Clinical trial NCT02910063: Study to Evaluate Safety and Efficacy of Blinatumomab in Subjects With Relapsed/Refractory (R/R) Aggressive B-Cell NHL
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: B-Cell Non Hodgkin Lymphoma
Keywords: Relapsed/Refractory Aggressive B-Cell Non Hodgkin Lymphoma
Blinatumomab
Leukemia
Standard of Care
SOC
Cancer
Chemotherapy
Lead sponsor: Amgen
Sponsor class: INDUSTRY
First posted: 2016-09-21
Enrollment: 41
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Phase 2: Percentage of Participants Who Achieved Complete Metabolic Response (CMR)
timeFrame: Up to 12 weeks after first dose of blinatumomab
measure: Phase 3: Number of Participants Who Achieved Complete Metabolic Response (CMR)
timeFrame: Up to 12 weeks after first dose of study treatment
Secondary outcomes:
measure: Phase 2: Overall Survival (OS)
timeFrame: From randomization until the end of study, up to 30 months
measure: Phase 2: Objective Response Rate (ORR)
timeFrame: Up to 12 weeks after first dose of blinatumomab
measure: Phase 2: Progression Free Survival (PFS)
timeFrame: From first dose of blinatumomab until the end of study, up to 30 months
measure: Phase 2: Duration of Response (DOR)
timeFrame: From first dose of blinatumomab up to 12 weeks
measure: Phase 2: Percentage of Participants Who Experienced Successful Mobilization
timeFrame: From first dose of blinatumomab until the end of study, up to 30 months
measure: Phase 2: Percentage of Participants Who Had Allogeneic or Autologous Post-baseline Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: From baseline HSCT until the end of study, up to 30 months
measure: 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
timeFrame: 100 days after HSCT
measure: Phase 2: Blinatumomab Steady State Concentrations (Css)
timeFrame: Pre-dose on Day 1, and post-dose on Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
measure: Phase 2: Blinatumomab Clearance (CL)
timeFrame: Pre-dose on Day 1, and post-dose on Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
measure: Phase 2: Half-life of Blinatumomab
timeFrame: Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
measure: Phase 2: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
timeFrame: From first dose of blinatumomab until 30 days after last dose. The maximum treatment duration for blinatumomab was 114 days
measure: Phase 3: Objective Response Rate (ORR)
timeFrame: Up to 12 weeks after first dose of study treatment
measure: Phase 3: Progression Free Survival (PFS)
timeFrame: From first dose of study treatment until the end of study, up to 30 months
measure: Phase 3: Duration of Response (DOR)
timeFrame: From first dose of study treatment up to 12 weeks
measure: Phase 3: Percentage of Participants Who Experienced Successful Mobilization
timeFrame: From baseline until the end of study, up to 30 months
measure: Phase 3: Percentage of Participants Who Had Allogeneic or Autologous Post-baseline Hematopoietic Stem Cell Transplant (HSCT)
timeFrame: From baseline HSCT until the end of study, up to 30 months
measure: Phase 3: Percentage of Participants Who Died Within 100 Days After Hematopoietic Stem Cell Transplantation (HSCT) That Was Not Due to Relapse
timeFrame: 100 days after HSCT
measure: Phase 3: Change From Baseline in Patient Reported Clinical Outcome Assessments Quality of Life (QOLCOA) Scores
timeFrame: Up to 30 days after last dose after study treatment
measure: Phase 3: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
timeFrame: From first dose of study treatment until 30 days after last dose
measure: Phase 3: Serum Blinatumomab Steady State Concentration (Css)
timeFrame: 24 hours after first dose of blinatumomab
measure: Phase 3: Blinatumomab Clearance (CL)
timeFrame: Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
measure: Phase 3: Half-life of Blinatumomab
timeFrame: Pre-dose on Day 1, and Days 2, 9 and 16 of Cycle 1 (Cycle 1 was 70 days)
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Research Site
state: California
city: Baltimore
country: United States
facility: Research Site
state: Maryland
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Greenville
country: United States
facility: Research Site
state: South Carolina
city: St Leonards
country: Australia
facility: Research Site
state: New South Wales
city: Herston
country: Australia
facility: Research Site
state: Queensland
city: Melbourne
country: Australia
facility: Research Site
state: Victoria
city: Parkville
country: Australia
facility: Research Site
state: Victoria
city: Murdoch
country: Australia
facility: Research Site
state: Western Australia
city: Bruxelles
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Leuven
country: Belgium
facility: Research Site
city: Montreal
country: Canada
facility: Research Site
state: Quebec
city: Bergamo
country: Italy
facility: Research Site
city: Firenze
country: Italy
facility: Research Site
city: Genova
country: Italy
facility: Research Site
city: Palermo
country: Italy
facility: Research Site
city: Pisa
country: Italy
facility: Research Site
city: Roma
country: Italy
facility: Research Site
city: Udine
country: Italy
facility: Research Site
city: San Juan
country: Puerto Rico
facility: Research Site
city: Cordoba
country: Spain
facility: Research Site
state: Andalucía
city: Valladolid
country: Spain
facility: Research Site
state: Castilla León
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Santiago de Compostela
country: Spain
facility: Research Site
state: Galicia
city: Madrid
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
city: Murcia
country: Spain
facility: Research Site
city: Bristol
country: United Kingdom
facility: Research Site
city: Nottingham
country: United Kingdom
facility: Research Site
city: Sheffield
country: United Kingdom
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References:
citation: Coyle L, Morley NJ, Rambaldi A, Mason KD, Verhoef G, Furness CL, Zhang A, Jung AS, Cohan D, Franklin JL. Open-Label, phase 2 study of blinatumomab as second salvage therapy in adults with relapsed/refractory aggressive B-cell non-Hodgkin lymphoma. Leuk Lymphoma. 2020 Sep;61(9):2103-2112. doi: 10.1080/10428194.2020.1759055. Epub 2020 Jun 16.