A Phase 2, Multicenter, Open-label Study of MEDI-551 in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL)

• Sponsor: MedImmune LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01466153
• Collaborator: (none)
• Enrollment: 183
• Locations: 54
• Arms: 3
• Duration (Months): 47
• Patients Per Site: 3.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The overall purpose of the study was to determine if MEDI-551, when used in combination with salvage chemotherapy (bendamustine) in participants with relapsed or refractory CLL who are not eligible for Autologous Stem Cell Transplant (ASCT), had superior efficacy compared to rituximab in the same population.

Condition or Disease	Intervention/Treatment	Phase
Chronic Lymphocytic Leukemia (CLL)	Drug: Rituximab; Drug: Bendamustine; Drug: MEDI-551	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 183 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Open-label Study of MEDI-551 and Bendamustine vs Rituximab and Bendamustine in Adults With Relapsed or Refractory CLL
• Study Start Date: Feb 7, 2012
• Actual Primary Completion Date: Jan 8, 2016
• Actual Study Completion Date: Jan 8, 2016

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rituximab + Bendamustine Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	Drug: Rituximab; Rituximab was administered by IV infusion as a dose of 375 mg/m^2 on Day 2 of Cycle 1 and then at 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycles; Other Names: Rituxan; MabThera ; Drug: Bendamustine; Bendamustine was administered by IV infusion as a dose of 70 mg/m^2 on Day 1 and Day 2 of each 5 subsequent 28-day cycle.
Experimental: MEDI-551 2 mg/kg + Bendamustine MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	Drug: Bendamustine; Bendamustine was administered by IV infusion as a dose of 70 mg/m^2 on Day 1 and Day 2 of each 5 subsequent 28-day cycle.; Drug: MEDI-551; MEDI-551 was administered at 2 mg/kg or 4 mg/kg by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycles.
Experimental: MEDI-551 4 mg/kg + Bendamustine MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	Drug: Bendamustine; Bendamustine was administered by IV infusion as a dose of 70 mg/m^2 on Day 1 and Day 2 of each 5 subsequent 28-day cycle.; Drug: MEDI-551; MEDI-551 was administered at 2 mg/kg or 4 mg/kg by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycles.

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   ORR, defined as the proportion of participants with complete response (CR) or partial response (PR) out of total number of participants. Responses were assessed by using National Cancer Institute - Working Group guidelines on CLL.

Secondary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs) [From time of consent to 90 days post last dose]

   An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug (MEDI-551). A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between administration of study drug and Day 90 that were absent before treatment or that worsened relative to pre-treatment state. An AESIs was one of scientific and medical interest specific to understanding of study product and may have required close monitoring and rapid communication by investigator to the sponsor. Treatment emergent AESIs were collected from the time of dosing through Day 90 after the last dose of study drug.Hepatic function abnormality and infusion reactions resulting in discontinuation were considered as AESIs.

2. Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs [From time of consent to 90 days post last dose]

   An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Laboratory evaluations (haematology, serum chemistry and urinalysis) of blood and urine samples were performed.

3. Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs [From time of consent to 90 days post last dose]

   AEs observed in participants with clinically significant ECG abnormalities were assessed.

4. Complete Response Rate [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   Complete response was as per IWG was the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.

5. Minimal Residual Disease Negative Complete Response (CR) Rate [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   The MRD-negative CR rate was defined as the percentage of participants who achieved CR and became MRD-negative as determined by flow cytometry. CR as per International Working Group (IWG) was complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.

6. Time to Response [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   Time to response was evaluated using the Kaplan-Meier method.

7. Time to Disease Progression (TTP) [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   TTP was defined as the time from onset of treatment with study drug until first evidence/diagnosis of progressive disease or - in the absence of any diagnosis of progressive disease - until the participant´s death.

8. Progression Free Survival (PFS) [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   PFS was measured from the start of treatment with study drug until the first documentation of disease progression or death due to any cause, whichever occurred first. Kaplan-Meier method was used for evaluation.

9. Overall Survival (OS) [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

   OS was determined as the time from the start of treatment with study drug until death due to any cause. For participants who were alive at the end of the study or lost to follow-up, OS was censored on the last date when the participant was known be alive. Kaplan-Meier method was used for evaluation.

10. Number of Participants Who Developed Detectable Anti-drug Antibodies (ADA) [From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)]

    A participant was considered ADA-positive across the study if they had a positive reading at any time point during the study.

11. Terminal Half Life (t1/2) of MEDI-551 [Pre-infusion and 1 hour post infusion on Days 2 and 8, Days 15 and 22 of cycle 1]

    Terminal phase elimination half-life (T1/2) was the time required for half of the drug to be eliminated from the serum.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 99 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically confirmed B-cell Chronic Lymphocytic Leukemia (CLL) according to the National Cancer Institute criteria; Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2; Adequate hematological function

Exclusion Criteria:

• Any chemotherapy, radiotherapy, immunotherapy, biologic, investigational, or hormonal therapy for treatment of lymphoma within 28 days prior to treatment;

• Exposure to bendamustine within the 180 days before study enrollment

• Prior autologous or allogeneic stem cell transplantation (SCT);

• Clinically significant abnormality on electrocardiogram (ECG) as determined by the treating physician or medical monitor;

• History of other invasive malignancy within 5 years except for localized/in situ carcinomas;

• Evidence of active infection, Confirmed current central nervous system involvement by leukemia or lymphoma;

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Birmingham	Alabama	United States
2	Research Site	Burbank	California	United States
3	Research Site	La Jolla	California	United States
4	Research Site	Palm Springs	California	United States
5	Research Site	Skokie	Illinois	United States
6	Research Site	Shreveport	Louisiana	United States
7	Research Site	Baltimore	Maryland	United States
8	Research Site	Detroit	Michigan	United States
9	Research Site	Fargo	North Dakota	United States
10	Research Site	Dayton	Ohio	United States
11	Research Site	Newark	Ohio	United States
12	Research Site	Watertown	South Dakota	United States
13	Research Site	Lubbock	Texas	United States
14	Research Site	Morgantown	West Virginia	United States
15	Research Site	Antwerpen		Belgium
16	Research Site	Arlon		Belgium
17	Research Site	Kortrijk		Belgium
18	Research Site	Mons		Belgium
19	Research Site	Wilrijk		Belgium
20	Research Site	Yvoir		Belgium
21	Research Site	Toronto	Ontario	Canada
22	Research Site	Greenfield Park	Quebec	Canada
23	Research Site	Montreal	Quebec	Canada
24	Research Site	Amiens		France
25	Research Site	Bayonne		France
26	Research Site	Bordeaux		France
27	Research Site	Le Mans		France
28	Research Site	Libourne Cedex		France
29	Research Site	Marseille		France
30	Research Site	Nimes		France
31	Research Site	Dortmund		Germany
32	Research Site	Essen		Germany
33	Research Site	Freiburg		Germany
34	Research Site	Muenchen		Germany
35	Research Site	Wuerzburg		Germany
36	Research Site	Haifa		Israel
37	Research Site	Ramat Gan		Israel
38	Research Site	Bari		Italy
39	Research Site	Lecce		Italy
40	Research Site	Meldola		Italy
41	Research Site	Milano		Italy
42	Research Site	Modena		Italy
43	Research Site	Napoli		Italy
44	Research Site	Orbassano		Italy
45	Research Site	Palermo		Italy
46	Research Site	Pisa		Italy
47	Research Site	Ravenna		Italy
48	Research Site	Rimini		Italy
49	Research Site	Roma		Italy
50	Research Site	San Giovanni Rotondo		Italy
51	Research Site	Torino		Italy
52	Research Site	Udine		Italy
53	Research Site	Gdynia		Poland
54	Research Site	Warszawa		Poland

Sponsors and Collaborators

• MedImmune LLC

Investigators

• Study Director: MedImmune, MedImmune LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: MedImmune LLC
• ClinicalTrials.gov Identifier: NCT01466153
• Other Study ID Numbers: CD-ON-MEDI-551-1019
• First Posted: Nov 6, 2011
• Last Update Posted: May 31, 2017
• Last Verified: Apr 1, 2017

• Keywords provided by MedImmune LLC: Chronic lymphocytic leukemia; leukemia; B-Cell malignancy; anti-CD19; monoclonal antibody; CLL; Refractory; Relapse; Non-Hodgkin's Lymphoma
• Additional relevant MeSH terms: Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Bendamustine Hydrochloride

Study Results

Participant Flow

Pre-assignment Detail	A total of 182 participants were screened and 159 participants were randomized.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Period Title: Overall Study
STARTED	62	36	61
COMPLETED	33	12	36
NOT COMPLETED	29	24	25

Baseline Characteristics

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine	TOTAL
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	Total of all reporting groups
Overall Participants	62	36	61	159
Age (YEARS) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [YEARS]	63.4 (8.8)	65.1 (8.7)	66.3 (8.9)	65.1 (8.8)
Sex: Female, Male (Count of Participants)
Female	16 25.8%	14 38.9%	18 29.5%	48 30.2%
Male	46 74.2%	22 61.1%	43 70.5%	111 69.8%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate
Description	ORR, defined as the proportion of participants with complete response (CR) or partial response (PR) out of total number of participants. Responses were assessed by using National Cancer Institute - Working Group guidelines on CLL.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Number (95% Confidence Interval) [Percentage of Participants]	59.7 96.3%	52.8 146.7%	63.9 104.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab + Bendamustine, MEDI-551 4 mg/kg + Bendamustine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4475
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

2. Secondary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs)
Description	An adverse event (AE) was any untoward medical occurrence attributed to study drug in a participant who received study drug (MEDI-551). A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience; persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between administration of study drug and Day 90 that were absent before treatment or that worsened relative to pre-treatment state. An AESIs was one of scientific and medical interest specific to understanding of study product and may have required close monitoring and rapid communication by investigator to the sponsor. Treatment emergent AESIs were collected from the time of dosing through Day 90 after the last dose of study drug.Hepatic function abnormality and infusion reactions resulting in discontinuation were considered as AESIs.
Time Frame	From time of consent to 90 days post last dose

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who received any investigational product.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	60	33	57
TEAEs	58 93.5%	33 91.7%	57 93.4%
TESAEs	19 30.6%	16 44.4%	19 31.1%
AESIs	2 3.2%	4 11.1%	6 9.8%

3. Secondary Outcome

Title	Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs
Description	An abnormal laboratory finding which required an action or intervention by the investigator, or a finding judged by the investigator to represent a change beyond the range of normal physiologic fluctuation were reported as an adverse event. Laboratory evaluations (haematology, serum chemistry and urinalysis) of blood and urine samples were performed.
Time Frame	From time of consent to 90 days post last dose

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who received any investigational product.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	60	33	57
Hyperbilirubinaemia	0 0%	2 5.6%	1 1.6%
Hypercalcaemia	1 1.6%	0 0%	0 0%
Hypercholesterolaemia	1 1.6%	0 0%	1 1.6%
Hyperglycaemia	4 6.5%	2 5.6%	1 1.6%
Hyperkalaemia	2 3.2%	1 2.8%	2 3.3%
Hyperlipidaemia	0 0%	1 2.8%	0 0%
Hypermagnesaemia	1 1.6%	0 0%	0 0%
Hyperphosphataemia	0 0%	1 2.8%	1 1.6%
Hypertriglyceridaemia	1 1.6%	0 0%	0 0%
Hyperuricaemia	3 4.8%	5 13.9%	2 3.3%
Hypoalbuminaemia	2 3.2%	0 0%	2 3.3%
Hypocalcaemia	3 4.8%	1 2.8%	1 1.6%
Hypokalaemia	6 9.7%	1 2.8%	4 6.6%
Hypomagnesaemia	2 3.2%	2 5.6%	1 1.6%
Hyponatraemia	2 3.2%	1 2.8%	0 0%
Alanine Aminotransferase Increased	1 1.6%	0 0%	3 4.9%
Aspartate Aminotransferase Increased	1 1.6%	0 0%	3 4.9%
Blood Alkaline Phosphatase Increased	1 1.6%	1 2.8%	2 3.3%
Blood Bilirubin Increased	0 0%	1 2.8%	1 1.6%
Blood Cholesterol Decreased	0 0%	0 0%	1 1.6%
Blood Creatinine Decreased	1 1.6%	0 0%	0 0%
Blood Creatinine Increased	1 1.6%	2 5.6%	1 1.6%
Blood Immunoglobulin G Decreased	0 0%	0 0%	1 1.6%
Blood Lactate Dehydrogenase Increased	4 6.5%	0 0%	0 0%
Blood Urea Increased	1 1.6%	1 2.8%	0 0%
Gamma-Glutamyltransferase Increased	1 1.6%	1 2.8%	2 3.3%
Hepatic enzyme Increased	1 1.6%	0 0%	0 0%
Anaemia	18 29%	7 19.4%	9 14.8%
Eosinophilia	0 0%	0 0%	1 1.6%
Lymphopenia	4 6.5%	3 8.3%	1 1.6%
Neutropenia	28 45.2%	10 27.8%	19 31.1%
Thromobocytopenia	12 19.4%	6 16.7%	10 16.4%
Activated Partial Thromboplastin Time Prolonged	2 3.2%	0 0%	0 0%
Blood Fibrinogen Increased	1 1.6%	0 0%	0 0%
Blood Immunoglobulin g Decreased	0 0%	0 0%	1 1.6%
Haemoglobin Decreased	0 0%	1 2.8%	0 0%
Lymphocyte Count Decreased	3 4.8%	0 0%	2 3.3%
Neutrophil Count Decreased	9 14.5%	1 2.8%	3 4.9%
Platelet Count Decreased	2 3.2%	2 5.6%	3 4.9%
Prothrombin Time Shortened	1 1.6%	0 0%	0 0%
Haematuria	0 0%	2 5.6%	1 1.6%
Proteinuria	0 0%	1 2.8%	0 0%
White Blood Cells in Urine	0 0%	0 0%	1 1.6%

4. Secondary Outcome

Title	Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs
Description	AEs observed in participants with clinically significant ECG abnormalities were assessed.
Time Frame	From time of consent to 90 days post last dose

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who received any investigational product.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	60	33	57
Atrial Fibrillation	1 1.6%	2 5.6%	1 1.6%
Atrioventricular Block	1 1.6%	0 0%	0 0%
Palpitations	0 0%	0 0%	2 3.3%
Sinus Bradycardia	1 1.6%	0 0%	0 0%
Sinus Tachycardia	1 1.6%	0 0%	0 0%
Tachycardia	2 3.2%	1 2.8%	1 1.6%
Pyrexia	20 32.3%	11 30.6%	14 23%
Dyspnoea	9 14.5%	2 5.6%	4 6.6%
Dyspnoea Exertional	3 4.8%	1 2.8%	0 0%
Hypertension	1 1.6%	0 0%	1 1.6%
Hypotension	5 8.1%	2 5.6%	6 9.8%
Orthostatic Hypotension	0 0%	0 0%	1 1.6%

5. Secondary Outcome

Title	Complete Response Rate
Description	Complete response was as per IWG was the complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Number (95% Confidence Interval) [Percentage of Participants]	6.5 10.5%	5.6 15.6%	11.5 18.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab + Bendamustine, MEDI-551 4 mg/kg + Bendamustine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3206
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

6. Secondary Outcome

Title	Minimal Residual Disease Negative Complete Response (CR) Rate
Description	The MRD-negative CR rate was defined as the percentage of participants who achieved CR and became MRD-negative as determined by flow cytometry. CR as per International Working Group (IWG) was complete disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Number (95% Confidence Interval) [Percentage of Participants]	1.6 2.6%	5.6 15.6%	4.9 8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab + Bendamustine, MEDI-551 4 mg/kg + Bendamustine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3130
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

7. Secondary Outcome

Title	Time to Response
Description	Time to response was evaluated using the Kaplan-Meier method.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Median (95% Confidence Interval) [Months]	2.1	1.9	2.1

8. Secondary Outcome

Title	Time to Disease Progression (TTP)
Description	TTP was defined as the time from onset of treatment with study drug until first evidence/diagnosis of progressive disease or - in the absence of any diagnosis of progressive disease - until the participant´s death.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Median (95% Confidence Interval) [Months]	15.4	15.0	16.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rituximab + Bendamustine, MEDI-551 4 mg/kg + Bendamustine
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9527
	Comments
	Method	Log Rank
	Comments

9. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	PFS was measured from the start of treatment with study drug until the first documentation of disease progression or death due to any cause, whichever occurred first. Kaplan-Meier method was used for evaluation.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Median (95% Confidence Interval) [Months]	14.8	15.0	16.1

10. Secondary Outcome

Title	Overall Survival (OS)
Description	OS was determined as the time from the start of treatment with study drug until death due to any cause. For participants who were alive at the end of the study or lost to follow-up, OS was censored on the last date when the participant was known be alive. Kaplan-Meier method was used for evaluation.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

Intent-to-treat (ITT) population includes all participants who were randomized into the study.

Arm/Group Title	Rituximab + Bendamustine	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	62	36	61
Number (95% Confidence Interval) [Months]	NA	NA	NA

11. Secondary Outcome

Title	Number of Participants Who Developed Detectable Anti-drug Antibodies (ADA)
Description	A participant was considered ADA-positive across the study if they had a positive reading at any time point during the study.
Time Frame	From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who received any investigational product. Participants whom ADA samples were available were analyzed for this outcome measure.

Arm/Group Title	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	31	57
Number [Participants]	4 6.5%	8 22.2%

12. Secondary Outcome

Title	Terminal Half Life (t1/2) of MEDI-551
Description	Terminal phase elimination half-life (T1/2) was the time required for half of the drug to be eliminated from the serum.
Time Frame	Pre-infusion and 1 hour post infusion on Days 2 and 8, Days 15 and 22 of cycle 1

Outcome Measure Data

Analysis Population Description

The safety population includes all participants who received any investigational product. Participants whom PK samples were available were analyzed for this outcome measure.

Arm/Group Title	MEDI-551 2 mg/kg + Bendamustine	MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.	MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
Measure Participants	12	38
Mean (Standard Deviation) [Day]	17.2 (9.56)	22.0 (14.4)

Adverse Events

Time Frame	From start of study drug administration until 90 days after the last dose of study drug
Arm/Group Title	Rituximab + Bendamustine		MEDI-551 2 mg/kg + Bendamustine		MEDI-551 4 mg/kg + Bendamustine
Arm/Group Description	Rituximab was administered by IV infusion as 375 mg/m^2 on Day 2 of Cycle 1 and then 500 mg/m^2 on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of rituximab in each cycle.		MEDI-551 2 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.		MEDI-551 4 mg/kg was administered by IV infusion on Days 2 and 8 of Cycle 1 and then on Day 1 of up to 5 subsequent 28-day cycle. Bendamustine was also administered by IV infusion on Day 1 and Day 2 of every cycle (total 6 cycles). Bendamustine was administered before the administration of MEDI-551 in each cycle.
All Cause Mortality
	Rituximab + Bendamustine		MEDI-551 2 mg/kg + Bendamustine		MEDI-551 4 mg/kg + Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Rituximab + Bendamustine		MEDI-551 2 mg/kg + Bendamustine		MEDI-551 4 mg/kg + Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/60 (31.7%)		16/33 (48.5%)		19/57 (33.3%)
Blood and lymphatic system disorders
Abdominal lymphadenopathy	0/60 (0%)	0	1/33 (3%)	1	0/57 (0%)	0
Anaemia	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Febrile neutropenia	6/60 (10%)	6	0/33 (0%)	0	2/57 (3.5%)	2
Lymphadenopathy	0/60 (0%)	0	1/33 (3%)	1	1/57 (1.8%)	1
Neutropenia	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Thrombocytopenia	0/60 (0%)	0	1/33 (3%)	1	1/57 (1.8%)	1
Cardiac disorders
Atrial fibrillation	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Atrioventricular block	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Cardiac failure	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Myocardial infarction	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Congenital, familial and genetic disorders
Thyroglossal cyst	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Eye disorders
Uveitis	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Gastrointestinal disorders
Ascites	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Diarrhoea	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Intestinal obstruction	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Nausea	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Small intestinal obstruction	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Upper gastrointestinal haemorrhage	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Vomiting	2/60 (3.3%)	2	0/33 (0%)	0	0/57 (0%)	0
General disorders
Asthenia	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Inflammation	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Systemic inflammatory response syndrome	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Immune system disorders
Anaphylactic reaction	0/60 (0%)	0	1/33 (3%)	1	1/57 (1.8%)	3
Infections and infestations
Abdominal infection	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Bronchitis	1/60 (1.7%)	1	1/33 (3%)	1	1/57 (1.8%)	1
Gastroenteritis norovirus	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Pneumonia	1/60 (1.7%)	1	4/33 (12.1%)	5	1/57 (1.8%)	1
Pneumonia pseudomonal	0/60 (0%)	0	1/33 (3%)	1	0/57 (0%)	0
Pneumonia viral	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Rhinovirus infection	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Sepsis	3/60 (5%)	3	1/33 (3%)	1	0/57 (0%)	0
Skin infection	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Viral myocarditis	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Injury, poisoning and procedural complications
Infusion related reaction	1/60 (1.7%)	1	5/33 (15.2%)	10	5/57 (8.8%)	14
Investigations
Haemoglobin decreased	0/60 (0%)	0	1/33 (3%)	2	0/57 (0%)	0
Platelet count decreased	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Metabolism and nutrition disorders
Decreased appetite	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Dehydration	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Diabetes mellitus	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Tumour lysis syndrome	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Bowen's disease	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Squamous cell carcinoma	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Nervous system disorders
Coma	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Syncope	1/60 (1.7%)	1	0/33 (0%)	0	1/57 (1.8%)	1
Renal and urinary disorders
Acute kidney injury	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Renal failure	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Reproductive system and breast disorders
Female genital tract fistula	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Cough	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Dyspnoea	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Epistaxis	0/60 (0%)	0	1/33 (3%)	1	0/57 (0%)	0
Lung disorder	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Pneumonitis	1/60 (1.7%)	2	0/33 (0%)	0	1/57 (1.8%)	1
Respiratory failure	0/60 (0%)	0	0/33 (0%)	0	1/57 (1.8%)	1
Respiratory tract inflammation	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Vascular disorders
Hypotension	1/60 (1.7%)	1	0/33 (0%)	0	0/57 (0%)	0
Other (Not Including Serious) Adverse Events
	Rituximab + Bendamustine		MEDI-551 2 mg/kg + Bendamustine		MEDI-551 4 mg/kg + Bendamustine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	58/60 (96.7%)		31/33 (93.9%)		54/57 (94.7%)
Blood and lymphatic system disorders
Anaemia	18/60 (30%)	64	7/33 (21.2%)	20	9/57 (15.8%)	13
Febrile neutropenia	4/60 (6.7%)	5	0/33 (0%)	0	1/57 (1.8%)	1
Leukopenia	3/60 (5%)	26	0/33 (0%)	0	1/57 (1.8%)	1
Lymphopenia	4/60 (6.7%)	26	3/33 (9.1%)	7	1/57 (1.8%)	5
Neutropenia	28/60 (46.7%)	78	10/33 (30.3%)	44	19/57 (33.3%)	58
Thrombocytopenia	12/60 (20%)	76	5/33 (15.2%)	8	10/57 (17.5%)	21
Cardiac disorders
Atrial fibrillation	1/60 (1.7%)	1	2/33 (6.1%)	2	0/57 (0%)	0
Tachycardia	2/60 (3.3%)	2	1/33 (3%)	1	1/57 (1.8%)	1
Ear and labyrinth disorders
Vertigo	2/60 (3.3%)	2	0/33 (0%)	0	1/57 (1.8%)	1
Eye disorders
Vision blurred	1/60 (1.7%)	1	0/33 (0%)	0	2/57 (3.5%)	2
Gastrointestinal disorders
Abdominal discomfort	3/60 (5%)	4	2/33 (6.1%)	2	1/57 (1.8%)	1
Abdominal distension	1/60 (1.7%)	1	2/33 (6.1%)	2	1/57 (1.8%)	1
Abdominal pain	7/60 (11.7%)	8	3/33 (9.1%)	3	7/57 (12.3%)	15
Abdominal pain upper	5/60 (8.3%)	6	1/33 (3%)	1	3/57 (5.3%)	3
Constipation	20/60 (33.3%)	23	9/33 (27.3%)	11	10/57 (17.5%)	11
Diarrhoea	13/60 (21.7%)	20	5/33 (15.2%)	5	11/57 (19.3%)	15
Dyspepsia	1/60 (1.7%)	1	2/33 (6.1%)	2	4/57 (7%)	5
Flatulence	3/60 (5%)	3	1/33 (3%)	1	0/57 (0%)	0
Gastrooesophageal reflux disease	3/60 (5%)	4	0/33 (0%)	0	2/57 (3.5%)	2
Gingival pain	1/60 (1.7%)	1	1/33 (3%)	1	1/57 (1.8%)	1
Haemorrhoids	2/60 (3.3%)	2	0/33 (0%)	0	1/57 (1.8%)	1
Nausea	29/60 (48.3%)	45	13/33 (39.4%)	23	29/57 (50.9%)	47
Vomiting	13/60 (21.7%)	14	7/33 (21.2%)	8	7/57 (12.3%)	7
General disorders
Asthenia	20/60 (33.3%)	31	4/33 (12.1%)	4	7/57 (12.3%)	17
Chest discomfort	2/60 (3.3%)	2	0/33 (0%)	0	2/57 (3.5%)	2
Chills	11/60 (18.3%)	15	6/33 (18.2%)	7	7/57 (12.3%)	10
Fatigue	18/60 (30%)	38	14/33 (42.4%)	19	20/57 (35.1%)	30
Oedema peripheral	3/60 (5%)	4	2/33 (6.1%)	3	7/57 (12.3%)	7
Peripheral swelling	1/60 (1.7%)	2	1/33 (3%)	2	1/57 (1.8%)	2
Pyrexia	20/60 (33.3%)	27	11/33 (33.3%)	14	14/57 (24.6%)	23
Hepatobiliary disorders
Hyperbilirubinaemia	0/60 (0%)	0	2/33 (6.1%)	2	1/57 (1.8%)	2
Immune system disorders
Cytokine release syndrome	0/60 (0%)	0	1/33 (3%)	1	2/57 (3.5%)	2
Hypogammaglobulinaemia	1/60 (1.7%)	1	1/33 (3%)	1	1/57 (1.8%)	2
Infections and infestations
Bronchitis	4/60 (6.7%)	4	3/33 (9.1%)	4	4/57 (7%)	4
Conjunctivitis	2/60 (3.3%)	2	0/33 (0%)	0	1/57 (1.8%)	1
Lung infection	2/60 (3.3%)	2	1/33 (3%)	1	1/57 (1.8%)	1
Nasopharyngitis	3/60 (5%)	5	2/33 (6.1%)	3	4/57 (7%)	5
Pneumonia	0/60 (0%)	0	1/33 (3%)	1	4/57 (7%)	5
Rhinitis	2/60 (3.3%)	2	2/33 (6.1%)	2	0/57 (0%)	0
Sinusitis	3/60 (5%)	3	1/33 (3%)	1	6/57 (10.5%)	6
Upper respiratory tract infection	4/60 (6.7%)	4	3/33 (9.1%)	4	1/57 (1.8%)	1
Urinary tract infection	3/60 (5%)	8	0/33 (0%)	0	1/57 (1.8%)	3
Injury, poisoning and procedural complications
Contusion	1/60 (1.7%)	1	0/33 (0%)	0	3/57 (5.3%)	3
Infusion related reaction	14/60 (23.3%)	25	21/33 (63.6%)	64	37/57 (64.9%)	123
Investigations
Alanine aminotransferase increased	1/60 (1.7%)	3	0/33 (0%)	0	3/57 (5.3%)	4
Aspartate aminotransferase increased	1/60 (1.7%)	4	0/33 (0%)	0	3/57 (5.3%)	4
Blood alkaline phosphatase increased	1/60 (1.7%)	3	1/33 (3%)	2	2/57 (3.5%)	2
Blood creatinine increased	1/60 (1.7%)	1	2/33 (6.1%)	3	1/57 (1.8%)	1
Blood lactate dehydrogenase increased	4/60 (6.7%)	7	0/33 (0%)	0	0/57 (0%)	0
Gamma-glutamyltransferase increased	1/60 (1.7%)	4	1/33 (3%)	1	2/57 (3.5%)	2
Lymphocyte count decreased	3/60 (5%)	8	0/33 (0%)	0	2/57 (3.5%)	2
Neutrophil count decreased	9/60 (15%)	16	1/33 (3%)	3	3/57 (5.3%)	6
Platelet count decreased	2/60 (3.3%)	4	2/33 (6.1%)	2	2/57 (3.5%)	2
Weight decreased	5/60 (8.3%)	6	1/33 (3%)	1	0/57 (0%)	0
White blood cell count decreased	3/60 (5%)	3	1/33 (3%)	1	2/57 (3.5%)	2
Metabolism and nutrition disorders
Decreased appetite	13/60 (21.7%)	17	4/33 (12.1%)	4	6/57 (10.5%)	6
Dehydration	1/60 (1.7%)	1	3/33 (9.1%)	3	0/57 (0%)	0
Hyperglycaemia	4/60 (6.7%)	4	2/33 (6.1%)	3	1/57 (1.8%)	1
Hyperkalaemia	2/60 (3.3%)	2	1/33 (3%)	1	2/57 (3.5%)	3
Hyperuricaemia	3/60 (5%)	5	5/33 (15.2%)	6	2/57 (3.5%)	2
Hypoalbuminaemia	2/60 (3.3%)	3	0/33 (0%)	0	2/57 (3.5%)	2
Hypocalcaemia	3/60 (5%)	3	1/33 (3%)	1	1/57 (1.8%)	1
Hypokalaemia	6/60 (10%)	7	1/33 (3%)	1	4/57 (7%)	4
Hypomagnesaemia	2/60 (3.3%)	2	2/33 (6.1%)	2	1/57 (1.8%)	1
Hyponatraemia	2/60 (3.3%)	2	1/33 (3%)	1	0/57 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	7/60 (11.7%)	7	1/33 (3%)	1	4/57 (7%)	4
Back pain	5/60 (8.3%)	5	4/33 (12.1%)	4	5/57 (8.8%)	8
Bone pain	4/60 (6.7%)	4	1/33 (3%)	1	5/57 (8.8%)	9
Muscle spasms	5/60 (8.3%)	9	1/33 (3%)	1	7/57 (12.3%)	9
Muscular weakness	3/60 (5%)	3	0/33 (0%)	0	1/57 (1.8%)	1
Musculoskeletal chest pain	0/60 (0%)	0	2/33 (6.1%)	2	2/57 (3.5%)	2
Musculoskeletal pain	2/60 (3.3%)	2	2/33 (6.1%)	2	2/57 (3.5%)	2
Myalgia	3/60 (5%)	6	0/33 (0%)	0	4/57 (7%)	5
Neck pain	1/60 (1.7%)	1	2/33 (6.1%)	2	2/57 (3.5%)	2
Pain in extremity	4/60 (6.7%)	4	2/33 (6.1%)	3	3/57 (5.3%)	3
Nervous system disorders
Dizziness	5/60 (8.3%)	5	3/33 (9.1%)	6	7/57 (12.3%)	10
Dysgeusia	5/60 (8.3%)	7	3/33 (9.1%)	3	1/57 (1.8%)	1
Headache	7/60 (11.7%)	9	6/33 (18.2%)	9	5/57 (8.8%)	6
Neuropathy peripheral	1/60 (1.7%)	1	1/33 (3%)	1	1/57 (1.8%)	1
Paraesthesia	3/60 (5%)	3	0/33 (0%)	0	1/57 (1.8%)	2
Restless legs syndrome	2/60 (3.3%)	2	1/33 (3%)	1	1/57 (1.8%)	1
Sciatica	1/60 (1.7%)	1	0/33 (0%)	0	2/57 (3.5%)	3
Psychiatric disorders
Anxiety	5/60 (8.3%)	5	0/33 (0%)	0	4/57 (7%)	5
Depression	2/60 (3.3%)	2	3/33 (9.1%)	3	2/57 (3.5%)	2
Insomnia	6/60 (10%)	7	2/33 (6.1%)	2	5/57 (8.8%)	5
Renal and urinary disorders
Dysuria	4/60 (6.7%)	5	0/33 (0%)	0	0/57 (0%)	0
Haematuria	0/60 (0%)	0	2/33 (6.1%)	2	1/57 (1.8%)	1
Pollakiuria	1/60 (1.7%)	1	1/33 (3%)	1	2/57 (3.5%)	2
Respiratory, thoracic and mediastinal disorders
Cough	11/60 (18.3%)	13	5/33 (15.2%)	9	19/57 (33.3%)	24
Dysphonia	1/60 (1.7%)	1	2/33 (6.1%)	2	0/57 (0%)	0
Dyspnoea	9/60 (15%)	13	2/33 (6.1%)	2	4/57 (7%)	5
Dyspnoea exertional	3/60 (5%)	4	1/33 (3%)	1	0/57 (0%)	0
Epistaxis	1/60 (1.7%)	1	1/33 (3%)	1	2/57 (3.5%)	2
Nasal congestion	3/60 (5%)	4	1/33 (3%)	1	3/57 (5.3%)	4
Oropharyngeal pain	1/60 (1.7%)	1	1/33 (3%)	1	2/57 (3.5%)	2
Pleural effusion	1/60 (1.7%)	1	2/33 (6.1%)	2	1/57 (1.8%)	1
Pulmonary congestion	1/60 (1.7%)	2	0/33 (0%)	0	2/57 (3.5%)	2
Rhinorrhoea	3/60 (5%)	3	1/33 (3%)	1	3/57 (5.3%)	3
Upper-airway cough syndrome	2/60 (3.3%)	2	0/33 (0%)	0	1/57 (1.8%)	1
Skin and subcutaneous tissue disorders
Dry skin	2/60 (3.3%)	2	2/33 (6.1%)	2	2/57 (3.5%)	2
Erythema	4/60 (6.7%)	4	0/33 (0%)	0	6/57 (10.5%)	6
Hyperhidrosis	7/60 (11.7%)	7	3/33 (9.1%)	3	2/57 (3.5%)	3
Night sweats	5/60 (8.3%)	6	1/33 (3%)	1	0/57 (0%)	0
Pruritus	9/60 (15%)	13	5/33 (15.2%)	9	6/57 (10.5%)	6
Rash	4/60 (6.7%)	7	4/33 (12.1%)	6	8/57 (14%)	10
Rash erythematous	3/60 (5%)	3	0/33 (0%)	0	0/57 (0%)	0
Rash pruritic	1/60 (1.7%)	1	0/33 (0%)	0	3/57 (5.3%)	3
Vascular disorders
Flushing	4/60 (6.7%)	7	2/33 (6.1%)	3	1/57 (1.8%)	1
Hypotension	4/60 (6.7%)	4	2/33 (6.1%)	2	6/57 (10.5%)	7

Limitations/Caveats

[Not Specified]

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

MedImmune has 60 days to review results communications prior to public release and may delete information that compromises ongoing studies or is considered proprietary. This restriction is not intended to compromise the objective scientific integrity of the manuscript, it being understood that results shall be published regardless of outcome.