Chronic Lymphocytic Leukemia
Conditions
Brief summary
This Primary objective is evaluating the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) for the treatment of previously untreated chronic lymphocytic leukemia (CLL). Secondary objectives: 1) To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C) based on IRC assessment of PFS per IWCLL 2008 criteria. 2)To compare obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib plus obinutuzumab (Arm B) and obinutuzumab plus chlorambucil (Arm A) versus acalabrutinib monotherapy (Arm C) in terms of: IRC-assessed objective response rate (ORR); Tine to next treatment (TTNT); Overall Survival (OS)
Detailed description
ELEVATE-TN is a global, phase 3, multicenter, open-label study in patients with treatment-naive chronic lymphocytic leukemia (CLL). Study enrollment is completed. The study randomized a total of 535 subjects in 142 study sites in 18 countries between 14 September 2015 through 08 February 2017. Patients were randomly assigned to receive Acalabrutinib and Obinutuzumab, Acalabrutinib monotherapy, or Obinutuzumab and oral Chlorambucil. The primary endpoint was progression-free survival between the two combination-therapy groups, defined as the time from randomization until disease progression by use of iwCLL 2008 criteria, or death, assessed by independent review committee (IRC). Crossover to Acalabrutinib was allowed in patients who progressed on Obinutuzumab-Chlorambucil. The results of this study provide new evidence for therapy in patients with treatment-naive chronic lymphocytic leukemia by showing the efficacy of Acalabrutinib used with or without Obinutuzumab compared with chemoimmunotherapy. Currently the study is in maintenance phase, with more than 430 subjects on study, to generate more evidence. We are not expecting any significant change in the near future.
Interventions
DRUGAcalabrutinib
DRUGObinutuzumab
DRUGChlorambucil
Sponsors
Acerta Pharma BV
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women: a. ≥ 65 years of age OR b. \> 18 and \< 65 years of age, provided that they meet at least one of the following criteria: i. Creatinine clearance 30 to 69 mL/min using the Cockcroft-Gault equation ii. A score higher than 6 on the CIRS-G (Appendix L). 2. ECOG performance status of 0, 1, or 2. 3. Diagnosis of CD20+ CLL that meets published diagnostic criteria (Hallek 2008): 1. Monoclonal B cells (either kappa or lambda light chain restricted) that are clonally co-expressing ≥ 1 B-cell marker (CD19, CD20, or CD23) and CD5. 2. Prolymphocytes may comprise ≤ 55% of blood lymphocytes. 3. Presence of ≥ 5 x 109 B lymphocytes/L (5000 μL) in the peripheral blood (at any point since diagnosis) 4. Active disease meeting ≥ 1 of the following IWCLL 2008 criteria for requiring treatment: 1. Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia (hemoglobin \< 10 g/dL) and/or thrombocytopenia (platelets \< 100,000/μL). 2. Massive (i.e., ≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly. 3. Massive nodes (i.e., ≥ 10 cm in the longest diameter), progressive, or symptomatic lymphadenopathy. 4. Progressive lymphocytosis with an increase of \> 50% over a 2-month period or a LDT of \< 6 months. LDT may be obtained by linear regression extrapolation of ALC obtained at intervals of 2 weeks over an observation period of 2 to 3 months. In subjects with initial blood lymphocyte counts of \< 30 x 109/L (30,000/μL), LDT should not be used as a single parameter to define indication for treatment. In addition, factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded. 5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to standard therapy. 6. Constitutional symptoms documented in the subject's chart with supportive objective measures, as appropriate, defined as ≥ 1 of the following disease-related symptoms or signs: i. Unintentional weight loss ≥ 10% within the previous 6 months before Screening. ii. Significant fatigue (i.e., ECOG performance status 2; inability to work or perform usual activities). iii. Fevers higher than 100.5°F or 38.0°C for 2 or more weeks before Screening without evidence of infection. iv. Night sweats for \> 1 month before Screening without evidence of infection. 5. This criterion was deleted as of Protocol Amendment 3. 6. Meet the following laboratory parameters: 1. ANC ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement, and independent of growth factor support 7 days before assessment. 2. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion support 7 days before assessment. Subjects with transfusion-dependent thrombocytopenia are excluded. 3. Serum AST and ALT/SGPT ≤ 3.0 x ULN. 4. Total bilirubin ≤ 1.5 x ULN. 5. Estimated creatinine clearance (i.e., eGFR using Cockcroft-Gault) ≥ 30 mL/min 7. Able to receive all outpatient treatment, all laboratory monitoring, and all radiologic evaluations. 8. Women who are sexually active and can bear children must agree to use highly effective forms of contraception while on the study and for 2 days after the last dose of acalabrutinib or 18 months after the last dose of obinutuzumab in combination with chlorambucil, whichever is longer. Highly effective forms of contraception are defined in Section 6.4.4. 9. Men who are sexually active and can beget children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. Highly effective forms of contraception are defined in Section 6.4.4. 10. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of obinutuzumab or chlorambucil, whichever is later. 11. Must be willing and able to adhere to the study visit schedule, understand and comply with other protocol requirements, and provide written informed consent and authorization to use protected health information (in accordance with national and local subject privacy regulations). Note vulnerable subjects, as defined in International Conference on Harmonisation (ICH) GCP, are not allowed on this protocol (e.g., prisoners or institutionalized subjects).
Exclusion criteria
1. Any prior systemic treatment for CLL (note: Prior localized radiotherapy is allowed). 2. Known CNS lymphoma or leukemia. 3. Known prolymphocytic leukemia or history of, or currently suspected, Richter's syndrome. 4. Missing or incomplete documentation of FISH results reflecting the presence or absence of 17p del and the percentage of cells with the deletion in subject records before randomization. 5. Uncontrolled AIHA or ITP defined as declining hemoglobin or platelet count secondary to autoimmune destruction within the screening period or requirement for high doses of steroids (\> 20 mg daily of prednisone daily or equivalent). 6. Corticosteroid use \> 20 mg within 1 week before first dose of study drug, except as indicated for other medical conditions such as inhaled steroid for asthma, topical steroid use, or as premedication for administration of study drug or contrast. For example, subjects requiring steroids at daily doses \> 20 mg prednisone equivalent systemic exposure daily, or those who are administered steroids for leukemia control or WBC count lowering are excluded. 7. Major surgery within 4 weeks before first dose of study drug. 8. History of prior malignancy except for the following: 1. Malignancy treated with curative intent and with no evidence of active disease present for more than 3 years before Screening and felt to be at low risk for recurrence by treating physician. 2. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer. 3. Adequately treated cervical carcinoma in situ without current evidence of disease. 9. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or QTc \> 480 msec at screening. 10. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction. 11. Uncontrolled active systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment) or ongoing intravenous anti-infective treatment. 12. Known history of infection with HIV. 13. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. 14\. Serologic status reflecting active hepatitis B or C infection. Subjects with hepatitis B core antibody positive who are surface antigen negative or who are hepatitis C antibody positive will need to have a negative PCR result before randomization. Those who are hepatitis B surface antigen positive or hepatitis B PCR positive and those who are hepatitis C PCR positive will be excluded. 15\. History of stroke or intracranial hemorrhage within 6 months before randomization. 16\. Known history of a bleeding diathesis (e.g., hemophilia, von Willebrand disease). 17\. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon) within 7 days of first dose of study drug. 18\. Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 19\. Breast feeding or pregnant. 20. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk. 21\. Concurrent participation in another therapeutic clinical trial. 22. Requires treatment with a strong CYP3A inhibitor/inducer. 23. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B | IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months. | To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival by IRC Assessment Arm A Versus Arm C | IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months. | To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib monotherapy (Arm C) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first. |
| IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C | IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months. | ORR was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, or PR at or before initiation of subsequent anticancer therapy. ORR including PRL was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, PR or PRL at or before initiation of subsequent anticancer therapy |
| Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C | From randomization date to start of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first assessed up to 40 months of follow-up. | TTNT was defined as the time from randomization to start date of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first. TTNT was analyzed in the same fashion as that for the primary efficacy analysis |
| Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C | From randomization date until death, withdrawal by subject, lost to follow-up, or by analysis data cut off date on 08Feb2019 whichever comes first up to 40 months of follow-up. | OS was defined as the time from the date of randomization to death due to any cause. |
Countries
Australia, Belgium, Brazil, Canada, Chile, Colombia, France, Germany, Hungary, Israel, Italy, Lithuania, New Zealand, Poland, Spain, Sweden, United Kingdom, United States
Contacts
STUDY_DIRECTORAstraZeneca Clinical Study Information Center
1-877-240-9479 information.center@astrazeneca.com
Participant flow
Recruitment details
A randomized, multicenter, open-label, 3 arm phase 3 study of Obinutuzumab in combination with Chlorambucil (Chlb+Obin), Acalabrutinib in combination with Obinutuzumab (Acala+Obin), and Acalabrutinib monotherapy (Acala) in subjects with previously untreated chronic lymphocytic leukemia. A total of 535 subjects recruited from 142 sites in 18 countries were randomized (1:1:1) as follows: 179/179 /177 subjects in Acla+Obin arm / Acala arm / Chlb+Obin arm respectively.
Participants by arm
| Arm | Count |
|---|---|
| Obinutuzumab in Combination With Chlorambucil Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles starting at Cycle 1 Day 1. Chlorambucil will be orally administered on Days 1 and 15 of Cycles 1 through 6. Obinutuzumab Chlorambucil | 177 |
| Acalabrutinib in Combination With Obinutuzumab Obinutuzumab IV infusions will be administered over a total of 6 treatment cycles starting at Cycle 2 Day 1. Acalabrutinib (ACP-196) will be orally administered starting on Cycle 1 Day 1. Daily administration of Acalabrutinib (ACP-196) will continue until disease progression or unacceptable toxicity. Acalabrutinib Obinutuzumab | 179 |
| Acalabrutinib Monotherapy Acalabrutinib will be orally administered on Cycle 1 Day 1 until disease progression or unacceptable toxicity. Acalabrutinib | 179 |
| Total | 535 |
Baseline characteristics
| Characteristic | Acalabrutinib in Combination With Obinutuzumab | Total | Obinutuzumab in Combination With Chlorambucil | Acalabrutinib Monotherapy |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 144 Participants | 448 Participants | 153 Participants | 151 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 87 Participants | 24 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 24 Participants | 11 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 169 Participants | 481 Participants | 156 Participants | 156 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 30 Participants | 10 Participants | 12 Participants |
| IXRS Randomization Stratification Factor: ECOG Performance Status 0-1 (0=Fully Active; 1 =Restricted in Physically Strenuous Activity) | 169 Participants | 504 Participants | 168 Participants | 167 Participants |
| IXRS Randomization Stratification Factor: ECOG Performance Status 2 (2=Ambulatory and capable of all selfcare but unable to carry out any work activities) | 10 Participants | 31 Participants | 9 Participants | 12 Participants |
| IXRS Randomization Stratification Factor: Geographic Region North America and West Europe | 104 Participants | 312 Participants | 103 Participants | 105 Participants |
| IXRS Randomization Stratification Factor: Geographic Region Other | 75 Participants | 223 Participants | 74 Participants | 74 Participants |
| IXRS Randomization Stratification Factor: Presence of 17p Deletion No | 158 Participants | 478 Participants | 160 Participants | 160 Participants |
| IXRS Randomization Stratification Factor: Presence of 17p Deletion Yes | 21 Participants | 57 Participants | 17 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 13 Participants | 4 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 18 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) White | 164 Participants | 499 Participants | 165 Participants | 170 Participants |
| Region of Enrollment Australia | 9 Participants | 26 Participants | 9 Participants | 8 Participants |
| Region of Enrollment Belgium | 5 Participants | 13 Participants | 5 Participants | 3 Participants |
| Region of Enrollment Brazil | 5 Participants | 14 Participants | 4 Participants | 5 Participants |
| Region of Enrollment Canada | 8 Participants | 22 Participants | 7 Participants | 7 Participants |
| Region of Enrollment Chile | 0 Participants | 5 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Colombia | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Region of Enrollment France | 3 Participants | 7 Participants | 3 Participants | 1 Participants |
| Region of Enrollment Germany | 1 Participants | 7 Participants | 3 Participants | 3 Participants |
| Region of Enrollment Hungary | 26 Participants | 58 Participants | 17 Participants | 15 Participants |
| Region of Enrollment Israel | 9 Participants | 26 Participants | 10 Participants | 7 Participants |
| Region of Enrollment Italy | 9 Participants | 25 Participants | 11 Participants | 5 Participants |
| Region of Enrollment Lithuania | 2 Participants | 17 Participants | 9 Participants | 6 Participants |
| Region of Enrollment New Zealand | 4 Participants | 17 Participants | 8 Participants | 5 Participants |
| Region of Enrollment Poland | 20 Participants | 59 Participants | 14 Participants | 25 Participants |
| Region of Enrollment Spain | 3 Participants | 13 Participants | 7 Participants | 3 Participants |
| Region of Enrollment Sweden | 3 Participants | 7 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United Kingdom | 16 Participants | 45 Participants | 12 Participants | 17 Participants |
| Region of Enrollment United States | 56 Participants | 173 Participants | 54 Participants | 63 Participants |
| Sex: Female, Male Female | 68 Participants | 207 Participants | 71 Participants | 68 Participants |
| Sex: Female, Male Male | 111 Participants | 328 Participants | 106 Participants | 111 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 17 / 177 | 9 / 179 | 11 / 179 | 2 / 45 |
| other Total, other adverse events | 167 / 169 | 171 / 178 | 170 / 179 | 37 / 45 |
| serious Total, serious adverse events | 37 / 169 | 69 / 178 | 57 / 179 | 6 / 45 |
Outcome results
Primary
Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B
To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib in combination with obinutuzumab (Arm B) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first.
Time frame: IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months.
Population: Intent to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Obinutuzumab in Combination With Chlorambucil | Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B | 22.6 Months |
| Arm B: Acalabrutinib in Combination With Obinutuzumab | Progression-free Survival by IRC (Independent Review Committee) Assessment in Arm A Compared to Arm B | NA Months |
Comparison: The primary test to compare PFS between treatment arms was the two-sided log-rank test, stratified by randomization stratification factors. The estimate of the HR (Arm B/Arm A) and the corresponding 95% CI was computed using a Cox proportional hazards model stratified by randomization stratification factors. Randomization stratification factors were based on the data recorded in IXRS.p-value: <0.000195% CI: [0.06, 0.17]Log Rank
Secondary
IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C
ORR was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, or PR at or before initiation of subsequent anticancer therapy. ORR including PRL was defined as the proportion of subjects who achieved a best response of CR, CRi, nPR, PR or PRL at or before initiation of subsequent anticancer therapy
Time frame: IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months.
Population: Intent to Treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A: Obinutuzumab in Combination With Chlorambucil | IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C | 78.5 percentage of participants |
| Arm B: Acalabrutinib in Combination With Obinutuzumab | IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C | 93.9 percentage of participants |
| Arm C: Acalabrutinib Monotherapy | IRC-assessed Objective Response Rate (ORR) in Arm A Versus Arm B and Arm A Versus Arm C | 85.5 percentage of participants |
p-value: <0.000195% CI: [8.3, 22.3]Cochran-Mantel-Haenszel
p-value: 0.076395% CI: [-1, 14.9]Cochran-Mantel-Haenszel
Secondary
Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C
OS was defined as the time from the date of randomization to death due to any cause.
Time frame: From randomization date until death, withdrawal by subject, lost to follow-up, or by analysis data cut off date on 08Feb2019 whichever comes first up to 40 months of follow-up.
Population: Intent to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Obinutuzumab in Combination With Chlorambucil | Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C | NA Months |
| Arm B: Acalabrutinib in Combination With Obinutuzumab | Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C | NA Months |
| Arm C: Acalabrutinib Monotherapy | Overall Survival (OS) in Arm A Versus Arm B and Arm A Versus Arm C | NA Months |
Comparison: The test to compare overall survival between treatment Arms A versus B and Arms A versus C was the two-sided log-rank test, stratified by randomization stratification factors. The estimate of the HR and the corresponding 95% CI was computed using a Cox proportional hazards model stratified by randomization stratification factors. Randomization stratification factors were based on the data recorded in IXRS.p-value: 0.057795% CI: [0.21, 1.06]Log Rank
p-value: 0.155695% CI: [0.28, 1.27]Log Rank
Secondary
Progression-free Survival by IRC Assessment Arm A Versus Arm C
To evaluate the efficacy of obinutuzumab in combination with chlorambucil (Arm A) compared with acalabrutinib monotherapy (Arm C) based on IRC assessment of progression-free survival (PFS) per International Workshop on Chronic Lymphocytic Leukemia criteria (IWCLL; Hallek et al. 2008) with incorporation of the clarification for treatment-related lymphocytosis (Cheson et al. 2012), hereafter referred to as IWCLL 2008 criteria, in subjects with previously untreated CLL. PFS, defined as the time from date of randomization to the date of first IRC-assessed disease progression or death due to any cause, whichever comes first.
Time frame: IRC assessments were done from randomization date until disease progression or death or IRC discontinuation date on 08Feb2019 (as the IA based on this data cutoff date showed the study crossing superiority boundary) whichever comes first up to 40 months.
Population: Intent to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Obinutuzumab in Combination With Chlorambucil | Progression-free Survival by IRC Assessment Arm A Versus Arm C | 22.6 Months |
| Arm B: Acalabrutinib in Combination With Obinutuzumab | Progression-free Survival by IRC Assessment Arm A Versus Arm C | NA Months |
Comparison: The test to compare PFS between treatment Arms A and C was the two-sided log-rank test, stratified by randomization stratification factors. The estimate of the HR and the corresponding 95% CI was computed using a Cox proportional hazards model stratified by randomization stratification factors. Randomization stratification factors were based on the data recorded in IXRS.p-value: <0.000195% CI: [0.13, 0.3]Log Rank
Secondary
Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C
TTNT was defined as the time from randomization to start date of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first. TTNT was analyzed in the same fashion as that for the primary efficacy analysis
Time frame: From randomization date to start of non-protocol specified subsequent anticancer therapy for CLL or death due to any cause, whichever came first assessed up to 40 months of follow-up.
Population: Intent to Treat (ITT)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm A: Obinutuzumab in Combination With Chlorambucil | Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C | NA Months |
| Arm B: Acalabrutinib in Combination With Obinutuzumab | Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C | NA Months |
| Arm C: Acalabrutinib Monotherapy | Time to Next Treatment (TTNT) in Arm A Versus Arm B and Arm A Versus Arm C | NA Months |
Comparison: The test to compare TTNT between treatment Arms A versus B and Arms A versus C was the two-sided log-rank test, stratified by randomization stratification factors. The estimate of the HR and the corresponding 95% CI was computed using a Cox proportional hazards model stratified by randomization stratification factors. Randomization stratification factors were based on the data recorded in IXRS.p-value: <0.000195% CI: [0.08, 0.26]Log Rank
p-value: <0.000195% CI: [0.15, 0.4]Log Rank