Study to Evaluate Safety and Efficacy of Blinatumomab in Subjects With Relapsed/Refractory (R/R) Aggressive B-Cell NHL

Study Overview
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Brief Summary
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This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for the treatment of subjects with Relapsed/Refractory (R/R) aggressive B-NHL not achieving CMR after 2 cycles of standard platinum-based chemotherapy regimens administered as S1. This study incorporates multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation. In the phase 3 part of the study, blinatumomab will be compared to Investigator's Choice chemotherapy. In March 2019, decision made to not proceed with phase 3.

Detailed Description
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This is a phase 2/3 open label, multicenter trial testing blinatumomab monotherapy for the treatment of subjects with R/R aggressive B-NHL not achieving CMR after standard platinum-based chemotherapy regimens administered as S1. This study incorporates multiple interim analyses for futility, efficacy, and unblinded sample-size re-estimation. In the phase 3 part of the study, blinatumomab will be compared to IC chemotherapy.The phase 2 component of the study will consist of up to a 28-day screening period, approximately 70 to 112 days of study treatment, a 30-day (+/- 3days) safety follow up, and long-term follow up that will conclude with the final analysis of the phase 3 component, estimated at 30 months after initiation of the phase 3 component. For the phase 3 component, the study will consist of up to a 28-day screening period, a treatment period of up to approximately 168 days, a 30-day safety follow-up visit, and long-term follow up. Long-term follow up will conclude with the final analysis.In the phase 2 component, enrolled subjects will receive blinatumomab monotherapy. In the phase 3 component, enrolled subjects will be randomized in a 1:1 ratio to blinatumomab or IC chemotherapy. In March 2019, decision made to not proceed with phase 3.

Official Title
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A Phase 2/3 Multi-center Study to Evaluate the Safety and Efficacy of Blinatumomab in Subjects With Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma

Conditions
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B-Cell Non Hodgkin Lymphoma

Intervention / Treatment
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* Drug: Blinatumomab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Biopsy proven aggressive B-cell Non-Hodgkin Lymphoma (B-NHL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), follicular lymphoma Grade 3B, PMBCL, T-cell rich B-cell lymphoma, or DLBCL that represents transformation of indolent non-Hodgkin's Lymphoma (NHL), (including follicular, marginal zone, and lymphoplasmacytoid lymphoma) excluding chronic lymphocytic leukemia or Hodgkin Lymphoma. The following histologies are not eligible: Lymphoblastic lymphoma Burkitt lymphoma Mantle cell lymphoma Any histologies not specifically mentioned must be discussed with medical monitor. Refractory (no prior CR/CMR) or relapsed (prior CMR) following front line treatment of standard multiagent chemotherapy containing an anthracycline AND an approved anti-CD20 agent. For subjects with refractory disease and who have received radiotherapy, PET positivity should be demonstrated no less than 6 weeks after the last dose of radiotherapy Biopsy proven confirmation of relapsed disease. Received a minimum of 2 cycles of standard of care platinum-based chemotherapy in the S1 setting and had a response of progressive metabolic disease (PMD), no metabolic response (NMR), partial metabolic response (PMR) as centrally assessed by PET-/ CT scan or received at least 1 cycle of S1 chemotherapy and had evidence of PMD as centrally assessed. A pre-salvage scan is required to be submitted to the central reader if a subject had only 1 cycle of pre-salvage chemotherapy. Radiographically measurable disease with a demarcated nodal lesion at least 1.5 cm in its largest dimension or a target extranodal lesion at least 1.0 cm in its largest dimension Eastern Cooperative Oncology Group performance status less than or equal to 2 Intention to proceed to high dose chemotherapy (HDT) and autologous hematopoietic stem cell transplant (HSCT) Laboratory parameters: Hematology: Absolute neutrophil count (ANC) ≥ 1.0 x 10^9/L Platelets ≥ 75 x 10^9/L Chemistry: Creatinine clearance ≥ 50 mL/min Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) < 3X upper limit of normal (ULN) Total bilirubin (TBL) < 2x ULN (unless Gilbert's disease or if liver involvement with lymphoma) Exclusion Criteria: CMR following S1 chemotherapy Treatment within 30 days prior to randomization with another investigational device or drug study (ies). Prior anti-CD19-directed therapies Prior HDT with autologous HSCT Prior allogeneic HSCT Clinically relevant central nervous system (CNS) pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis Evidence of CNS involvement by NHL Known infection with human immunodeficiency virus or chronic infection with hepatitis B virus (hepatitis B surface antigen positive) or hepatitis C virus (anti hepatitis C virus positive) History of malignancy other than B-NHL within the past 3 years with the exception of: Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment Adequately treated non-melanoma skin cancer or lentigo maligna Adequately treated cervical carcinoma in situ Adequately treated breast ductal carcinoma in situ Prostatic intraepithelial neoplasia without evidence of prostate cancer Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ Known sensitivity to immunoglobulins or any of the components to be administered during dosing. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required procedures. History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. Female subjects who are pregnant or breastfeeding or planning to become pregnant or breastfeed, or of childbearing potential unwilling to use an effective method of contraception while receiving, and for an additional 48 hours after the last dose of blinatumomab.

Ages Eligible for Study
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Minimum Age: 18 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
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>Blinatumomab is administered as a continuous intravenous infusion (CIVI). A single cycle of blinatumomab is continuous infusion with step dosing of 9 µg/day x 7 days, 28 µg/day x 7 days, and 112 µg/days until the end of the cycle. | Drug: Blinatumomab<br>* Blinatumomab monotherapy<br>* Other names: Blincyto;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Percentage of Participants Who Achieved Complete Metabolic Response (CMR) | Complete metabolic response (CMR) was determined by central radiographic assessment of positron emission tomography and computed tomography (PET/CT) scans using the Lugano Classification. | Up to 12 weeks after first dose of blinatumomab | 
| Phase 3: Number of Participants Who Achieved Complete Metabolic Response (CMR) | Complete metabolic response (CMR) was determined by central radiographic assessment of positron emission tomography and computed tomography (PET/CT) scans using the Lugano Classification. | Up to 12 weeks after first dose of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Overall Survival (OS) | OS was defined as the time from the date of randomization until death due to any cause. OS was calculated using Kaplan-Meier estimates. | From randomization until the end of study, up to 30 months | 
| Phase 2: Objective Response Rate (ORR) | ORR is inclusive of all participants who achieved CMR or those who achieved partial metabolic response (PMR), as determined by central radiographic assessment of PET/CT scans using the Lugano Classification. | Up to 12 weeks after first dose of blinatumomab | 
| Phase 2: Progression Free Survival (PFS) | PFS was defined as the time from start of treatment with blinatumomab until the date of diagnosis of progression of lymphoma, or date of death, whichever is earliest. PFS was estimated using Kaplan-Meier method. | From first dose of blinatumomab until the end of study, up to 30 months | 
| Phase 2: Duration of Response (DOR) | DOR was calculated only for participants who achieve a response (CMR or PMR). The duration was calculated from the date a response, CMR or PMR, was first achieved until the earliest date of a disease assessment indicating disease progression or death, whichever occured first. DOR was estimated using Kaplan-Meier method. | From first dose of blinatumomab up to 12 weeks | 
| Phase 2: Percentage of Participants Who Experienced Successful Mobilization | Successful mobilization rate was defined as the percentage of participants who initiated mobilization while in remission and without any other anti-tumor therapy where the mobilization procedure had an outcome of 'Successful'. Successful mobilization was dictated by institutional standards and defined when the target cell dose was no less than 2 x 10^6 CD34+ cells/kg. | From first dose of blinatumomab until the end of study, up to 30 months | 
| Phase 2: Percentage of Participants Who Had Allogeneic or Autologous Post-baseline Hematopoietic Stem Cell Transplant (HSCT) | The percentage of responders per investigator's review (participants who achieved either CMR or PMR during the treatment) who have undergone allogeneic (allo) HSCT or autologous (auto) HSCT while in remission and without any other anti-cancer treatment. | From baseline HSCT until the end of study, up to 30 months | 
| Phase 2: Cumulative Incidence Function Estimate of 100-day Mortality After HSCT Presented as Percentage of Participants That Died Not Due to Relapse, With Relapse and Death Due to Relapse as Competing Events | Non-relapse mortality rate at 100 days after HSCT was calculated as the percentage of participants who died not due to relapse. Only participants who achieved a response per investigator's review and underwent autoHSCT are included. | 100 days after HSCT | 
| Phase 2: Blinatumomab Steady State Concentrations (Css) | Pharmacokinetic (PK) parameters were estimated by non compartmental analysis. The Css of blinatumomab was summarized as the observed concentrations collected after at least 24 hours after the start of continuous IV infusion or start of dose step, where appropriate. | Pre-dose on Day 1, and post-dose on Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days) | 
| Phase 2: Blinatumomab Clearance (CL) | Serum blinatumomab CL was calculated as CL=R0/Css,DN; where R0 is the infusion rate (μg/hr) and Css,DN is the dose normalized average Css. For the CL calculation, the Css,DN was normalized to the 112 μg/day dose in which the value of dose in units of μg/hr was used for the infusion rate. | Pre-dose on Day 1, and post-dose on Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days) | 
| Phase 2: Half-life of Blinatumomab |  | Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days) | 
| Phase 2: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-emergent adverse events were events with an onset after the administration of the first dose of blinatumomab. TEAEs were graded using the Common Terminology Criteria for Adverse Events (CTCAE). Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limited age appropriate instrumental activities of daily life (ADL). Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolonged hospitalization indicated; disabling; limited self care ADL. Grade 4 Life-threatening consequences; urgent interventions indicated. | From first dose of blinatumomab until 30 days after last dose. The maximum treatment duration for blinatumomab was 114 days | 
| Phase 3: Objective Response Rate (ORR) |  | Up to 12 weeks after first dose of study treatment | 
| Phase 3: Progression Free Survival (PFS) |  | From first dose of study treatment until the end of study, up to 30 months | 
| Phase 3: Duration of Response (DOR) |  | From first dose of study treatment up to 12 weeks | 
| Phase 3: Percentage of Participants Who Experienced Successful Mobilization |  | From baseline until the end of study, up to 30 months | 
| Phase 3: Percentage of Participants Who Had Allogeneic or Autologous Post-baseline Hematopoietic Stem Cell Transplant (HSCT) |  | From baseline HSCT until the end of study, up to 30 months | 
| Phase 3: Percentage of Participants Who Died Within 100 Days After Hematopoietic Stem Cell Transplantation (HSCT) That Was Not Due to Relapse |  | 100 days after HSCT | 
| Phase 3: Change From Baseline in Patient Reported Clinical Outcome Assessments Quality of Life (QOLCOA) Scores |  | Up to 30 days after last dose after study treatment | 
| Phase 3: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) |  | From first dose of study treatment until 30 days after last dose | 
| Phase 3: Serum Blinatumomab Steady State Concentration (Css) |  | 24 hours after first dose of blinatumomab | 
| Phase 3: Blinatumomab Clearance (CL) |  | Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days) | 
| Phase 3: Half-life of Blinatumomab |  | Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma, Blinatumomab, Leukemia, Standard of Care, SOC, Cancer, Chemotherapy