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

Chronic Lymphocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02320487
• Other study ID #: ML29538
• Status: Completed
• Phase: Phase 2
• Start date: March 31, 2015
• Est. completion date: February 6, 2019

Study information

• Verified date: February 2020
• Source: Genentech, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 102
• Est. completion date: February 6, 2019
• Est. primary completion date: November 7, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Bendamustine
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.
• Obinutuzumab
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.

Locations

Country	Name	City	State
United States	Texas Oncology-Arlington	Arlington	Texas
United States	Piedmont Cancer Institute, PC	Atlanta	Georgia
United States	Rocky Mountain Cancer Center - Aurora	Aurora	Colorado
United States	Center For Cancer and Blood Disorders	Bethesda	Maryland
United States	Ironwood Cancer TX & Rsch Ctrs	Chandler	Arizona
United States	Virginia Cancer Specialists, PC	Fairfax	Virginia
United States	San Juan Oncology Associates	Farmington	New Mexico
United States	Highlands Oncology Group	Fayetteville	Arkansas
United States	Cancer Care and Hematology	Fort Collins	Colorado
United States	Fort Wayne Med Oncology & Hematology Inc	Fort Wayne	Indiana
United States	Clearview Cancer Institute	Huntsville	Alabama
United States	Texas Oncology-Tyler	Irving	Texas
United States	Joe Arrington Cancer Research & Treatment Center	Lubbock	Texas
United States	Northwest Georgia Oncology Centers PC - Marietta	Marietta	Georgia
United States	Southern Cancer Center - Mobile	Mobile	Alabama
United States	Regional Cancer Care Associates LLC - Morristown	Morristown	New Jersey
United States	Cancer Care Centers of South Texas-HOAST - San Antonio	New Braunfels	Texas
United States	Cancer Care & Hematology; Specialists of Chicagoland	Niles	Illinois
United States	Northern Utah Associates	Ogden	Utah
United States	Northwest Cancer Specialists - Portland (N Broadway)	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Willamette Valley Cancer Insitute and Research Center	Springfield	Oregon
United States	Stony Brook University Hospital	Stony Brook	New York
United States	Arizona Oncology Associates, PC - HAL	Tempe	Arizona
United States	Arizona Oncology Associates, PC - HOPE	Tucson	Arizona
United States	Yakima Valley Memorial Hospital/North Star Lodge	Yakima	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Genentech, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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