Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab 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 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
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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.

Official Title
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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)

Conditions
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Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Intervention / Treatment
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* Drug: Blinatumomab
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 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: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab<br>Participants received blinatumomab administered as a continuous intravenous infusion (CIVI) for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days then 28 µg/day for the remaining days of treatment. Starting on Day 15 participants also received 200 mg pembrolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles. | Drug: Blinatumomab<br>* Up to 2 cycles of blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion.<br>* Other names: Formerly known as MT103 or bscCD19xCD3;Drug: Pembrolizumab<br>* One cycle of pembrolizumab is a 200 mg IV injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.<br>* Other names: MK-3475;|
| Experimental: Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab<br>Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 56 µg/day for the remaining days of treatment. Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. | Drug: Blinatumomab<br>* Up to 2 cycles of blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion.<br>* Other names: Formerly known as MT103 or bscCD19xCD3;Drug: Pembrolizumab<br>* One cycle of pembrolizumab is a 200 mg IV injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.<br>* Other names: MK-3475;|
| Experimental: Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab<br>Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 112 µg/day for the remaining days of treatment. Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. | Drug: Blinatumomab<br>* Up to 2 cycles of blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion.<br>* Other names: Formerly known as MT103 or bscCD19xCD3;Drug: Pembrolizumab<br>* One cycle of pembrolizumab is a 200 mg IV injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.<br>* Other names: MK-3475;|
| Experimental: Expansion Cohort<br>This cohort will test the maximum tolerated dose of blinatumomab in combination with pembrolizumab identified in Part 1 of the study. | Drug: Blinatumomab<br>* Up to 2 cycles of blinatumomab may be given, where cycle 1 lasts 8 weeks, and cycle 2 lasts 28 days. The treatment is given as a continuous intravenous infusion.<br>* Other names: Formerly known as MT103 or bscCD19xCD3;Drug: Pembrolizumab<br>* One cycle of pembrolizumab is a 200 mg IV injection lasting 30 minutes. One cycle will be given every 3 weeks until disease progression, or for a maximum of 35 cycles.<br>* Other names: MK-3475;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) | Dose-limiting toxicities were grade 3-5 adverse events that occurred during the DLT-evaluation period that were judged by the Investigator to be possibly, probably or definitely related to study drug administration. All toxicities were graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate During the First 12 Weeks Using Revised Response Criteria | Objective response rate is defined as the percentage of participants with either a complete response (CR) or a partial response (PR) according to the Revised Response Criteria (2007) during the first 12 weeks of blinatumomab treatment. CR: Disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy: If fluorodeoxyglucose (FDG)-avid or positron emission tomography (PET) positive before therapy, a residual mass of any size is permitted if it is PET negative; For variably FDG-avid or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on computed tomography (CT) to normal size. Spleen or liver should not be palpable and normal size. Bone marrow infiltrate must have cleared or be negative by immunohistochemistry. PR: Regression of measurable disease and no new sites (≥ 50% decrease in size of up to six of the largest dominant nodes or nodal masses and splenic and hepatic nodules). | First 12 weeks of of blinatumomab treatment | 
| Objective Response Rate During the First 12 Weeks Using the Lugano Classification | Objective response rate is defined as the percentage of participants with either a complete response or a partial response according to the Lugano classification (2014) during the first 12 weeks of blinatumomab treatment. CR: For PET-computed tomography (CT)-based response, score of 1-3 on the Deauville five-point scale (5PS) for lymph nodes and extralymphatic sites, no evidence of FDG-avid disease in marrow. For CT-based response, target nodes/masses regress to 1.5 cm in longest transverse diameter, no extralymphatic sites of disease, normal bone marrow morphology PR: For PET-CT-based response, score of 4 or 5 on 5PS with reduced uptake compared to baseline for lymph nodes and extralymphatic sites, residual uptake reduced compared to baseline in the bone marrow. For CT-based response, ≥ 50% decrease in sum of the product of the perpendicular diameters of up to 6 target measurable nodes and extranodal sites, spleen must have regressed by > 50% in length beyond normal. | First 12 weeks of of blinatumomab treatment | 
| Objective Response Rate During the Treatment Period Using Revised Response Criteria | Objective response rate is defined as the percentage of participants with either a complete response (CR) or a partial response (PR) according to the Revised Response Criteria (2007) during the treatment period. CR: Disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy: If FDG-avid or PET positive before therapy, a residual mass of any size is permitted if it is PET negative; For variably FDG-avid or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size. Spleen or liver should not be palpable and normal size. Bone marrow infiltrate must have cleared or be negative by immunohistochemistry. PR: Regression of measurable disease and no new sites (≥ 50% decrease in size of up to six of the largest dominant nodes or nodal masses and splenic and hepatic nodules). | 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. | 
| Objective Response Rate During the Treatment Period Using the Lugano Classification | Objective response rate is defined as the percentage of participants with either a complete response (CR) or a partial response (PR) according to the Lugano classification (2014). CR: For PET-CT-based response, score of 1-3 on the Deauville five-point scale (5PS) for lymph nodes and extralymphatic sites, no evidence of FDG-avid disease in marrow. For CT-based response, target nodes/masses regress to 1.5 cm in longest transverse diameter, no extralymphatic sites of disease, normal bone marrow morphology PR: For PET-CT-based response, score of 4 or 5 on 5PS with reduced uptake compared to baseline for lymph nodes and extralymphatic sites, residual uptake reduced compared to baseline in the bone marrow. For CT-based response, ≥ 50% decrease in sum of the product of the perpendicular diameters of up to 6 target measurable nodes and extranodal sites, spleen must have regressed by > 50% in length beyond normal. | 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. | 
| Complete Response Rate During the First 12 Weeks Using the Revised Response Criteria | Complete response rate is defined as the percentage of participants with a complete response (CR) according to the Revised Response Criteria (2007) during the first 12 weeks of blinatumomab treatment. CR: Disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy: If fluorodeoxyglucose (FDG)-avid or positron emission tomography (PET) positive before therapy, a residual mass of any size is permitted if it is PET negative; For variably FDG-avid or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on computed tomography (CT) to normal size. Spleen or liver should not be palpable and normal size. Bone marrow infiltrate must have cleared or be negative by immunohistochemistry. | First 12 weeks of of blinatumomab treatment | 
| Complete Response Rate During the First 12 Weeks Using the Lugano Classification | Complete response rate is defined as the percentage of participants with a complete response according to the Lugano classification (2014) during the first 12 weeks of blinatumomab treatment. CR: For PET-computed tomography (CT)-based response, score of 1-3 on the Deauville five-point scale (5PS) for lymph nodes and extralymphatic sites, no evidence of FDG-avid disease in marrow. For CT-based response, target nodes/masses regress to 1.5 cm in longest transverse diameter, no extralymphatic sites of disease, normal bone marrow morphology. | First 12 weeks of of blinatumomab treatment | 
| Complete Response Rate During the Treatment Period Using the Revised Response Criteria | Complete response rate is defined as the percentage of participants with a complete response according to the Revised Response Criteria (2007) during the treatment period. CR: Disappearance of all detectable clinical evidence of disease and disease-related symptoms if present before therapy: If FDG-avid or PET positive before therapy, a residual mass of any size is permitted if it is PET negative; For variably FDG-avid or if a pretreatment PET scan was negative, all lymph nodes and nodal masses must have regressed on CT to normal size. Spleen or liver should not be palpable and normal size. Bone marrow infiltrate must have cleared or be negative by immunohistochemistry. | 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. | 
| Complete Response Rate During the Treatment Period Using the Lugano Classification | Complete response rate is defined as the percentage of participants with a complete response according to the Lugano classification (2014). CR: For PET-CT-based response, score of 1-3 on the Deauville five-point scale (5PS) for lymph nodes and extralymphatic sites, no evidence of FDG-avid disease in marrow. For CT-based response, target nodes/masses regress to 1.5 cm in longest transverse diameter, no extralymphatic sites of disease, normal bone marrow morphology. | 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. | 
| Progression Free Survival by the Revised Response Criteria | Progression-free survival (PFS) was calculated as the time from the date of the first dose of blinatumomab until the date of diagnosis of progression of lymphoma using the Revised Response Criteria (2007), or date of death, whichever was earliest. Participants who were alive and did not have progression were censored at the last radiological non-missing evaluable tumor assessment date. Progressive disease per the revised response criteria is any new lesion or increase of 50% or greater in size of nodal masses or lesions or new or recurrent nodal involvement. | From first dose of blinatumomab up to the data cut-off date of 17 November 2020; maximum time on follow-up for PFS was 24.4, 16.4, and 6.7 months in each cohort, respectively. | 
| Progression Free Survival Using the Lugano Classification | Progression-free survival was calculated as the time from the date of the first dose of blinatumomab until the date of diagnosis of progression of lymphoma using the Lugano 2014 classification, or date of death, whichever was earliest. For diagnosis of progression of lymphoma, the progression of radiographic assessment of PET-CT using the Lugano Classification was used. Participants who were alive and did not have progression were censored at the last radiological non-missing evaluable tumor assessment date. Progressive disease per the Lugano criteria is a score of 4 or 5 on the 5PS with an increase in intensity of uptake from baseline and/or new FDG-avid foci consistent with lymphoma. | From first dose of blinatumomab up to the data cut-off date of 17 November 2020; maximum time on follow-up was 3.3 months. | 
| Overall Survival | Overall survival (OS) was calculated as the time from the date of first dose of blinatumomab until death due to any cause. Participants who were alive at the analysis date were censored at the date last known to be alive. | From first dose of blinatumomab up to the data cut-off date of 17 November 2020; maximum time on follow-up for OS was 29.7, 16.4, and 6.7 months in each cohort respectively. | 
| Duration of Response Response for Participants Who Achieved CR/PR Using the Revised Response Criteria | Duration of response (DOR) was calculated from the date a response of CR or PR was first achieved until the earliest date of a disease assessment indicating a disease progression or death, whichever occurred first. Participants who did not have a relapse event were censored on their last radiological non-missing evaluable tumor assessment date. | Up to the data cut-off date of 17 November 2020; Maximum time on follow-up for DOR was 22.3, 14.2, and 4.3 months in each cohort, respectively. | 
| Duration of Response for Participants Who Achieved CR/PR Using the Lugano Classification | The duration of response (DOR) was calculated from the date a response of CR or PR was first achieved until the earliest date of a disease assessment indicating a disease progression using the Lugano classification or death, whichever occurred first. Participants who did not have a relapse event were censored on their last radiological non-missing evaluable tumor assessment date. | Up to the data cut-off date of 17 November 2020; Maximum time on follow-up for DOR was 1 month. | 
| Blinatumomab Steady State Concentration | Serum blinatumomab concentrations were quantified using a validated enzyme-linked immunosorbent assay (ELISA). The lower limit of quantification (LLOQ) for the assay is 50 pg/mL. The steady-state concentration (Css) of serum blinatumomab was summarized as the average of the observed concentrations collected after 24 hours from the start of continuous IV infusion or start of the dose step. For calculation of Css at 9 µg/day and 28 µg/day dosing, participants in all cohorts were combined. | 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). | 
| Blinatumomab Clearance | Systemic clearance (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. | 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). | 
| Pembrolizumab Peak Plasma Concentration | Pembrolizumab serum concentrations were quantified using a validated electro-chemiluminescent-based immunoassay with a lower limit of quantification of 25 ng/mL. | Pembrolizumab cycle 1 day 1 (study day 15 for Cohort Ia, study day 19 for Cohorts IIa and IIIa) and cycle 8 day 1 (study day 162 for Cohort Ia and day 166 for Cohorts IIa and IIIa) within approximately 30 minutes after the end of the infusion. | 
| Pembrolizumab Minimum Plasma Concentration | Pembrolizumab serum concentrations were quantified using a validated electrochemiluminescent-based immunoassay with a lower limit of quantification of 25 ng/mL. | Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively for Cohort Ia and study days 40, 82, 124, 166, and 250, respectively, for Cohorts IIa and IIIa) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DLBCL Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT), Antibodies, Bispecific in combination with PD-1/PD-L1 inhibitor