A Phase 2, Multicenter, Randomized, Open-label Study of MEDI-551 in Adults With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2 Randomized Open-label Study of MEDI-551 in Adults With Relapsed or Refractory DLBCL

Conditions
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Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: MEDI-551 2 mg/kg
* Drug: Rituximab
* Drug: ICE
* Drug: DHAP
* Procedure: Autologous Stem Cell Transplant (ASCT)
* Drug: MEDI-551 4 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed aggressive B-cell DLBCL, including FL transforming to DLBCL & Grade III FL Relapsed from or refractory to at least one treatment containing rituximab or another anti-CD20 based immunotherapy combined with anthracycline- or anthracenedione-based chemotherapy Eligible for ASCT Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 Life expectancy of ≥ 12 weeks Adequate hematological function Exclusion Criteria: Any chemotherapy, radiotherapy, immunotherapy, biologic, investigational or hormonal therapy for treatment of lymphoma within 28 days prior to treatment Previous cancer therapy for DLBCL other than anthracycline- or anthracenedione based chemoimmunotherapy, monotherapy rituximab prior to first line therapy and/or as a maintenance therapy, or limited field radiotherapy Prior autologous or allogeneic SCT New York Heart Association ≥ Class II congestive heart failure; Clinically significant abnormality on ECG History of other invasive malignancy within 5 years except for localized/in situ, carcinomas such as cervical carcinoma in situ. Evidence of active infection Documented 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+ ICE/DHAP<br>Participants will receive Rituximab in combination with ifosfamide + carboplatin + etoposide (ICE) or dexamethasone + cisplatin + cytarabine (DHAP) for 3 cycles (21-day cycles) and will followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). Rituximab (375 mg/m^2) will be administered intravenous (IV) on 2 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of rituximab, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of rituximab, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles. | Drug: Rituximab<br>* 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).<br>* Other names: Rituxan; MabThera;Drug: ICE<br>* 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.<br>Drug: DHAP<br>* 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.<br>Procedure: Autologous Stem Cell Transplant (ASCT)<br>* Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.<br>|
| Experimental: MEDI-551 2 mg/kg + ICE/DHAP<br>Participants will receive MEDI-551 (2 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and will be followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (2 mg/kg) will be administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles. | Drug: MEDI-551 2 mg/kg<br>* 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).<br>* Other names: Inebilizumab;Drug: ICE<br>* 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.<br>Drug: DHAP<br>* 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.<br>Procedure: Autologous Stem Cell Transplant (ASCT)<br>* Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.<br>|
| Experimental: MEDI-551 4 mg/kg + ICE/DHAP<br>Participants will receive MEDI-551 (4 mg/kg) in combination with ICE or DHAP for 3 cycles (21-day cycles) and will be followed until end of the study (36 months after the date of randomization for last participant, or date the sponsor stops the trial, whichever occurs first). MEDI-551 (4 mg/kg) will be administered IV on 7 days before the start of Cycle 1 and on Day 1 of each cycle. After completion of MEDI-551, IV infusion of ICE as: ifosfamide 5 g/ m^2 continuously for 24 hours with mesna on Day 2; carboplatin AUC=5 mg/mL x min (800 mg maximum) on Day 2; etoposide 100 mg/ m^2 on Days 1, 2, and 3 in 21-day cycles. After completion of MEDI-551, IV infusion of DHAP as: dexamethasone 40 mg on Days 1, 2, 3, and 4; cisplatin 100 mg/m^2 continuously for 24 hours on Day 1; cytarabine 2 g/m^2 in 3-hour infusion repeated after 12 hours (2 doses) on Day 2 in 21-day cycles. | Drug: ICE<br>* 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.<br>Drug: DHAP<br>* 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.<br>Procedure: Autologous Stem Cell Transplant (ASCT)<br>* Subjects who achieve CR or PR will undergo stem cell harvest and autologous stem cell transplantation (ASCT) following standard institutional protocols.<br>Drug: MEDI-551 4 mg/kg<br>* 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).<br>* Other names: Inebilizumab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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). | 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) | 
| 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). | 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). | 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). | 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). | 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. | 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. | 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). | 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). | 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. | 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. | 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. | 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. | 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. | Cycle 1 and EOT (Day 21 of Cycle 3 [each cycle of 21 days] or earlier cycles if treatment stopped before Cycle 3) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphoma, Non-Hodgkin's Lymphoma, Diffuse Large B-Cell Lymphoma, DLBCL, B-Cell Malignancy, anti-CD19, monoclonal antibody, second line, ASCT, Refractory