Clinical trial NCT03340766: Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adults With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Official title: A Phase 1b Open Label Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adult Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Keywords: DLBCL Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT)
Antibodies
Bispecific in combination with PD-1/PD-L1 inhibitor
Lead sponsor: Amgen
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-11-14
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to determine the maximum tolerated dose (MTD) of blinatumomab in combination with pembrolizumab in adults with relapsed or refractory (r/r) DLBCL.

Detailed description: The study was planned as 2 parts:

* Part 1 will test the safety of up to 3 different blinatumomab target dose levels in combination with pembrolizumab in a rolling 6 design. A Dose Level Review Team (DLRT) will review the safety data to evaluate possible drug effects and dose-limiting toxicities (DLTs).
* Part 2 will consist of an expansion cohort to assess pharmacokinetics (PK), safety, and preliminary efficacy data at the chosen target dose. The part 2 dose will be determined by the totality of the clinical data from part 1 as determined by the DLRT.

Based on the results from Part 1, a decision was made not to proceed with Part 2 of this study.

Secondary objectives of the study are to evaluate the safety, efficacy, and pharmacokinetics (PK) of blinatumomab in combination with pembrolizumab. Tumor response will be evaluated according to the Revised Response Criteria for Malignant Lymphoma (Cheson et al, 2007). With implementation of Protocol Amendment 5, response will also be assessed according to the Lugano Classification (Cheson et al, 2014). Only participants enrolled after implementation of Protocol Amendment 5 (03 December 2019) will have tumor assessments using the Lugano criteria.

Eligibility criteria: Inclusion Criteria:

* Have histologically confirmed diffuse large B-cell lymphoma that is either:
* Refractory after at least one regimen of systemic chemotherapy and/or targeted therapy, or
* In first or later relapse if have received at least 2 systemic regimens since time of diagnosis, or
* Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT) with adequate organ function after proximity to transplantation time exclusions
* Have measurable disease
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Life expectancy of ≥ 12 weeks in the opinion of the Investigator
* Biopsy proven DLBCL (biopsy proven at least at primary diagnosis of DLBCL)

Other Inclusion Criteria May Apply

Exclusion Criteria:

* Richter's transformation (DLBCL arising in the setting of prior chronic lymphocytic leukemia) or primary mediastinal B cell lymphoma (PMBCL)
* History or presence of clinically relevant central nervous system pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
* Has a diagnosis of immunodeficiency or has received systemic steroid therapy (in excess of 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol specified therapy.
* Has undergone prior allogeneic HSCT:
* within the last 5 years OR
* greater than 5 years ago but has active graft versus host disease (GvHD) requiring systemic treatment.
* Has received autologous HSCT within 6 weeks prior to start of treatment.

Other Exclusion Criteria May Apply.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities (DLTs)
timeFrame: The DLT evaluation period was 42 days from initiation of pembrolizumab treatment (Day 15 for Cohort Ia and Day 19 for Cohorts IIa and IIIa)
Secondary outcomes:
measure: Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria
timeFrame: First 12 weeks of blinatumomab treatment
measure: Cohort IIIa Only: Objective Response Rate During the First 12 Weeks Using the Lugano Classification
timeFrame: First 12 weeks of blinatumomab treatment
measure: Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria
timeFrame: From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
measure: Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification
timeFrame: From study Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
measure: Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria
timeFrame: First 12 weeks of blinatumomab treatment
measure: Cohort IIIa Only: Complete Response Rate During the First 12 Weeks Using the Lugano Classification
timeFrame: First 12 weeks of blinatumomab treatment
measure: Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria
timeFrame: From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
measure: Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification
timeFrame: From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
measure: Progression Free Survival by the Revised Response Cheson Criteria
timeFrame: From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).
measure: Cohort IIIa Only: Progression Free Survival Using the Lugano Classification
timeFrame: From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).
measure: Overall Survival
timeFrame: From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).
measure: Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria
timeFrame: From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).
measure: Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using the Lugano Classification
timeFrame: From first dose of blinatumomab up to the end of study. Median (min, max) time on study was 188.0 days (19.0, 1512.0).
measure: Blinatumomab Steady State Concentration (Css)
timeFrame: Day 2 for 9 µg/day Css (all cohorts), days 10, 15, 22, 29, and 43 for 28 µg/day Css (Cohort Ia), day 10 for 28 µg/day Css (Cohorts IIa and IIIa), and days 19, 26, and 40 for 56 µg/day and 112 µg/day Css (Cohorts IIa and IIIa respectively).
measure: Blinatumomab Clearance
timeFrame: Day 2 for 9 µg/day Css (all cohorts), days 10, 15, 22, 29, and 43 for 28 µg/day Css (Cohort Ia), day 10 for 28 µg/day Css (Cohorts IIa and IIIa), and days 19, 26, and 40 for 56 µg/day and 112 µg/day Css (Cohorts IIa and IIIa respectively).
measure: Pembrolizumab Peak Serum Concentration
timeFrame: Within approximately 30 minutes after the end of the infusion in cycle 1 (study day 15 for Cohort Ia, study day 19 for Cohorts IIa and IIIa) and cycle 8 (study day 162 for Cohort Ia and day 166 for Cohorts IIa and IIIa).
measure: Pembrolizumab Minimum Serum Concentration
timeFrame: Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively).
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
timeFrame: From first dose of blinatumomab to minimum of 30 days after last dose of blinatumomab or pembrolizumab (whichever was later) or end of study: median (min, max) duration was 22.7 (1.0, 85.8) days.
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: Research Site
state: California
city: Charleston
country: United States
facility: Research Site
state: South Carolina
city: Greenville
country: United States
facility: Research Site
state: South Carolina
city: Darlinghurst
country: Australia
facility: Research Site
state: New South Wales
city: St Leonards
country: Australia
facility: Research Site
state: New South Wales
city: Adelaide
country: Australia
facility: Research Site
state: South Australia
city: East Melbourne
country: Australia
facility: Research Site
state: Victoria
city: Geelong
country: Australia
facility: Research Site
state: Victoria
city: Melbourne
country: Australia
facility: Research Site
state: Victoria
city: Murdoch
country: Australia
facility: Research Site
state: Western Australia
city: Créteil Cedex
country: France
facility: Research Site
city: Nantes Cedex 1
country: France
facility: Research Site
city: Pierre-Benite
country: France
facility: Research Site
city: Heidelberg
country: Germany
facility: Research Site
city: Ulm
country: Germany
facility: Research Site
city: Würzburg
country: Germany
facility: Research Site
city: Maastricht
country: Netherlands
facility: Research Site
city: Rotterdam
country: Netherlands
facility: Research Site
city: Santander
country: Spain
facility: Research Site
state: Cantabria
city: Salamanca
country: Spain
facility: Research Site
state: Castilla León
city: Barcelona
country: Spain
facility: Research Site
state: Cataluña
city: Madrid
country: Spain
facility: Research Site
Study officials:
affiliation: Amgen
name: MD
role: STUDY_DIRECTOR
References: