The overall purpose of the study is to determine if MEDI-551, when used in combination with salvage chemotherapy, Ifosfamide-carboplatin-etoposide (ICE) or Dexamethasone-cytarabine (DHAP) in patients with relapsed or refractory DLBCL who are eligible for Autologous Stem Cell Transplant (ASCT), has superior efficacy compared to rituximab in the same population.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
187
MEDI-551 at the assigned dose will be administered via Intravenous (IV) infusion. Subjects will receive 3 cycles of M-ICE or M-DHAP unless CR is achieved at the end of Cycle 2, disease progression is noted at the end of Cycle 2, or a significant/serious drug related toxicity occurs (as per the opinion of the investigator).
Rituximab at 375 mg/m2 will be administered via IV infusion 2 days before the start of Cycle 1 and on Day 1 of each cycle. The infusion time for rituximab will be 50 400 mg/hr, depending on subject's tolerance. Subjects will receive 3 cycles of Rituximab with Ice (R ICE) or Rituximab with DHAP (R-DHAP) unless CR is achieved at the end of Cycle 2, disease progression is noted at the end of Cycle 2, or a significant/serious drug related toxicity occurs (as per the opinion of the investigator).
Objective Response Rate (ORR)
Objective Response Rate is defined as the proportion of participants with a best response of complete response (CR) or partial response (PR) according to the International Working Group criteria. CR is defined as disappearance of all evidence of disease. PR is defined as 50 percent (%) decrease in the sum of the product of the perpendicular diameters (SPD) of up to 6 largest dominant nodal masses and greater than or equal to (\>=) 50% decrease in SPD of spleen/liver nodules.
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Progression-Free Survival (PFS)
Progression-free survival (PFS) is defined as the time from randomization until the first documentation of progressive disease (PD) or death due to any cause, whichever occurs first according to the International Working Group criteria. PD is defined as appearance of any new lesions or \>= 50% increase in SPD of more than one node or \>= 50% increase in longest diameter of a previously identified node or \>50% increase from nadir in the SPD of any previous lesions. PFS (months) = (Date of PD/death or censoring - Date of randomization + 1) / (365.25/12).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Event-Free Survival (EFS)
Event-Free Survival (EFS) is defined as the time from randomization until the first documentation of EFS events which include PD, initiation of alternative antitumor treatment or death due to any cause, whichever occurs first according to the International Working Group criteria. PD is defined as appearance of any new lesions or \>= 50% increase in SPD of more than one node or \>= 50% increase in longest diameter of a previously identified node or \>50% increase from nadir in the SPD of any previous lesions. EFS (months) = (Date of EFS or censoring - Date of randomization + 1) / (365.25/12).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
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ICE will be administered via IV infusion as follows: ifosfamide 5 g/m2 continuously for 24 hours with mesna on Days 2 and 3; carboplatin AUC=5 mg/mL x min \[800 mg maximum) on Day 2; etoposide 100 mg/m2 on Days 1, 2, and 3) in 21-day cycles.
DHAP will be administered via IV infusion as follows: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m2 continuously for 24 hours on Day 1 of dosing cycle; cytarabine 2 g/m2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles.
Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.
MEDI-551 at the assigned dose will be administered via Intravenous (IV) infusion. Subjects will receive 3 cycles of M-ICE or M-DHAP unless CR is achieved at the end of Cycle 2, disease progression is noted at the end of Cycle 2, or a significant/serious drug related toxicity occurs (as per the opinion of the investigator).
Research Site
Birmingham, Alabama, United States
Research Site
Burbank, California, United States
Research Site
Palm Springs, California, United States
Research Site
Sylmar, California, United States
Research Site
Atlanta, Georgia, United States
Research Site
Westwood, Kansas, United States
Research Site
Hazard, Kentucky, United States
Research Site
Lafayette, Louisiana, United States
Research Site
Shreveport, Louisiana, United States
Research Site
Baltimore, Maryland, United States
...and 71 more locations
Overall Survival (OS)
Overall survival is defined as the time from randomization until death due to any cause according to the International Working Group criteria. OS (months) = (Date of death or censoring - Date of randomization + 1) / (365.25/12).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Time to Progression (TTP)
Time to Progression (TTP) is defined as the time from randomization until the first documentation of PD according to the International Working Group criteria. PD is defined as appearance of any new lesions or \>= 50% increase in SPD of more than one node or \>= 50% increase in longest diameter of a previously identified node or \>50% increase from nadir in the SPD of any previous lesions. TTP (months) = (Date of PD or censoring - Date of randomization + 1) / (365.25/12).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Time to Response (TTR)
Time to response (TTR) is defined as the time from randomization until the first documentation of disease response according to the International Working Group criteria. Only participants who have achieved objective response (confirmed CR or confirmed PR) assessed by investigator were evaluated for TTR. CR is defined as disappearance of all evidence of disease. PR is defined as 50% decrease in the SPD of up to 6 largest dominant nodal masses and \>= 50% decrease in SPD of spleen/liver nodules. TTR (months) = (Date of first disease response - Date of randomization + 1) / (365.25/12).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Duration of Response (DR)
Duration of Response (DR) is defined as time from start of first documented objective response (confirmed CR or confirmed PR) to first documented PD according to the International Working Group criteria. CR is defined as disappearance of all evidence of disease. PR is defined as 50% decrease in the SPD of up to 6 largest dominant nodal masses and \>= 50% decrease in SPD of spleen/liver nodules. PD: appearance of any new lesions or \>= 50% increase in SPD of more than one node or \>= 50% increase in longest diameter of a previously identified node or \> 50% increase from nadir in the SPD of any previous lesions. Only participants who have achieved objective response assessed by investigator were evaluated. DR calculated as (months) = (Date of PD or censoring - Date of first disease response + 1)/ (365.25/12).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Number of Participants With Best Overall Response Assessed by Blinded Independent Central Review (BICR)
The best overall response was calculated, based upon the disease assessments recorded during the study visits, and summarized with the number of participants for the following categories: CR, PR, stable disease (SD), PD, and unknown. Responses were assessed according to the International Working Group criteria. CR: disappearance of all evidence of disease; PR: 50% decrease in the SPD of up to 6 largest dominant nodal masses and \>= 50% decrease in SPD of spleen/liver nodules; PD: appearance of any new lesions or \>= 50% increase in SPD of more than one node or \>= 50% increase in longest diameter of a previously identified node or \>50% increase from nadir in the SPD of any previous lesions; SD: failure to attain CR/PR or PD.
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Acceptable Dose of MEDI-551
Acceptable dose for MEDI-551 was evaluated based on the benefit-risk analysis.
Time frame: After the administration of the first dose of MEDI-551 (7 days before the Cycle 1) to last dose of MEDI-551 (Cycle 3 Day 1) (each cycle of 21 days)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
An Adverse Event (AE) is any unfavourable and unintended signs, symptoms, or diseases temporally associated with use of study drug, whether or not considered related to study drug. Serious adverse event (SAE) is any AE that resulted in death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, life-threatening, a congenital anomaly/birth defect, or an important medical event. TEAEs are defined as AEs present at baseline that worsened in intensity after administration of study drug, or events absent at baseline that emerged after administration of study drug, up to 90 days after the end of treatment (EOT).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Hematology/Coagulation Laboratory Results
An abnormal laboratory finding that was judged by the investigator to be clinically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-551, or events absent at baseline that emerged after administration of MEDI-551, for the period extending to 90 days after the end of study treatment (EOT).
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Chemistry Laboratory Results (Include Urinalysis)
An abnormal laboratory findings that was judged by the investigator to be clinically significant was reported as an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-551, or events absent at baseline that emerged after administration of MEDI-551, for the period extending to 90 days after the end of study treatment.
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Related to Vital Signs and ECG Abnormalities
Vital signs included parameters such as heart rate, blood pressure, temperature, and respiratory rate. An abnormal vital signs and ECG findings that was judged by the investigator to be clinically significant was reported an AE. TEAEs were defined as events present at baseline that worsened in intensity after administration of MEDI-551, or events absent at baseline that emerged after administration of MEDI-551, for the period extending to 90 days after the end of study treatment.
Time frame: From treatment administration (Day 1) to 90 days after the end of study treatment (up to approximately 36 months from the randomization of last participant)
Number of Participants Who Developed Detectable MEDI-551 Anti-drug Antibodies (ADA)
A participant was considered ADA-positive across the study if they had a positive reading (titer of 50 or higher) at any time point during the study.
Time frame: 7 days before the start of Cycle 1, Day 1 of each subsequent Cycle, EOT, and post EOT on Days 30, 60, 90 and 270 (up to 36 months from the randomization of last participant)
Mean Serum Concentration of MEDI-551
The mean serum concentration of MEDI-551 were observed.
Time frame: Cycle 1 Day -7 Post dose, pre-dose and postdose on Day 1, post-dose on Days 4, 8, 15 of Cycle 1, pre-dose and postdose on Day 1 of Cycle 2 and Cycle 3
Half-life (T1/2) of MEDI-551
Terminal elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the serum.
Time frame: Cycle 1 and EOT (Day 21 of Cycle 3 [each cycle of 21 days] or earlier cycles if treatment stopped before Cycle 3)