A Study of Obinutuzumab (GA101; RO5072759) in Combination With Chemotherapy in Participants With Previously Untreated Chronic Lymphocytic Leukemia (CLL) (GALTON)

• Sponsor: Genentech, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01300247
• Collaborator: (none)
• Enrollment: 41
• Locations: 18
• Arms: 2
• Duration (Months): 55
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This open-label, 2-arm, nonrandomized, multicenter, Phase Ib study will investigate the safety and efficacy of obinutuzumab (RO5072759; GA101) administered in combination with chemotherapy (bendamustine or fludarabine + cyclophosphamide [FC] regimens) in participants with previously untreated cluster of differentiation 20 (CD20)-positive B-CLL. Participants will be enrolled to receive a maximum of 6 cycles of obinutuzumab (1000 milligrams [mg] intravenous [IV] infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2 - 6) plus bendamustine (90 milligrams per meter square [mg/m^{2] IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2 - 6) on 28 day cycles or a maximum of 6 cycles of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2 - 6) plus FC (fludarabine 25 mg/m}2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2 - 6; cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2

• 1. on 28 day cycles.

Condition or Disease	Intervention/Treatment	Phase
Lymphocytic Leukemia, Chronic	Drug: Fludarabine; Drug: Obinutuzumab; Drug: Bendamustine; Drug: Cyclophosphamide	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multicenter, Phase Ib Trial of GA101 (RO5072759) in Combination With Chemotherapy in Patients With Previously Untreated Chronic Lymphocytic Leukemia
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Obinutuzumab + Fludarabine + Cyclophosphamide Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6), and cyclophosphamide (250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6).	Drug: Fludarabine; Participants will receive 6 cycles (each 28-day cycle) of fludarabine at dose of 25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6.; Drug: Obinutuzumab; Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab at dose of 1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6.; Other Names: RO5072759; GA101 ; Drug: Cyclophosphamide; Participants will receive 6 cycles (each 28-day cycle) of cyclophosphamide at dose of 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6.
Experimental: Obinutuzumab + Bendamustine Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).	Drug: Obinutuzumab; Participants will receive 6 cycles (each 28-day cycle) of obinutuzumab at dose of 1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6.; Other Names: RO5072759; GA101 ; Drug: Bendamustine; Participants will receive 6 cycles (each 28-day cycle) of bendamustine at dose of 90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Human Anti-Human Antibodies (HAHAs) [Cycle 1 Day 1 (cycle length = 28 days) up to clinical data cutoff date 24 January 2013 (up to approximately 1.75 years)]

Secondary Outcome Measures

1. Area Under the Plasma Concentration-Time Curve (AUC) of Obinutuzumab [Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)]

   AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.

2. Maximum Plasma Concentration (Cmax) of Obinutuzumab [Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)]

3. Trough Plasma Concentration (Ctrough) of Obinutuzumab [Pre-dose on C1D1, C1D3, 8, 15, C2D1, C4D1, C6D1]

4. Clearance of Obinutuzumab [Pre-dose on C1D1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)]

   Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.

5. Volume of Distribution of Obinutuzumab [Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)]

   Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.

6. Half-Life of Obinutuzumab [Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)]

   Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.

7. Percentage of Participants With Objective Response, Assessed According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines [Baseline up to relapse or progression or death from any cause, whichever occurred first up to end of treatment response visit (up to approximately 9 months)]

   Objective response was defined as a complete response (CR), CR with incomplete marrow recovery (CRi) or partial response (PR), as determined by investigator. CR:required peripheral blood lymphocytes <4x10^9/L; absence of lymphadenopathy; no hepatomegaly or splenomegaly by physical examination as determined by measurement below relevant costal margin; absence of disease/constitutional symptoms; bone marrow at least normocellular for age, with <30% of nucleated cells being lymphocytes. PR:Greater than equal to (>=) 50% decrease in peripheral blood lymphocyte count, >=50% reduction in lymphadenopathy, >=50% reduction of liver and/or spleen enlargement, either neutrophil, platelet, or hemoglobin (Hb) recovery. CRi:met all CR criteria including confirmed lymphocyte infiltration <30%; may not meet Hb, platelet or neutrophil count recovery. The 95% confidence interval (CI) was estimated by Clopper-Pearson method. The end of treatment response visit occurred 2-3 months after end of treatment.

8. Duration of Objective Response (DOR), Assessed by the Investigator According to IWCLL Guidelines [From first documented objective response up to disease progression or relapse or death, whichever occurred first (up to approximately 6 months)]

   DOR for participants with OR: time from first CR, CRi or PR to disease progression (DP), relapse, or death, assessed by the investigator. DP: >=50% increase in lymphocytes to at least 5x10^9/L;new palpable lymph nodes (>15 millimeters [mm] in longest diameter) or any new extra-nodal lesion; >=50% increase in the longest diameter of any previous site of lymphadenopathy; >=50% increase in the enlargement of the liver and/or spleen; transformation to a more aggressive histology. CR:peripheral blood lymphocytes (PBL) <4x10^9/L; no lymphadenopathy; no hepatomegaly or splenomegaly (below relevant costal margin); no symptoms; bone marrow at least normocellular for age, with <30% of nucleated cells being lymphocytes. PR: >=50% decrease in PBL, >=50% reduction in lymphadenopathy, >=50% reduction of liver and/or spleen enlargement, either neutrophil, platelet, or hemoglobin (Hb) recovery. CRi: met CR criteria, lymphocyte infiltration <30%; may not meet Hb, platelet or neutrophil count recovery.

9. Percentage of Participants Who Were Alive and Progression Free [Baseline up to relapse or progression or death from any cause, whichever occurred first, up to end of study (up to approximately 4 years)]

   Progressive disease assessed using IWCLL: >=50% increase in the absolute number of circulating lymphocytes to at least 5x10^9/L; Appearance of new palpable lymph nodes (>15 millimeters [mm] in longest diameter) or any new extra-nodal lesion; >=50% increase in the longest diameter of any previous site of lymphadenopathy; >=50% increase in the enlargement of the liver and/or spleen; transformation to a more aggressive histology.

10. Percentage of Participants Who Were Alive [Baseline up to relapse or progression or death from any cause, whichever occurred first, up to end of study (up to approximately 4 years)]

11. Percentage of Participants Who Had B-Cell Depletion [Up to the end of the treatment period, and follow-up at 6 months, 6-12 months and after 12 months up to end of study (up to approximately 4 years)]

    B-cell depletion was defined as cluster of differentiation 19 (CD19) <0.07×10^9/L and could occur only after at least one dose of study drug had been administered.

12. Percentage of Participants Who Had B-Cell Recovery [Follow-up at 6 months, 6-12 months and after 12 months up to end of study (up to approximately 4 years)]

    B-cell recovery was defined as CD19 >=0.07×10^9/L, where participants' CD19 were previously depleted. B-cell recovery was only considered possible when the participant had received the last dose of study treatment.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Confirmed diagnosis of CD20-positive B-CLL

• Rai Stage III/IV or Binet Stage C disease

• Rai Stage I/II or Binet Stage B disease that requires treatment

• Adequate baseline bone marrow function, unless there is clear evidence of extensive bone marrow involvement with tumor infiltration, myelodysplasia, or hypocellularity

• No previous treatment for CLL by chemotherapy, radiotherapy, or immunotherapy

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

• Life expectancy of greater than (>) 6 months

Exclusion Criteria:

• Treatment with any other investigational agent or participation in another clinical trial within 28 days prior to the start of Cycle 1

• Transformation of CLL to aggressive B-cell malignancy

• Creatinine clearance less than equal to (<=) 60 milliliters per minute (mL/min), calculated according to the formula of Cockcroft and Gault

• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN)

• Total bilirubin greater than equal to (>=) 3 x ULN

• History of severe allergic or anaphylactic reactions to monoclonal antibody therapy

• History of sensitivity to mannitol (if bendamustine is to be administered)

• History of other malignancy that could affect compliance with the protocol or interpretation of results

• Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease or pulmonary disease

• Known active bacterial, viral, fungal, mycobacterial, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (related to the completion of the course of antibiotics) within 4 weeks before the start of Cycle 1

• Recent major surgery (within 4 weeks prior to the start of Cycle 1), other than for diagnosis

• Known infection with human immunodeficiency virus (HIV) seropositive status

• Presence of positive test results for hepatitis B (hepatitis B virus [HBV] surface antigen [HBsAg] and/or total hepatitis B core antibody [anti-HBc]) or hepatitis C (hepatitis C virus [HCV] antibody serology testing). Participants with chronic HBV infection, occult HBV infection, or past HBV infection will be excluded. Participants who have received IV immunoglobulin within 3 months of enrollment and who are anti-HBc positive but HBV deoxyribonucleic acid (DNA) negative will be considered for inclusion on the study by the Medical Monitor on a case-by-case basis. Participants positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA).

• Women who are pregnant or lactating

• Fertile men or women of childbearing potential unless 1) surgically sterile or 2) using an adequate measure of contraception such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly

• Concurrent (or within 7 days prior to the first dose of study treatment) systemic corticosteroid use except low-dose corticosteroid therapy used to treat an illness other than lymphoma

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Huntsville	Alabama	United States	35805
2		Duarte	California	United States	91010
3		La Jolla	California	United States	92093
4		Los Angeles	California	United States	90095
5		Southington	Connecticut	United States	06489
6		Tampa	Florida	United States	33612-9497
7		Atlanta	Georgia	United States	30322
8		Marietta	Georgia	United States	30060
9		Chicago	Illinois	United States	60637
10		Boston	Maryland	United States	02115
11		Boston	Massachusetts	United States	02114
12		St. Louis Park	Minnesota	United States	55426
13		Springfield	Missouri	United States	65807
14		Rochester	New York	United States	14642
15		Houston	Texas	United States	77030
16		Seattle	Washington	United States	98109
17		Tacoma	Washington	United States	98405
18		Madison	Wisconsin	United States	53705

Sponsors and Collaborators

• Genentech, Inc.

Investigators

• Study Director: Clinical Trials, Genentech, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Genentech, Inc.
• ClinicalTrials.gov Identifier: NCT01300247
• Other Study ID Numbers: GAO4779g; GO01298
• First Posted: Feb 21, 2011
• Last Update Posted: Feb 2, 2017
• Last Verified: Dec 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Cyclophosphamide; Bendamustine Hydrochloride; Fludarabine; Obinutuzumab

Study Results

Participant Flow

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 milligrams [mg] intravenous [IV] infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 milligrams per meter square [mg/m^2] IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Period Title: Overall Study
STARTED	21	20
COMPLETED	17	18
NOT COMPLETED	4	2

Baseline Characteristics

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine	Total
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).	Total of all reporting groups
Overall Participants	21	20	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.8 (11.1)	62.0 (9.0)	59.8 (10.2)
Gender (Count of Participants)
Female	4 19%	5 25%	9 22%
Male	17 81%	15 75%	32 78%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Human Anti-Human Antibodies (HAHAs)
Time Frame	Cycle 1 Day 1 (cycle length = 28 days) up to clinical data cutoff date 24 January 2013 (up to approximately 1.75 years)

Outcome Measure Data

Analysis Population Description

Safety evaluable population

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
Number [participants]	0 0%	0 0%

2. Secondary Outcome

Title	Area Under the Plasma Concentration-Time Curve (AUC) of Obinutuzumab
Description	AUC is a measure of the serum concentration of the drug over time. It is used to characterize drug absorption.
Time Frame	Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) variables could not be calculated as the PK samples were not collected accurately.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	0	0

3. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) of Obinutuzumab
Time Frame	Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)

Outcome Measure Data

Analysis Population Description

The PK variables could not be calculated as the PK samples were not collected accurately.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	0	0

4. Secondary Outcome

Title	Trough Plasma Concentration (Ctrough) of Obinutuzumab
Time Frame	Pre-dose on C1D1, C1D3, 8, 15, C2D1, C4D1, C6D1

Outcome Measure Data

Analysis Population Description

The PK variables could not be calculated as the PK samples were not collected accurately.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	0	0

5. Secondary Outcome

Title	Clearance of Obinutuzumab
Description	Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Clearance was estimated from population PK modeling. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time Frame	Pre-dose on C1D1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)

Outcome Measure Data

Analysis Population Description

The PK variables could not be calculated as the PK samples were not collected accurately.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	0	0

6. Secondary Outcome

Title	Volume of Distribution of Obinutuzumab
Description	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/F) is influenced by the fraction absorbed.
Time Frame	Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)

Outcome Measure Data

Analysis Population Description

The PK variables could not be calculated as the PK samples were not collected accurately.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	0	0

7. Secondary Outcome

Title	Half-Life of Obinutuzumab
Description	Plasma decay half-life is the time measured for the plasma concentration to decrease by one half.
Time Frame	Pre-dose on Cycle (C) 1 Day (D) 1, immediately after end of infusion (0.5 hour), 0.5 hour of split dose of C1D2, pre-dose and immediately after end of infusion on C1D3, 8, 15, C2D1, C4D1, C6D1 and at progression (up to 1.75 year overall)

Outcome Measure Data

Analysis Population Description

The PK variables could not be calculated as the PK samples were not collected accurately.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	0	0

8. Secondary Outcome

Title	Percentage of Participants With Objective Response, Assessed According to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) Guidelines
Description	Objective response was defined as a complete response (CR), CR with incomplete marrow recovery (CRi) or partial response (PR), as determined by investigator. CR:required peripheral blood lymphocytes <4x10^9/L; absence of lymphadenopathy; no hepatomegaly or splenomegaly by physical examination as determined by measurement below relevant costal margin; absence of disease/constitutional symptoms; bone marrow at least normocellular for age, with <30% of nucleated cells being lymphocytes. PR:Greater than equal to (>=) 50% decrease in peripheral blood lymphocyte count, >=50% reduction in lymphadenopathy, >=50% reduction of liver and/or spleen enlargement, either neutrophil, platelet, or hemoglobin (Hb) recovery. CRi:met all CR criteria including confirmed lymphocyte infiltration <30%; may not meet Hb, platelet or neutrophil count recovery. The 95% confidence interval (CI) was estimated by Clopper-Pearson method. The end of treatment response visit occurred 2-3 months after end of treatment.
Time Frame	Baseline up to relapse or progression or death from any cause, whichever occurred first up to end of treatment response visit (up to approximately 9 months)

Outcome Measure Data

Analysis Population Description

Safety evaluable population

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
Number (95% Confidence Interval) [percentage of participants]	61.9 294.8%	90.0 450%

9. Secondary Outcome

Title	Duration of Objective Response (DOR), Assessed by the Investigator According to IWCLL Guidelines
Description	DOR for participants with OR: time from first CR, CRi or PR to disease progression (DP), relapse, or death, assessed by the investigator. DP: >=50% increase in lymphocytes to at least 5x10^9/L;new palpable lymph nodes (>15 millimeters [mm] in longest diameter) or any new extra-nodal lesion; >=50% increase in the longest diameter of any previous site of lymphadenopathy; >=50% increase in the enlargement of the liver and/or spleen; transformation to a more aggressive histology. CR:peripheral blood lymphocytes (PBL) <4x10^9/L; no lymphadenopathy; no hepatomegaly or splenomegaly (below relevant costal margin); no symptoms; bone marrow at least normocellular for age, with <30% of nucleated cells being lymphocytes. PR: >=50% decrease in PBL, >=50% reduction in lymphadenopathy, >=50% reduction of liver and/or spleen enlargement, either neutrophil, platelet, or hemoglobin (Hb) recovery. CRi: met CR criteria, lymphocyte infiltration <30%; may not meet Hb, platelet or neutrophil count recovery.
Time Frame	From first documented objective response up to disease progression or relapse or death, whichever occurred first (up to approximately 6 months)

Outcome Measure Data

Analysis Population Description

Safety evaluable population.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
Number (95% Confidence Interval) [percentage of participants]	NA NaN	100.00 500%

10. Secondary Outcome

Title	Percentage of Participants Who Were Alive and Progression Free
Description	Progressive disease assessed using IWCLL: >=50% increase in the absolute number of circulating lymphocytes to at least 5x10^9/L; Appearance of new palpable lymph nodes (>15 millimeters [mm] in longest diameter) or any new extra-nodal lesion; >=50% increase in the longest diameter of any previous site of lymphadenopathy; >=50% increase in the enlargement of the liver and/or spleen; transformation to a more aggressive histology.
Time Frame	Baseline up to relapse or progression or death from any cause, whichever occurred first, up to end of study (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

Safety evaluable population.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
Number [percentage of participants]	90.5 431%	90.0 450%

11. Secondary Outcome

Title	Percentage of Participants Who Were Alive
Time Frame	Baseline up to relapse or progression or death from any cause, whichever occurred first, up to end of study (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

Safety evaluable population.

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
Number [percentage of participants]	95.2 453.3%	95.0 475%

12. Secondary Outcome

Title	Percentage of Participants Who Had B-Cell Depletion
Description	B-cell depletion was defined as cluster of differentiation 19 (CD19) <0.07×10^9/L and could occur only after at least one dose of study drug had been administered.
Time Frame	Up to the end of the treatment period, and follow-up at 6 months, 6-12 months and after 12 months up to end of study (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

Safety evaluable population

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
End of the treatment period	90.5 431%	100.0 500%
Follow-up at 6 months	85.7 408.1%	100.0 500%
Within 6-12 months of follow-up	81.0 385.7%	100.0 500%
After 12 months follow-up	47.6 226.7%	70.0 350%

13. Secondary Outcome

Title	Percentage of Participants Who Had B-Cell Recovery
Description	B-cell recovery was defined as CD19 >=0.07×10^9/L, where participants' CD19 were previously depleted. B-cell recovery was only considered possible when the participant had received the last dose of study treatment.
Time Frame	Follow-up at 6 months, 6-12 months and after 12 months up to end of study (up to approximately 4 years)

Outcome Measure Data

Analysis Population Description

Safety evaluable population

Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide	Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
Measure Participants	21	20
Follow-up at 6 months	0 0%	0 0%
Within 6-12 months of follow-up	9.5 45.2%	0 0%
After 12 months follow-up	42.9 204.3%	30.0 150%

Adverse Events

Time Frame	Up to the end of the study (up to approximately 4 years).
Adverse Event Reporting Description	All adverse events (related and unrelated to treatment) were to be collected up to 28 days after the last dose of obinutuzumab. After 28 days after the last dose of obinutuzumab, investigators were to report only serious adverse events that were attributed to obinutuzumab; these were to be reported to Genentech/Roche Drug Safety indefinitely (even if the study was closed). Significant abnormalities in laboratory parameters were reported as adverse events.
Arm/Group Title	Obinutuzumab + Fludarabine + Cyclophosphamide		Obinutuzumab + Bendamustine
Arm/Group Description	Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6), fludarabine (25 mg/m^2 IV, on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6) and cyclophosphamide 250 mg/m^2 IV on Days 2, 3 and 4 of Cycle 1 and Days 1, 2 and 3 of Cycles 2-6). The Cycle 1 Day 1 dose of obinutuzumab was split over two days (Cycle 1 Day 1 and Cycle 1 Day 2).		Participants received 6 cycles (each 28-day cycle) of obinutuzumab (1000 mg IV infusion, on Days 1, 8 and 15 of Cycle 1 and Day 1 of Cycles 2-6) and bendamustine (90 mg/m^2 IV, on Days 2 and 3 of Cycle 1 and Days 1 and 2 of Cycles 2-6).
All Cause Mortality
	Obinutuzumab + Fludarabine + Cyclophosphamide		Obinutuzumab + Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Obinutuzumab + Fludarabine + Cyclophosphamide		Obinutuzumab + Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/21 (28.6%)		11/20 (55%)
Blood and lymphatic system disorders
Febrile neutropenia	3/21 (14.3%)		2/20 (10%)
Leukopenia	0/21 (0%)		1/20 (5%)
Neutropenia	0/21 (0%)		1/20 (5%)
Cardiac disorders
Tachycardia	0/21 (0%)		1/20 (5%)
Gastrointestinal disorders
Nausea	1/21 (4.8%)		1/20 (5%)
Vomiting	1/21 (4.8%)		1/20 (5%)
Diarrhoea	1/21 (4.8%)		0/20 (0%)
General disorders
Pyrexia	0/21 (0%)		2/20 (10%)
Fatigue	0/21 (0%)		1/20 (5%)
Infections and infestations
Appendicitis	1/21 (4.8%)		0/20 (0%)
Cellulitis	1/21 (4.8%)		0/20 (0%)
Pneumonia	1/21 (4.8%)		0/20 (0%)
Skin infection	0/21 (0%)		1/20 (5%)
Injury, poisoning and procedural complications
Infusion related reaction	0/21 (0%)		3/20 (15%)
Investigations
Neutrophil count decreased	1/21 (4.8%)		0/20 (0%)
Metabolism and nutrition disorders
Tumour lysis syndrome	0/21 (0%)		1/20 (5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Small cell lung cancer	0/21 (0%)		1/20 (5%)
Squamous cell carcinoma	0/21 (0%)		1/20 (5%)
Nervous system disorders
Syncope	0/21 (0%)		1/20 (5%)
Psychiatric disorders
Mental status changes	0/21 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Pneumonitis	0/21 (0%)		1/20 (5%)
Pneumothorax	0/21 (0%)		1/20 (5%)
Respiratory failure	0/21 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Swelling face	0/21 (0%)		1/20 (5%)
Vascular disorders
Hypertension	0/21 (0%)		1/20 (5%)
Other (Not Including Serious) Adverse Events
	Obinutuzumab + Fludarabine + Cyclophosphamide		Obinutuzumab + Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/21 (100%)		20/20 (100%)
Blood and lymphatic system disorders
Neutropenia	5/21 (23.8%)		10/20 (50%)
Anaemia	5/21 (23.8%)		3/20 (15%)
Thrombocytopenia	3/21 (14.3%)		5/20 (25%)
Febrile neutropenia	2/21 (9.5%)		0/20 (0%)
Cytopenia	0/21 (0%)		2/20 (10%)
Lymphadenopathy	0/21 (0%)		1/20 (5%)
Leukopenia	0/21 (0%)		1/20 (5%)
Cardiac disorders
Tachycardia	0/21 (0%)		1/20 (5%)
Ear and labyrinth disorders
Vertigo	0/21 (0%)		1/20 (5%)
Eye disorders
Vision blurred	1/21 (4.8%)		1/20 (5%)
Gastrointestinal disorders
Nausea	16/21 (76.2%)		12/20 (60%)
Constipation	10/21 (47.6%)		7/20 (35%)
Vomiting	7/21 (33.3%)		2/20 (10%)
Diarrhoea	4/21 (19%)		10/20 (50%)
Abdominal pain	1/21 (4.8%)		2/20 (10%)
Dyspepsia	1/21 (4.8%)		2/20 (10%)
Epigastric discomfort	1/21 (4.8%)		2/20 (10%)
Dysphagia	0/21 (0%)		2/20 (10%)
Gastrooesophageal reflux disease	2/21 (9.5%)		0/20 (0%)
Abdominal distension	0/21 (0%)		1/20 (5%)
Abdominal pain upper	0/21 (0%)		1/20 (5%)
Gastrointestinal disorder	0/21 (0%)		1/20 (5%)
Mouth ulceration	0/21 (0%)		1/20 (5%)
Stomatitis	0/21 (0%)		1/20 (5%)
General disorders
Fatigue	12/21 (57.1%)		7/20 (35%)
Pyrexia	5/21 (23.8%)		8/20 (40%)
Chills	2/21 (9.5%)		7/20 (35%)
Oedema peripheral	2/21 (9.5%)		1/20 (5%)
Pain	0/21 (0%)		3/20 (15%)
Asthenia	1/21 (4.8%)		1/20 (5%)
Injection site pain	0/21 (0%)		2/20 (10%)
Axillary pain	0/21 (0%)		1/20 (5%)
Catheter site pain	0/21 (0%)		1/20 (5%)
Chest discomfort	0/21 (0%)		1/20 (5%)
Malaise	0/21 (0%)		1/20 (5%)
Mucosal inflammation	0/21 (0%)		1/20 (5%)
Adverse drug reaction	1/21 (4.8%)		1/20 (5%)
Immune system disorders
Drug hypersensitivity	0/21 (0%)		1/20 (5%)
Cytokine release syndrome	0/21 (0%)		1/20 (5%)
Hypersensitivity	0/21 (0%)		1/20 (5%)
Infections and infestations
Upper respiratory tract infection	4/21 (19%)		3/20 (15%)
Sinusitis	0/21 (0%)		3/20 (15%)
Urinary tract infection	3/21 (14.3%)		0/20 (0%)
Bronchitis	1/21 (4.8%)		1/20 (5%)
Candida infection	2/21 (9.5%)		0/20 (0%)
Paronychia	2/21 (9.5%)		0/20 (0%)
Tooth infection	2/21 (9.5%)		0/20 (0%)
Clostridium difficile infection	0/21 (0%)		1/20 (5%)
Herpes zoster	1/21 (4.8%)		1/20 (5%)
Pharyngitis	0/21 (0%)		1/20 (5%)
Pneumonia	0/21 (0%)		1/20 (5%)
Injury, poisoning and procedural complications
Infusion related reaction	16/21 (76.2%)		11/20 (55%)
Contusion	0/21 (0%)		1/20 (5%)
Skin Abrasion	0/21 (0%)		1/20 (5%)
Investigations
Alanine aminotransferase increased	4/21 (19%)		1/20 (5%)
Aspartate aminotransferase increased	3/21 (14.3%)		1/20 (5%)
Blood creatinine increased	0/21 (0%)		1/20 (5%)
Electrocardiogram QT prolonged	0/21 (0%)		1/20 (5%)
Transaminases increased	0/21 (0%)		1/20 (5%)
Metabolism and nutrition disorders
Dehydration	2/21 (9.5%)		3/20 (15%)
Hypocalcaemia	0/21 (0%)		5/20 (25%)
Hypokalaemia	0/21 (0%)		3/20 (15%)
Hypomagnesaemia	0/21 (0%)		2/20 (10%)
Hyponatraemia	0/21 (0%)		2/20 (10%)
Decreased appetite	0/21 (0%)		1/20 (5%)
Gout	0/21 (0%)		1/20 (5%)
Hyperphosphataemia	0/21 (0%)		1/20 (5%)
Vitamin D deficiency	0/21 (0%)		1/20 (5%)
Hyperkalaemia	0/21 (0%)		1/20 (5%)
Musculoskeletal and connective tissue disorders
Bone pain	2/21 (9.5%)		4/20 (20%)
Arthralgia	1/21 (4.8%)		3/20 (15%)
Muscle spasms	2/21 (9.5%)		1/20 (5%)
Back pain	0/21 (0%)		2/20 (10%)
Joint swelling	0/21 (0%)		2/20 (10%)
Muscular weakness	1/21 (4.8%)		1/20 (5%)
Pain in extremity	2/21 (9.5%)		1/20 (5%)
Flank pain	0/21 (0%)		1/20 (5%)
Musculoskeletal pain	0/21 (0%)		1/20 (5%)
Nervous system disorders
Dizziness	2/21 (9.5%)		5/20 (25%)
Headache	0/21 (0%)		5/20 (25%)
Memory impairment	0/21 (0%)		2/20 (10%)
Aphonia	0/21 (0%)		1/20 (5%)
Balance disorder	0/21 (0%)		1/20 (5%)
Disturbance in attention	0/21 (0%)		1/20 (5%)
Hypoaesthesia	0/21 (0%)		1/20 (5%)
Muscle contractions involuntary	0/21 (0%)		1/20 (5%)
Neuropathy peripheral	0/21 (0%)		1/20 (5%)
Restless leg syndrome	0/21 (0%)		1/20 (5%)
Somnolence	0/21 (0%)		1/20 (5%)
Psychiatric disorders
Insomnia	4/21 (19%)		3/20 (15%)
Anxiety	0/21 (0%)		5/20 (25%)
Communication disorder	0/21 (0%)		1/20 (5%)
Depression	0/21 (0%)		1/20 (5%)
Renal and urinary disorders
Pollakiuria	2/21 (9.5%)		0/20 (0%)
Dysuria	0/21 (0%)		1/20 (5%)
Acute kidney injury	0/21 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	2/21 (9.5%)		6/20 (30%)
Dyspnoea	3/21 (14.3%)		3/20 (15%)
Dysphonia	1/21 (4.8%)		1/20 (5%)
Oropharyngeal pain	0/21 (0%)		2/20 (10%)
Pleural effusion	0/21 (0%)		2/20 (10%)
Productive cough	0/21 (0%)		2/20 (10%)
Dyspnoea exertional	0/21 (0%)		1/20 (5%)
Hiccups	0/21 (0%)		1/20 (5%)
Pulmonary oedema	0/21 (0%)		1/20 (5%)
Throat irritation	0/21 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Rash	2/21 (9.5%)		5/20 (25%)
Pruritus	1/21 (4.8%)		4/20 (20%)
Erythema	1/21 (4.8%)		2/20 (10%)
Dry skin	1/21 (4.8%)		1/20 (5%)
Petechiae	0/21 (0%)		2/20 (10%)
Pruritus generalized	0/21 (0%)		2/20 (10%)
Rash maculo-papular	0/21 (0%)		2/20 (10%)
Rash pruritic	2/21 (9.5%)		0/20 (0%)
Acne	0/21 (0%)		1/20 (5%)
Butterfly rash	0/21 (0%)		1/20 (5%)
Eczema nummular	0/21 (0%)		1/20 (5%)
Hyperhidrosis	0/21 (0%)		1/20 (5%)
Psoriasis	0/21 (0%)		1/20 (5%)
Rash erythematous	0/21 (0%)		1/20 (5%)
Rash generalized	0/21 (0%)		1/20 (5%)
Rash macular	0/21 (0%)		1/20 (5%)
Surgical and medical procedures
Radiotherapy	0/21 (0%)		1/20 (5%)
Sinus operation	0/21 (0%)		1/20 (5%)
Vascular disorders
Flushing	1/21 (4.8%)		4/20 (20%)
Hypotension	1/21 (4.8%)		2/20 (10%)
Phlebitis	0/21 (0%)		1/20 (5%)
Haematoma	0/21 (0%)		1/20 (5%)
Hypertension	0/21 (0%)		1/20 (5%)
Intermittent claudication	0/21 (0%)		1/20 (5%)
Phlebitis superficial	0/21 (0%)		2/20 (10%)

Limitations/Caveats

The interim data reported here (up to clinical cutoff date of 24 January 2013) were for participants who had completed treatment response assessment, which took place approximately 2 months after the last infusion of study treatment.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.