Trial Outcomes & Findings for Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adults With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL) (NCT NCT03340766)

Last Updated: 2024-10-17

Results Overview

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: * Grade 3: Severe or medically significant but not immediately life-threatening. * Grade 4: Life-threatening. * Grade 5: Death.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

31 participants

Primary outcome 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)

Results posted on

2024-10-17

Participant Flow

This study was conducted at 11 centers in Australia, France, Netherlands, Spain, and the United States. The study was planned as 2 parts. Based on the results from Part 1, a decision was made not to proceed with Part 2 of the study.

Participants were enrolled into each dose cohort sequentially using a rolling 6 study design. A Dose Level Review Team (DLRT) reviewed the safety data to evaluate possible drug effects and dose-limiting toxicities (DLTs).

Participant milestones

Participant milestones
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab Participants in Cohort Ia 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.
Overall Study STARTED	12	10	9
Overall Study Received Blinatumomab	12	10	9
Overall Study Received Pembrolizumab	10	7	7
Overall Study COMPLETED	4	2	1
Overall Study NOT COMPLETED	8	8	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab Participants in Cohort Ia 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.
Overall Study Withdrawal by Subject	2	1	3
Overall Study Lost to Follow-up	0	0	1
Overall Study Death	6	7	4

Baseline Characteristics

Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adults With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Total n=31 Participants Total of all reporting groups
Age, Customized Adults (18-64 years)	7 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants	14 Participants n=4 Participants
Age, Customized From 65-84 years	5 Participants n=5 Participants	7 Participants n=7 Participants	5 Participants n=5 Participants	17 Participants n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants	9 Participants n=4 Participants
Sex: Female, Male Male	10 Participants n=5 Participants	8 Participants n=7 Participants	4 Participants n=5 Participants	22 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	12 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	29 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race/Ethnicity, Customized Asian	1 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	2 Participants n=4 Participants
Race/Ethnicity, Customized White	11 Participants n=5 Participants	7 Participants n=7 Participants	8 Participants n=5 Participants	26 Participants n=4 Participants
Race/Ethnicity, Customized Other	0 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants

PRIMARY outcome

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)

Population: DLT Analysis Set: Included participants who experienced a DLT, OR were removed from treatment for an adverse event/toxicity that was not a DLT or for other reasons and had been exposed to study treatment for ≥ 12 days OR completed the DLT evaluation period.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=6 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=5 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Number of Participants With Dose Limiting Toxicities (DLTs)	1 Participants	0 Participants	2 Participants	—

SECONDARY outcome

Timeframe: First 12 weeks of blinatumomab treatment

Population: Full Analysis Set: Included all participants who received blinatumomab.

Objective response rate is defined as the percentage of participants with either a complete response (CR) or a partial response (PR): * 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). Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria	16.7 percentage of participants 95% Confidence Interval 2.1 • Interval 2.1 to 48.4	30.0 percentage of participants 95% Confidence Interval 6.7 • Interval 6.7 to 65.3	33.3 percentage of participants 95% Confidence Interval 7.5 • Interval 7.5 to 70.1	—

SECONDARY outcome

Timeframe: First 12 weeks of blinatumomab treatment

Population: Full Analysis Set: Included all participants who received blinatumomab.

Objective response rate is defined as the percentage of participants with either a complete metabolic response (CMR) or a partial metabolic response (PMR): * CMR: 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 * PMR: 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. Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Cohort IIIa Only: Objective Response Rate During the First 12 Weeks Using the Lugano Classification	11.1 percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 48.3	—	—	—

SECONDARY outcome

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.

Population: Full Analysis Set: Included all participants who received blinatumomab.

Objective response rate is defined as the percentage of participants with either a CR or a PR according to the Revised Response Criteria (2007): * 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). Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria	25.0 percentage of participants 95% Confidence Interval 5.5 • Interval 5.5 to 57.2	40.0 percentage of participants 95% Confidence Interval 12.2 • Interval 12.2 to 73.8	33.3 percentage of participants 95% Confidence Interval 7.5 • Interval 7.5 to 70.1	—

SECONDARY outcome

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.

Population: Full Analysis Set: Included all participants who received blinatumomab.

Objective response rate is defined as the percentage of participants with either a CMR or a CMR. * CMR: For PET-CT-based response, score of 1-3 on the Deauville 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 * PMR: 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. Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification	11.1 percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 48.3	—	—	—

SECONDARY outcome

Timeframe: First 12 weeks of blinatumomab treatment

Population: Full Analysis Set: Included all participants who received blinatumomab.

Complete response rate is defined as the percentage of participants with a CR according to the Revised Response Criteria (2007): \- 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. Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria	0.0 percentage of participants 95% Confidence Interval 0.0 • Interval 0.0 to 26.5	20.0 percentage of participants 95% Confidence Interval 2.5 • Interval 2.5 to 55.6	11.1 percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 48.3	—

SECONDARY outcome

Timeframe: First 12 weeks of blinatumomab treatment

Population: Full Analysis Set: Included all participants who received blinatumomab.

Complete response rate is defined as the percentage of participants with a CMR according to the Lugano classification (2014): CMR: For PET-CT-based response, score of 1-3 on the Deauville 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. Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Cohort IIIa Only: Complete Response Rate During the First 12 Weeks Using the Lugano Classification	11.1 percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 48.3	—	—	—

SECONDARY outcome

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.

Population: Full Analysis Set: Included all participants who received blinatumomab.

Complete response rate is defined as the percentage of participants with a complete response according to the Revised Response Criteria (2007): \- 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. Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria	16.7 percentage of participants 95% Confidence Interval 2.1 • Interval 2.1 to 48.4	30.0 percentage of participants 95% Confidence Interval 6.7 • Interval 6.7 to 65.3	11.1 percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 48.3	—

SECONDARY outcome

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.

Population: Full Analysis Set: Included all participants who received blinatumomab.

Complete response rate is defined as the percentage of participants with a CMR according to the Lugano classification (2014): \- CMR: For PET-CT-based response, score of 1-3 on the Deauville 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. Participants with no post-baseline response assessments were considered non-responders.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification	11.1 percentage of participants 95% Confidence Interval 0.3 • Interval 0.3 to 48.3	—	—	—

SECONDARY outcome

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).

Population: Full Analysis Set: Included all participants who received blinatumomab.

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 Cheson 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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Progression Free Survival by the Revised Response Cheson Criteria	4.2 months 95% Confidence Interval 0.7 • Interval 0.7 to 24.1	1.9 months 95% Confidence Interval 0.6 • Interval 0.6 to 12.8	2.8 months 95% Confidence Interval 1.4 • Interval 1.4 to 6.8	—

SECONDARY outcome

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).

Population: Full Analysis Set: Included all participants who received blinatumomab with available post-baseline response per 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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Cohort IIIa Only: Progression Free Survival Using the Lugano Classification	4.8 months Interval 2.8 to Upper limit was not estimable due to low number of events.	—	—	—

SECONDARY outcome

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).

Population: Full Analysis Set: Included all participants who received blinatumomab.

Overall survival 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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Overall Survival	9.2 months Interval 0.7 to Upper limit was not estimable due to low number of events.	7.0 months Interval 0.7 to Upper limit was not estimable due to low number of events.	NA months Interval 1.4 to Median and upper limit were not estimable due to low number of events.	—

SECONDARY outcome

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).

Population: Full Analysis Set: Included all participants with a CR or PR during the first 12 weeks of blinatumomab treatment according to the revised response criteria were included.

Duration of response 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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=2 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=3 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=3 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria	NA months Median, lower limit and upper limit were not estimable due to low number of events.	27.0 months Interval 5.5 to Upper limit was not estimable due to low number of events.	4.4 months Interval 0.9 to Upper limit was not estimable due to low number of events.	—

SECONDARY outcome

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).

Population: Full Analysis Set: Included all participants with a CMR or PMR during the first 12 weeks of blinatumomab treatment according to the Lugano classification.

The duration of response was calculated from the date a response of CMR or PMR 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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=1 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using the Lugano Classification	8.0 months Lower and upper limit were not estimable due to low number of events.	—	—	—

SECONDARY outcome

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).

Population: Pharmacokinetic Analysis Set: Included all participants who received any infusion of blinatumomab or pembrolizumab and had at least 1 pharmacokinetic sample collected.

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 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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=27 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=24 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=3 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day n=2 Participants Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Blinatumomab Steady State Concentration (Css)	280 pg/mL Standard Deviation 215	711 pg/mL Standard Deviation 307	1380 pg/mL Standard Deviation 478	2090 pg/mL Standard Deviation 396

SECONDARY outcome

Population: Pharmacokinetic Analysis Set: Included all participants who received any infusion of blinatumomab or pembrolizumab and had at least 1 pharmacokinetic sample collected.

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.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=8 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Blinatumomab Clearance	1.84 liters/hour Standard Deviation 0.829 • Interval 0.829 to	2.06 liters/hour Standard Deviation 0.432 • Interval 0.432 to	1.76 liters/hour Standard Deviation 0.614 • Interval 0.614 to	—

SECONDARY outcome

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).

Population: Pharmacokinetic Analysis Set: Included all participants who received any infusion of blinatumomab or pembrolizumab and had at least 1 pharmacokinetic sample collected.

Pembrolizumab serum concentrations were quantified using a validated electro-chemiluminescent-based immunoassay with a lower limit of quantification of 25 ng/mL. The pembrolizumab pharmacokinetic data from all cohorts were combined for analysis.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=21 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Pembrolizumab Peak Serum Concentration Cycle 1	52.7 μg/mL Geometric Coefficient of Variation 24.7	—	—	—
Pembrolizumab Peak Serum Concentration Cycle 8	124 μg/mL Geometric Coefficient of Variation 27.8	—	—	—

SECONDARY outcome

Timeframe: Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively).

Population: Pharmacokinetic Analysis Set: Included all participants who received any infusion of blinatumomab or pembrolizumab and had at least 1 pharmacokinetic sample collected.

Pembrolizumab serum concentrations were quantified using a validated electrochemiluminescent-based immunoassay with a lower limit of quantification of 25 ng/mL. The pembrolizumab pharmacokinetic data from all cohorts were combined for analysis.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=16 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Pembrolizumab Minimum Serum Concentration Cycle 12	53.2 μg/mL Geometric Coefficient of Variation 15.7	—	—	—
Pembrolizumab Minimum Serum Concentration Cycle 2	13.9 μg/mL Geometric Coefficient of Variation 25.7	—	—	—
Pembrolizumab Minimum Serum Concentration Cycle 4	34.2 μg/mL Geometric Coefficient of Variation 29.9	—	—	—
Pembrolizumab Minimum Serum Concentration Cycle 6	50.5 μg/mL Geometric Coefficient of Variation 23.1	—	—	—
Pembrolizumab Minimum Serum Concentration Cycle 8	62.6 μg/mL Geometric Coefficient of Variation 27.3	—	—	—

SECONDARY outcome

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.

Population: Safety Analysis Set: Included all participants who received blinatumomab.

A TEAE was defined as any untoward medical occurrence in a clinical trial participant that started after the initiation of blinatumomab. All TEAEs were graded using NCI CTCAE Version 4.0: * Grade 2: Moderate * Grade 3: Severe or medically significant but not immediately life-threatening.

Outcome measures

Outcome measures
Measure	Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab n=12 Participants Participants in Cohort Ia received blinatumomab administered as 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 21 days of treatment. Starting on study Day 15 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab n=10 Participants Participants in Cohort IIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab n=9 Participants Participants in Cohort IIIa received blinatumomab administered as a CIVI for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received an additional 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 21 days of treatment. Starting on study Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles.	Blinatumomab 112 µg/Day Participants received blinatumomab administered via a continuous intravenous infusion of 112 µg/day.
Number of Participants With Treatment-emergent Adverse Events (TEAEs) TEAEs	12 Participants	10 Participants	9 Participants	—
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Grade ≥ 2 TEAEs	12 Participants	10 Participants	9 Participants	—
Number of Participants With Treatment-emergent Adverse Events (TEAEs) Grade ≥ 3 TEAEs	11 Participants	9 Participants	9 Participants	—

Adverse Events

Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab

Serious events: 9 serious events

Other events: 12 other events

Deaths: 6 deaths

Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab

Serious events: 7 serious events

Other events: 10 other events

Deaths: 7 deaths

Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab

Serious events: 9 serious events

Other events: 9 other events

Deaths: 4 deaths

Serious adverse events

Other adverse events

Additional Information

Study Director

Amgen Inc.

Phone: 866-572-6436

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Clinical Trial Agreement generally does not restrict an investigator's discussion of trial results after completion. The Agreement permits Amgen a limited period of time to review material discussing trial results (typically up to 45 days and possible extension). Amgen may remove confidential information, but authors have final control and approval of publication content. For multicenter studies, the investigator agrees not to publish any results before the first multi-center publication.
Publication restrictions are in place

Restriction type: OTHER