Trial Outcomes & Findings for A Phase 2, Multicenter, Open-label Study of MEDI-551 in Adults With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) (NCT NCT01466153)

Last Updated: 2017-05-31

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

183 participants

Primary outcome timeframe

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

Results posted on

2017-05-31

Participant Flow

A total of 182 participants were screened and 159 participants were randomized.

Participant milestones

Participant milestones
Measure	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.	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.	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.
Overall Study STARTED	62	36	61
Overall Study COMPLETED	33	12	36
Overall Study NOT COMPLETED	29	24	25

Reasons for withdrawal

Reasons for withdrawal
Measure	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.	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.	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.
Overall Study Disease Progression	2	2	0
Overall Study Adverse Event	14	13	17
Overall Study Withdrawal of Consent	2	0	0
Overall Study Investigator Discretion	3	2	2
Overall Study Randomized-Not Treated	2	3	4
Overall Study Other-Unspecified	6	4	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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 n=159 Participants Total of all reporting groups
Age, Continuous	63.4 YEARS STANDARD_DEVIATION 8.8 • n=5 Participants	65.1 YEARS STANDARD_DEVIATION 8.7 • n=7 Participants	66.3 YEARS STANDARD_DEVIATION 8.9 • n=5 Participants	65.1 YEARS STANDARD_DEVIATION 8.8 • n=4 Participants
Sex: Female, Male Female	16 Participants n=5 Participants	14 Participants n=7 Participants	18 Participants n=5 Participants	48 Participants n=4 Participants
Sex: Female, Male Male	46 Participants n=5 Participants	22 Participants n=7 Participants	43 Participants n=5 Participants	111 Participants n=4 Participants

PRIMARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Objective Response Rate	59.7 Percentage of Participants Interval 46.4 to 71.9	52.8 Percentage of Participants Interval 35.5 to 69.6	63.9 Percentage of Participants Interval 50.6 to 75.8

SECONDARY outcome

Timeframe: From time of consent to 90 days post last dose

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=60 Participants 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 + Bendamustine n=33 Participants 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 + Bendamustine n=57 Participants 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.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs) TEAEs	58 Participants	33 Participants	57 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs) TESAEs	19 Participants	16 Participants	19 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs) AESIs	2 Participants	4 Participants	6 Participants

SECONDARY outcome

Timeframe: From time of consent to 90 days post last dose

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=60 Participants 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 + Bendamustine n=33 Participants 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 + Bendamustine n=57 Participants 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.
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypertriglyceridaemia	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyperuricaemia	3 Participants	5 Participants	2 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyponatraemia	2 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Alanine Aminotransferase Increased	1 Participants	0 Participants	3 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Bilirubin Increased	0 Participants	1 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Anaemia	18 Participants	7 Participants	9 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Activated Partial Thromboplastin Time Prolonged	2 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Fibrinogen Increased	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypercalcaemia	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypercholesterolaemia	1 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyperglycaemia	4 Participants	2 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyperkalaemia	2 Participants	1 Participants	2 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyperlipidaemia	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypermagnesaemia	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyperphosphataemia	0 Participants	1 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypoalbuminaemia	2 Participants	0 Participants	2 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypocalcaemia	3 Participants	1 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypokalaemia	6 Participants	1 Participants	4 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hypomagnesaemia	2 Participants	2 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Aspartate Aminotransferase Increased	1 Participants	0 Participants	3 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Alkaline Phosphatase Increased	1 Participants	1 Participants	2 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Cholesterol Decreased	0 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Creatinine Decreased	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Creatinine Increased	1 Participants	2 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Immunoglobulin G Decreased	0 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Lactate Dehydrogenase Increased	4 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Urea Increased	1 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Gamma-Glutamyltransferase Increased	1 Participants	1 Participants	2 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hepatic enzyme Increased	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Eosinophilia	0 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Lymphopenia	4 Participants	3 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Neutropenia	28 Participants	10 Participants	19 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Thromobocytopenia	12 Participants	6 Participants	10 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Blood Immunoglobulin g Decreased	0 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Haemoglobin Decreased	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Lymphocyte Count Decreased	3 Participants	0 Participants	2 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Neutrophil Count Decreased	9 Participants	1 Participants	3 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Platelet Count Decreased	2 Participants	2 Participants	3 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Prothrombin Time Shortened	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Haematuria	0 Participants	2 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Proteinuria	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs White Blood Cells in Urine	0 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs Hyperbilirubinaemia	0 Participants	2 Participants	1 Participants

SECONDARY outcome

Timeframe: From time of consent to 90 days post last dose

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

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

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=60 Participants 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 + Bendamustine n=33 Participants 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 + Bendamustine n=57 Participants 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.
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Dyspnoea	9 Participants	2 Participants	4 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Dyspnoea Exertional	3 Participants	1 Participants	0 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Atrial Fibrillation	1 Participants	2 Participants	1 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Atrioventricular Block	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Palpitations	0 Participants	0 Participants	2 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Sinus Bradycardia	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Sinus Tachycardia	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Tachycardia	2 Participants	1 Participants	1 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Pyrexia	20 Participants	11 Participants	14 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Hypertension	1 Participants	0 Participants	1 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Hypotension	5 Participants	2 Participants	6 Participants
Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs Orthostatic Hypotension	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Complete Response Rate	6.5 Percentage of Participants Interval 1.8 to 15.7	5.6 Percentage of Participants Interval 0.7 to 18.7	11.5 Percentage of Participants Interval 4.7 to 22.2

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Minimal Residual Disease Negative Complete Response (CR) Rate	1.6 Percentage of Participants Interval 0.0 to 8.7	5.6 Percentage of Participants Interval 0.7 to 18.7	4.9 Percentage of Participants Interval 1.0 to 13.7

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Time to Response	2.1 Months Interval 1.9 to 2.6	1.9 Months Interval 1.7 to 2.9	2.1 Months Interval 1.9 to 3.5

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Time to Disease Progression (TTP)	15.4 Months Interval 12.0 to 27.2	15.0 Months Interval 5.8 to 23.3	16.1 Months Interval 12.5 to 24.0

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Progression Free Survival (PFS)	14.8 Months Interval 11.4 to 23.5	15.0 Months Interval 5.8 to 22.1	16.1 Months Interval 12.5 to 21.6

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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.

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=62 Participants 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 + Bendamustine n=36 Participants 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 + Bendamustine n=61 Participants 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.
Overall Survival (OS)	NA Months The median was not reached and the upper and lower limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.	NA Months The median was not reached and the upper and lower limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.	NA Months Interval 23.9 to The median was not reached and the upper limit of the 95% confidence interval was not calculable because an insufficient number of participants reached the event at the final time point for assessment.

SECONDARY outcome

Timeframe: From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months)

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

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

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=31 Participants 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 + Bendamustine n=57 Participants 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 + 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.
Number of Participants Who Developed Detectable Anti-drug Antibodies (ADA)	4 Participants	8 Participants	—

SECONDARY outcome

Timeframe: Pre-infusion and 1 hour post infusion on Days 2 and 8, Days 15 and 22 of cycle 1

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

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

Outcome measures

Outcome measures
Measure	Rituximab + Bendamustine n=12 Participants 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 + Bendamustine n=38 Participants 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 + 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.
Terminal Half Life (t1/2) of MEDI-551	17.2 Day Standard Deviation 9.56	22.0 Day Standard Deviation 14.4	—

Adverse Events

Rituximab + Bendamustine

Serious events: 19 serious events

Other events: 58 other events

Deaths: 0 deaths

MEDI-551 2 mg/kg + Bendamustine

Serious events: 16 serious events

Other events: 31 other events

Deaths: 0 deaths

MEDI-551 4 mg/kg + Bendamustine

Serious events: 19 serious events

Other events: 54 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

AstraZeneca Clinical Study Information Center

AstraZeneca

Phone: 1-877-240-9479

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER