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

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Open-label Study of MEDI-551 and Bendamustine vs Rituximab and Bendamustine in Adults With Relapsed or Refractory CLL

Conditions
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Chronic Lymphocytic Leukemia (CLL)

Intervention / Treatment
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* Drug: Rituximab
* Drug: Bendamustine
* Drug: MEDI-551


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rituximab + Bendamustine<br>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<br>* 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<br>* Other names: Rituxan; MabThera;Drug: Bendamustine<br>* 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.<br>|
| Experimental: MEDI-551 2 mg/kg + Bendamustine<br>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<br>* 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.<br>Drug: MEDI-551<br>* 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.<br>|
| Experimental: MEDI-551 4 mg/kg + Bendamustine<br>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<br>* 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.<br>Drug: MEDI-551<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate | 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. | From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs), Treatment Emergent Serious Adverse Events (TESAEs) and Adverse Events of Special Interest (AESIs) | 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. | From time of consent to 90 days post last dose | 
| Number of Participants With Abnormal Clinical Laboratory Parameters Reported as AEs | 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. | From time of consent to 90 days post last dose | 
| Number of Participants With Abnormal Vital Signs and Electrocardiogram Reported as AEs | AEs observed in participants with clinically significant ECG abnormalities were assessed. | From time of consent to 90 days post last dose | 
| Complete Response Rate | 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. | From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months) | 
| Minimal Residual Disease Negative Complete Response (CR) Rate | 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. | 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 | Time to response was evaluated using the Kaplan-Meier method. | 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 Disease Progression (TTP) | 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. | From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months) | 
| Progression Free Survival (PFS) | 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. | From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months) | 
| Overall Survival (OS) | 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. | From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months) | 
| Number of Participants Who Developed Detectable Anti-drug Antibodies (ADA) | A participant was considered ADA-positive across the study if they had a positive reading at any time point during the study. | From treatment administration (Day 1) until disease progression, death, initiation of alternative therapy, withdrawal of consent, or end of study (up to 24 months) | 
| Terminal Half Life (t1/2) of MEDI-551 | Terminal phase elimination half-life (T1/2) was the time required for half of the drug to be eliminated from the serum. | Pre-infusion and 1 hour post infusion on Days 2 and 8, Days 15 and 22 of cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic lymphocytic leukemia; leukemia; B-Cell malignancy; anti-CD19; monoclonal antibody; CLL; Refractory; Relapse; Non-Hodgkin's Lymphoma