A Study of Obinutuzumab + Bendamustine (BG) in Participants With Previously Untreated Chronic Lymphocytic Leukemia (CLL)

Study Overview
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Brief Summary
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This is a Phase 2, open-label, multicenter study to evaluate the safety and efficacy of BG induction therapy in participants with previously untreated CLL. The anticipated time on study treatment is 24 weeks.

Official Title
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A Phase II, Open-Label Study of Obinutuzumab Plus Bendamustine (BG) in Patients With Previously Untreated Chronic Lymphocytic Leukemia

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Bendamustine
* Drug: Obinutuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must satisfy one of the criteria for treatment initiation, as outlined in the iwCLL NCI-WG guidelines. The criteria include: (a) Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia, (b) Massive (i.e., greater than or equal to [>=] 6 centimeters [cm] below the left costal margin) or progressive or symptomatic splenomegaly, (c) Massive nodes (i.e., >= 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy, (d) Progressive lymphocytosis with an increase of greater than (>) 50 percent (%) over a 2-month period or lymphocyte doubling time (LDT) of less than (<) 6 months, (e) Autoimmune anemia and/or thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy, (f) Constitutional symptoms, defined as any one or more of the following disease-related symptoms or signs: unintentional weight loss of >=10% within the previous 6 months, significant fatigue (i.e., Eastern Cooperative Oncology Group Performance Status [ECOG PS] of 2 or worse or the inability to work or perform usual activities), fevers higher than 100.5 degrees Fahrenheit (°F)/38.0 degrees Celsius (°C) for >= 2 weeks without other evidence of infection, or night sweats for >1 month without evidence of infection Absolute neutrophil count (ANC) >=1.5 × 10^9 per liter (/L) and platelets >=75 × 10^9/L unless cytopenia is caused by the underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g., myelodysplastic syndrome, hypoplastic bone marrow) Life expectancy >6 months ECOG PS of 0, 1, or 2 Willing to use acceptable contraceptive measures as defined by the protocol during and at least for 6 months (male participants) or 12 months (female participants) after the last dose of study drug Exclusion Criteria: Pregnant or lactating, or intending to become pregnant during the study: Women who are not postmenopausal (>=12 months of non-therapy-induced amenorrhea) or surgically sterile must have a negative serum pregnancy test result within 14 days prior to initiation of study drug Participants who have received previous CLL therapy, including investigational therapies Transformation of CLL to aggressive non-Hodgkin's lymphoma (Richter's transformation) Inadequate renal function Inadequate liver function: National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Grade 3 liver function tests (aspartate aminotransferase [AST] or alanine aminotransferase [ALT] >5× upper limit of normal [ULN] for >2 weeks; bilirubin >3× ULN) unless due to underlying disease History of other malignancy, which could affect compliance with the protocol or interpretation of results Participants with active bacterial, viral, or fungal infection requiring systemic treatment Participants with known infection with human immunodeficiency virus (HIV) or human T-cell leukemia virus 1 (HTLV-1) Positive hepatitis serology: (a) Participants with positive serology for hepatitis B, defined as positivity for hepatitis B surface antigen (HBsAg), or participants who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive, (b) Participants positive for anti-HBc, but with negative hepatitis B Virus (HBV) deoxyribonucleic acid (DNA), will be considered for inclusion by the Medical Monitor on a case-by-case basis in order to ensure feasibility of monthly DNA testing and availability of appropriate care in case of hepatitis B reactivation, (c) Participants with positive serology for hepatitis C (HCV) unless HCV (by ribonucleic acid [RNA]) is confirmed negative History of severe allergic or anaphylactic reactions to monoclonal antibodies Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of symptomatic bronchospasm) Vaccination with a live vaccine a minimum of 30 days prior to study treatment Use of investigational agents of any kind within 30 days before study treatment

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Obinutuzumab + Bendamustine (BG)<br>Participants received obinutuzumab + bendamustine (BG) induction therapy in 28-day cycles for 6 cycles. | Drug: Bendamustine<br>* Bendamustine was administered as an intravenous infusion at a dose of 90 milligrams per square meter (mg/m^2) on Days 2 and 3 Cycle 1; and on Days 1 and 2 Cycles 2-6.<br>* Other names: Levact;Drug: Obinutuzumab<br>* Obinutuzumab was administered as an intravenous infusion at a dose of 100 milligrams (mg) on Day 1 Cycle 1; at a dose of 900 mg on Day 2 Cycle 1; at a dose of 1000 mg on Days 8 and 15 Cycle 1, and Day 1 Cycles 2-6.<br>* Other names: RO5072759;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Complete Response (CR), as Determined by the Investigator Using International Workshop on Chronic Lymphocytic Leukemia National Cancer Institute-Working Group (iwCLL NCI-WG) Guidelines | The CR rate was defined as CR or CR with incomplete blood count recovery (CRi), assessed by the investigator according to iwCLL NCI-WG criteria. The definition of confirmed CR required all of the following criteria as assessed at least 2 months after completion of therapy: peripheral blood lymphocytes < 4 times 10^9 cells/L; absence of significant lymphadenopathy, hepatomegaly, or splenomegaly due to CLL involvement; absence of constitutional symptoms; normal complete blood count (CBC) without need for transfusion or exogenous growth factors, as exhibited by neutrophils >/= 1.5 times 10^9 cells/L, platelets > 100 times 10^9 cells/L, and hemoglobin > 11.0 g/dL; normocellular BM aspirate with < 30% lymphocytes; absence of lymphoid nodules; and BM biopsy without CLL activity. Those fulfilling CR criteria but who have persistent anemia, thrombocytopenia, or neutropenia were considered CRi. | 2 to 3 months after the last infusion of study treatment (up to approximately 228 to 258 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Objective Response of CR or Partial Response (PR) at the End of Induction Therapy, as Determined by the Investigator Using iwCLL NCI-WG Guidelines | CR is defined in the previous outcome measure. The definition of PR required that the following be documented for minimum 2 months: >/= 50% decrease in peripheral blood lymphocytes from Baseline; reduction in lymphadenopathy; >/= 50% reduction in spleen or liver enlargement; and CBC with one of the following without need for transfusion or exogenous growth factors: polymorphonuclear leukocytes >/= 1.5 times 10^9 cells/L, platelets > 100 times 10^9 cells/L or >/= 50% improvement from Baseline, or hemoglobin > 11.0 g/dL or >/= 50% improvement from Baseline. | 2 to 3 months after the last infusion of study treatment (up to approximately 228 to 258 days) | 
| Duration of Response Among Participants With Objective Response of CR or PR, as Determined by the Investigator Using iwCLL NCI-WG Guidelines | Duration of response was defined as the time from the first assessment of CR, CRi, PR, or nodular partial response (nPR) to the first documentation of PD or death, whichever occurred first. CR, CRi, and PR are identified in previous outcome measures. Participants with lymphoid nodules who otherwise met CR criteria were considered nPR. Participants with post-baseline response assessments (excluding progressive disease) but with no end-of-induction treatment response available were censored on Day 1, and those with end-of-induction treatment response available but who did not experience death or disease progression before the end of the study were censored on the day of the last available assessment. | From the first assessment of CR, CRi, PR, or nPR (at up to approximately 228 to 258 days) until disease progression, relapse, or death from any cause, whichever occurred first (up to 46 months) | 
| Progression-Free Survival (PFS), as Determined by the Investigator Using iwCLL NCI-WG Guidelines | PFS was defined as the time from the start of induction treatment (Day 1) to the first occurrence of disease progression, relapse as determined by the investigator using iwCLL NCI WG guidelines, or death (within 28 days after the last dose of study drug), whichever occurred first. Disease progression: at least one of the following: lymphadenopathy; increase in the liver or spleen size by 50% or more or the appearance of hepatomegaly or splenomegaly; an increase in the number of blood lymphocytes by 50% or more with at least 5000 B lymphocytes per microliter; transformation to a more aggressive histology; occurrence of cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL. Relapse: Having achieved CR or PR, but after a period of 6 or more months, having demonstrated evidence of disease progression. Participants who did not experience death or disease progression before the end of the study were censored on the day of the last available assessment. | Day 1 until disease progression, relapse, or death from any cause, whichever occurred first (up to 46 months) | 
| Overall Survival (OS) | OS was defined as the time from the start of induction treatment to death from any cause. Participants who did not experience death or disease progression before the end of the study were censored on the day of the last available assessment. | Day 1 until death from any cause (up to 46 months) | 
| Percentage of Participants Who Achieved Minimal Residual Disease (MRD)-Negative Status in Bone Marrow at Any Time During the Study | MRD was assessed by 4-color flow cytometry, using iwCLL criteria for MRD negativity (<1 CLL cell detected in 10,000 leukocytes) in bone marrow aspirate. Flow cytometry provides rapid analysis of multiple characteristics of single cells by using light to count and profile cells in a fluid mixture. | Up to 46 months | 
| Percentage of Participants Who Achieved MRD-Negative Status in Peripheral Blood at Any Time During the Study | MRD was assessed by 4-color flow cytometry, using iwCLL criteria for MRD negativity (<1 CLL cell detected in 10,000 leukocytes) in peripheral blood. Flow cytometry provides rapid analysis of multiple characteristics of single cells by using light to count and profile cells in a fluid mixture. | Baseline up to 46 months | 
| Time to MRD-Negative Status in Peripheral Blood | MRD was assessed by 4-color flow cytometry, using iwCLL criteria for MRD negativity if the value is <10^-4 (<1 CLL cell detected in 10,000 leukocytes) in peripheral blood. Flow cytometry provides rapid analysis of multiple characteristics of single cells by using light to count and profile cells in a fluid mixture. Time to MRD-negative status is defined as the time between MRD positivity (>= 10^-4) or the time of first dose treatment for patients who were missing MRD status assessment at baseline to the first achievement of MRD negativity in the peripheral blood. | Baseline up to 46 months | 
| Duration of MRD-Negativity in Peripheral Blood Among Participants Who Achieved MRD-Negative Status | MRD was assessed by 4-color flow cytometry, using iwCLL criteria for MRD negativity (<1 CLL cell detected in 10,000 leukocytes) in peripheral blood. Flow cytometry provides rapid analysis of multiple characteristics of single cells by using light to count and profile cells in a fluid mixture. Duration of MRD-negativity among patients who achieved MRD negativity in the study is defined as the period between the first occurrence of MRD-negative status and a subsequent MRD-positive status. | Baseline up to 46 months | 
| Minimum Observed Concentration (Ctrough) of Obinutuzumab After Cycle 2 | Ctrough is the measured concentration of a drug at the end of a dosing interval at steady state. | Pre-infusion (0 hours) on Day 1 Cycle 3 (1 cycle = 28 days) | 
| Ctrough of Obinutuzumab After Cycle 4 | Ctrough is the measured concentration of a drug at the end of a dosing interval at steady state. | Pre-infusion (0 hours) on Day 1 Cycle 5 (1 cycle = 28 days) | 
| Change From Baseline in the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) Score | The EORTC QLQ-C30 included global health status, functional scales (physical, role, emotional, cognitive, and social), symptom scales (fatigue, nausea/vomiting, and pain) and single items (dyspnoea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). Most questions used a 4-point scale (1 'Not at all' to 4 'Very much'; 2 questions used 7-point scale [1 'very poor' to 7 'Excellent']). Scores were averaged and transformed to 0 - 100 scale, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive change from Day 1, Cycle 1 (baseline) indicates improvement. EOT=end of treatment. | Day 1 Cycles 1 (baseline), 3, 6; end of treatment, 2 months after last dose, every 3 months thereafter for 2 years (up to 46 months) (1 cycle = 28 days) | 
| Change From Baseline in the EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) Score | The EORTC Quality of Life Questionnaire-Chronic Lymphocytic Leukemia 16 (QLQ-CLL16) module included assessments of fatigue, treatment side effects, disease symptoms, infection, social activities, and future health worries. Final scores are transformed such that they range from 0 - 100, whereby higher scores indicate greater functioning, greater quality of life, or a greater degree of symptoms, with changes of 5 - 10 points considered to be a minimally important difference to participants. A positive change from Day 1, Cycle 1 (baseline) indicates improvement. EOT=end of treatment. | Day 1 Cycles 1 (baseline), 3, 6; end of treatment, 2 months after last dose, every 3 months thereafter for 2 years (up to 46 months) (1 cycle = 28 days) | 
| Number of Hospitalizations Due to Adverse Events (AEs) | An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. | Day 1 up to 46 months | 
| Percentage of Participants With Adverse Events (AEs) | An AE is any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not considered related to the study drug. | Day 1 up to 46 months |