 weeks later. |
| Duration of Overall Response (DOR) - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date. |
| Time to Progression (TTP) - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology. |
| Progression-Free Survival (PFS) - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology. |
| Overall Survival (OS) - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology. |
| Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis | From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months. | The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (\< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status. |
| Minimal Residual Disease (MRD) Negativity Rate - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (\< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status. |
| Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity. |
| Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Final Analysis | From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months. | Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes. CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity. |
Countries
Austria, Belgium, Canada, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Netherlands, Norway, Portugal, Puerto Rico, Spain, Sweden, Switzerland, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at 59 sites in 19 countries. The primary analysis of results occurred after all participants completed the Week 48 disease assessment, with a data cut-off date of 30 June 2019.
Participants by arm
| Arm | Count |
|---|---|
| Venetoclax Participants received venetoclax on a once daily dosing schedule for up to 108 weeks. The starting dose was 20 mg daily, increasing over a period of 5 weeks up to the daily dose of 400 mg. Participants who continued to derive benefit after 2 years of treatment may have continued venetoclax therapy for up to 3 additional years. | 258 |
| Total | 258 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 70 |
| Overall Study | Lost to Follow-up | 3 |
| Overall Study | Other | 10 |
| Overall Study | Transitioned to Long-term Extension Study M19-388 (NCT03844048) | 49 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Venetoclax |
|---|---|
| Age, Continuous | 67.7 years STANDARD_DEVIATION 9.04 |
| Age, Customized < 65 years | 94 Participants |
| Age, Customized >= 65 years | 164 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 248 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Geographic Region Europe | 161 Participants |
| Geographic Region North America | 28 Participants |
| Geographic Region Rest of the World | 69 Participants |
| Prior Treatment With B-cell Receptor Inhibitor (BCRi) BCRi-exposed | 67 Participants |
| Prior Treatment With B-cell Receptor Inhibitor (BCRi) BCRi-naive | 191 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants |
| Race/Ethnicity, Customized Black or African American | 3 Participants |
| Race/Ethnicity, Customized Missing | 1 Participants |
| Race/Ethnicity, Customized White | 252 Participants |
| Sex: Female, Male Female | 78 Participants |
| Sex: Female, Male Male | 180 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 70 / 258 |
| other Total, other adverse events | 246 / 258 |
| serious Total, serious adverse events | 136 / 258 |
Outcome results
Primary
Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis
Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 Modified International Workshop for Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (IWCLL NCI-WG) criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes. CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: All enrolled participants treated with at least one dose of venetoclax who had not previously received treatment with BCRi
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Venetoclax | Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Primary Analysis | 35.1 percentage of participants |
Comparison: The null hypothesis stated that the CR rate for BCRi-naïve participants would be ≤ 6%, based on the CR rate reported for current therapies at the time the study was designed, with an alternative hypothesis that the CR rate would be \> 6%. If the p-value for this test was \< 0.025, the null hypothesis would be rejected.p-value: <0.001Binomial test
Secondary
Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score
The EQ-5D-5L is a generic measure of health status consisting of two parts: a descriptive system consisting of 5 items and a visual analog scale (VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The participant is asked to rate each dimension on 5 levels of severity (1: no problems, 2: slight problems, 3: moderate problems, 4: severe problems, 5: extreme problems). The scores for the 5 dimensions are used to compute a single health utility index score representing the general health status of the individual. The health index score ranges from zero (defined as a health state equivalent to being dead) to 1 (full health).
Time frame: Baseline and Weeks 48 and 108
Population: All enrolled participants treated with at least one dose of venetoclax with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Venetoclax | Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score | Week 48 | 0.0 score on a scale | Standard Deviation 0.14 |
| Venetoclax | Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Health Index Score | Week 108 | 0.0 score on a scale | Standard Deviation 0.15 |
Secondary
Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score
The EQ-5D-5L is a generic measure of health status consisting of two parts, a descriptive system consisting of 5 items and a visual analog scale (VAS). The VAS assesses the participant's self-rated overall health on a scale from 0 (worst health imaginable) to 100 (best health imaginable).
Time frame: Baseline and Weeks 48 and 108
Population: All enrolled participants treated with at least one dose of venetoclax with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Venetoclax | Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score | Week 48 | 8.5 score on a scale | Standard Deviation 14.43 |
| Venetoclax | Change From Baseline in EuroQoL 5 Dimension 5 Level Questionnaire (EQ-5D-5L) Visual Analog Scale Score | Week 108 | 7.1 score on a scale | Standard Deviation 14.61 |
Secondary
Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu)
The FACT-Leu is a 44-item, leukemia-specific questionnaire designed to assess health-related quality of life (HRQoL) and leukemia-specific symptoms using a core set of questions (Functional Assessment of Cancer Therapy-General; FACT-G), and a cancer site-specific leukemia subscale. Questions are scored on a scale from 0 (not at all) to 4 (very much). FACT-G consists of 27 general items divided into 4 primary HRQoL domains: Physical Well-being (PWB; 7 items; score range 0-28), Social/Family Well-being (SWB; 7 items; score range 0-28), Emotional Well-being (EWB; 6 items; score range 0-24), Functional Well-being (FWB; 7 items; score range 0-28). The leukemia subscale consists of 17 items (score range 0-68) that assess patient concerns relating to leukemia. Three summary scales were calculated: FACT-Trial Outcome Index composed of the PWB, FWB, and leukemia subscale (score range 0-124); FACT-G (score range 0-108) and the FACT-Leu Total (range 0-176). Higher scores reflect better HRQoL.
Time frame: Baseline and Weeks 48 and 108
Population: All enrolled participants treated with at least one dose of venetoclax with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Physical well-being - Week 48 | 1.2 score on a scale | Standard Deviation 4.07 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Physical well-being - Week 108 | 0.9 score on a scale | Standard Deviation 4.2 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Social/family well-being - Week 48 | 0.2 score on a scale | Standard Deviation 5.14 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Social/family well-being - Week 108 | -0.4 score on a scale | Standard Deviation 4.86 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Emotional well-being - Week 48 | 2.1 score on a scale | Standard Deviation 3.52 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Emotional well-being - Week 108 | 1.7 score on a scale | Standard Deviation 3.94 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Functional well-being - Week 48 | 1.8 score on a scale | Standard Deviation 5.63 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Functional well-being - Week 108 | 1.4 score on a scale | Standard Deviation 5.67 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Leukemia subscale - Week 48 | 6.8 score on a scale | Standard Deviation 7.99 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | Leukemia subscale - Week 108 | 6.0 score on a scale | Standard Deviation 9.08 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | FACT-G total score - Week 48 | 5.5 score on a scale | Standard Deviation 12.34 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | FACT-G total score - Week 108 | 3.6 score on a scale | Standard Deviation 13.56 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | FACT-leukemia trial outcome index - Week 48 | 9.8 score on a scale | Standard Deviation 14.23 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | FACT-leukemia trial outcome index - Week 108 | 8.2 score on a scale | Standard Deviation 15.61 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | FACT-leukemia total score - Week 48 | 12.3 score on a scale | Standard Deviation 18.18 |
| Venetoclax | Change From Baseline in Functional Assessment of Cancer Therapy - Leukemia Questionnaire (FACT-Leu) | FACT-leukemia total score - Week 108 | 9.5 score on a scale | Standard Deviation 20.62 |
Secondary
Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue)
The FACIT-Fatigue questionnaire measures fatigue and its effect on functioning and daily activities. The FACIT-Fatigue includes 13 items answered on a 5-point rating scale based on a 7-day recall period. Scores range from 0 to 52, with lower scores reflecting greater fatigue.
Time frame: Baseline and Weeks 48 and 108
Population: All enrolled participants treated with at least one dose of venetoclax with available data at each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Venetoclax | Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) | Week 48 | 4.9 score on a scale | Standard Deviation 9.43 |
| Venetoclax | Change From Baseline in Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACIT-Fatigue) | Week 108 | 3.3 score on a scale | Standard Deviation 9.96 |
Secondary
Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis
Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: All enrolled participants treated with at least one dose of venetoclax who were previously treated with BCRi
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Venetoclax | Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Primary Analysis | 25.4 percentage of participants |
Secondary
Duration of Overall Response (DOR) - Primary Analysis
Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: Enrolled participants treated with at least one dose of venetoclax who had an overall response of CR, CRi, nPR, or confirmed PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Duration of Overall Response (DOR) - Primary Analysis | 25.2 months |
Secondary
Overall Response Rate (ORR) - Primary Analysis
Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator. CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met: * 50% decrease in peripheral blood lymphocyte count from the Baseline value; * 50% reduction in lymphadenopathy; * 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy); In addition at least 1 of the following criteria must be met: * Neutrophils \> 1,500/μL or ≥ 50% improvement over Baseline; * Platelets \> 100,000/μL or ≥ 50% improvement over Baseline; * Hemoglobin \> 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors. PR must have been confirmed at least 7 weeks later.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: All enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Venetoclax | Overall Response Rate (ORR) - Primary Analysis | 79.8 percentage of participants |
Secondary
Overall Survival (OS) - Primary Analysis
Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: Enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Overall Survival (OS) - Primary Analysis | NA months |
Secondary
Progression-Free Survival (PFS) - Primary Analysis
Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: Enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Progression-Free Survival (PFS) - Primary Analysis | 30.5 months |
Secondary
Time to Progression (TTP) - Primary Analysis
Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: Enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Time to Progression (TTP) - Primary Analysis | 30.5 months |
Other Pre-specified
Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Final Analysis
Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes. CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: All enrolled participants treated with at least one dose of venetoclax who had not previously received treatment with BCRi
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Venetoclax | Complete Remission Rate in Participants Not Previously Treated With BCRi Therapy - Final Analysis | 34.6 percentage of participants |
Comparison: The null hypothesis stated that the CR rate for BCRi-naïve participants would be ≤ 6%, based on the CR rate reported for current therapies at the time the study was designed, with an alternative hypothesis that the CR rate would be \> 6%. If the p-value for this test was \< 0.025, the null hypothesis would be rejected.p-value: <0.001Binomial test
Other Pre-specified
Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Final Analysis
Complete remission rate is defined as the percentage of participants achieving a best response of complete remission (CR) or complete remission with incomplete marrow recovery (CRi) assessed by the investigator based on 2008 modified IWCLL NCI-WG criteria. CR required all of the following: * Peripheral blood lymphocytes \< 4000/μL * Absence of lymphadenopathy by physical examination and computed tomography scan * No hepatomegaly or splenomegaly by physical examination * Absence of disease or constitutional symptoms (unexplained fevers \> 38°C, drenching night sweats, \> 10% weight loss in last 6 months) * Blood counts above the following: * Neutrophils \> 1500/μL * Platelets \> 100,000/μL * Hemoglobin \> 110 g/L * Bone marrow at least normocellular for age, \< 30% lymphocytes CRi was defined as for CR but with persistent cytopenia apparently unrelated to CLL but related to drug toxicity.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: All enrolled participants treated with at least one dose of venetoclax who were previously treated with BCRi
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Venetoclax | Complete Remission Rate in Participants Previously Treated With BCRi Therapy - Final Analysis | 26.9 percentage of participants |
Other Pre-specified
Duration of Overall Response (DOR) - Final Analysis
Duration of response was defined as the time from the date of first response (CR, CRi, nPR, or PR) to the earliest date that progressive disease (PD) was objectively documented (radiographic or clinical) or death. Duration of response was analyzed by Kaplan-Meier (K-M) methodology. If a participant was still responding the data were censored at the date of the last available disease assessment prior to the data cutoff date.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: Enrolled participants treated with at least one dose of venetoclax who had an overall response of CR, CRi, nPR, or confirmed PR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Duration of Overall Response (DOR) - Final Analysis | 25.1 months |
Other Pre-specified
Minimal Residual Disease (MRD) Negativity Rate - Final Analysis
The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (\< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: All enrolled participants who received at least one dose of venetoclax
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Venetoclax | Minimal Residual Disease (MRD) Negativity Rate - Final Analysis | Peripheral blood | 40.3 percentage of participants |
| Venetoclax | Minimal Residual Disease (MRD) Negativity Rate - Final Analysis | Bone marrow | 10.5 percentage of participants |
Other Pre-specified
Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis
The MRD negativity rate is defined as the percentage of participants who had MRD negative status with less than one CLL cell per 10,000 leukocytes (\< 10-⁴) in peripheral blood and bone marrow. MRD was evaluated using next-generation sequencing. Per protocol, peripheral blood MRD assessments were to be collected from all participants at Week 24 and Week 48 and at the time the bone marrow assessment for confirmation of CR/CRi, and bone marrow (BM) MRD assessments were to be collected for participants undergoing a bone marrow procedure for confirmation of CR/CRi. Participants with no blood or BM MRD assessments were included in the calculation of MRD negativity rate as not having MRD negative status.
Time frame: From first dose of study drug until the last participant completed Week 48 assessments (data cut-off date 30 June 2019); overall median time on follow-up was 23.2 months.
Population: All enrolled participants who received at least one dose of venetoclax
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Venetoclax | Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis | Peripheral blood | 39.9 percentage of participants |
| Venetoclax | Minimal Residual Disease (MRD) Negativity Rate - Primary Analysis | Bone marrow | 9.7 percentage of participants |
Other Pre-specified
Overall Response Rate (ORR) - Final Analysis
Overall response rate was defined as the percentage of participants with an overall best response of CR, CRi, nodular partial remission (nPR), or confirmed partial remission (PR) based on the 2008 modified IWCLL NCI-WG criteria assessed by the investigator. CR and CRi are defined above. nPR is defined as for CR but bone marrow nodules could be identified histologically. For PR at least 2 of the following must be met: * 50% decrease in peripheral blood lymphocyte count from the Baseline value; * 50% reduction in lymphadenopathy; * 50% reduction in the size of the liver and/or spleen (if abnormal prior to therapy); In addition at least 1 of the following criteria must be met: * Neutrophils \> 1,500/μL or ≥ 50% improvement over Baseline; * Platelets \> 100,000/μL or ≥ 50% improvement over Baseline; * Hemoglobin \> 11.0 g/dL or ≥ 50% improvement over Baseline without transfusions or exogenous growth factors. PR must have been confirmed at least 7 weeks later.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: All enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Venetoclax | Overall Response Rate (ORR) - Final Analysis | 79.8 percentage of participants |
Other Pre-specified
Overall Survival (OS) - Final Analysis
Overall survival (time to death) was defined as the time from the first dose date of venetoclax to the date of death. If a participant had not died the data were censored at the date when they were last known to be alive prior to the cutoff date. Overall survival was analyzed using Kaplan-Meier methodology.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: Enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Overall Survival (OS) - Final Analysis | NA months |
Other Pre-specified
Progression-Free Survival (PFS) - Final Analysis
Progression-free survival (PFS) was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical) or death. Participants who did not experience disease progression or death were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline tumor assessment or clinical assessment for progression were censored at the date of first dose plus 1 day. Progression-free survival was analyzed by Kaplan-Meier methodology.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: Enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Progression-Free Survival (PFS) - Final Analysis | 28.3 months |
Other Pre-specified
Time to Progression (TTP) - Final Analysis
Time to progression was defined as the time from the date of first dose of venetoclax to the date of earliest PD (radiographic or clinical). Participants who did not experience disease progression were censored at the date of the last available disease assessment prior to the data cutoff date; participants with no post-baseline disease assessments were censored at the first dose date plus 1 day. Time to progression was estimated using Kaplan-Meier methodology.
Time frame: From first dose of study drug until the end of study; overall median time on follow-up was 49.5 months.
Population: Enrolled participants treated with at least one dose of venetoclax
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Venetoclax | Time to Progression (TTP) - Final Analysis | 28.3 months |