Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Conditions
Keywords
DLBCL Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT), Antibodies, Bispecific in combination with PD-1/PD-L1 inhibitor
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.
Interventions
DRUGBlinatumomab
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.
DRUGPembrolizumab
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.
Sponsors
Merck Sharp & Dohme LLC
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicities (DLTs) | 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) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cohort IIIa Only: Objective Response Rate During the First 12 Weeks Using the Lugano Classification | First 12 weeks of blinatumomab treatment | 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. |
| Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria | From 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 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. |
| Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification | 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 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. |
| Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria | First 12 weeks of blinatumomab treatment | 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. |
| Pembrolizumab Minimum Serum Concentration | Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively). | 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. |
| Cohort IIIa Only: Complete Response Rate During the First 12 Weeks Using the Lugano Classification | First 12 weeks of blinatumomab treatment | 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. |
| Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria | From 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 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. |
| Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification | From 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 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. |
| Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria | First 12 weeks of blinatumomab treatment | 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. |
| Cohort IIIa Only: Progression Free Survival Using the Lugano Classification | 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). | 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. |
| Overall Survival | 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). | 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. |
| Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria | 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). | 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. |
| Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using the Lugano Classification | 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). | 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. |
| Blinatumomab Steady State Concentration (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). | 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. |
| Blinatumomab Clearance | 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). | 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. |
| Pembrolizumab Peak Serum Concentration | 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). | 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. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | 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. | 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. |
| Progression Free Survival by the Revised Response Cheson Criteria | 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). | 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. |
Countries
Australia, France, Germany, Netherlands, Spain, United States
Participant flow
Recruitment details
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.
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab 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. | 12 |
| 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. | 10 |
| 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. | 9 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 6 | 7 | 4 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 3 |
Baseline characteristics
| Characteristic | Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Total |
|---|---|---|---|---|
| Age, Customized Adults (18-64 years) | 7 Participants | 3 Participants | 4 Participants | 14 Participants |
| Age, Customized From 65-84 years | 5 Participants | 7 Participants | 5 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 9 Participants | 8 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 11 Participants | 7 Participants | 8 Participants | 26 Participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 5 Participants | 9 Participants |
| Sex: Female, Male Male | 10 Participants | 8 Participants | 4 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 12 | 7 / 10 | 4 / 9 |
| other Total, other adverse events | 12 / 12 | 10 / 10 | 9 / 9 |
| serious Total, serious adverse events | 9 / 12 | 7 / 10 | 9 / 9 |
Outcome results
Primary
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: * Grade 3: Severe or medically significant but not immediately life-threatening. * Grade 4: Life-threatening. * Grade 5: Death.
Time frame: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Number of Participants With Dose Limiting Toxicities (DLTs) | 1 Participants |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Number of Participants With Dose Limiting Toxicities (DLTs) | 0 Participants |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Blinatumomab Clearance | 1.84 liters/hour | Standard Deviation 0.829 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Blinatumomab Clearance | 2.06 liters/hour | Standard Deviation 0.432 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Blinatumomab Clearance | 1.76 liters/hour | Standard Deviation 0.614 |
Secondary
Blinatumomab Steady State Concentration (Css)
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Blinatumomab Steady State Concentration (Css) | 280 pg/mL | Standard Deviation 215 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Blinatumomab Steady State Concentration (Css) | 711 pg/mL | Standard Deviation 307 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Blinatumomab Steady State Concentration (Css) | 1380 pg/mL | Standard Deviation 478 |
| Blinatumomab 112 µg/Day | Blinatumomab Steady State Concentration (Css) | 2090 pg/mL | Standard Deviation 396 |
Secondary
Cohort IIIa Only: Complete Response Rate During the First 12 Weeks Using the Lugano Classification
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.
Time frame: First 12 weeks of blinatumomab treatment
Population: Full Analysis Set: Included all participants who received blinatumomab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | 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 |
Secondary
Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification | 11.1 percentage of participants | 95% Confidence Interval 0.3 |
Secondary
Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using 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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using the Lugano Classification | 8.0 months |
Secondary
Cohort IIIa Only: 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 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.
Time frame: First 12 weeks of blinatumomab treatment
Population: Full Analysis Set: Included all participants who received blinatumomab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | 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 |
Secondary
Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification | 11.1 percentage of participants | 95% Confidence Interval 0.3 |
Secondary
Cohort IIIa Only: 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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Cohort IIIa Only: Progression Free Survival Using the Lugano Classification | 4.8 months |
Secondary
Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria
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.
Time frame: First 12 weeks of blinatumomab treatment
Population: Full Analysis Set: Included all participants who received blinatumomab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria | 0.0 percentage of participants | 95% Confidence Interval 0 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria | 20.0 percentage of participants | 95% Confidence Interval 2.5 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria | 11.1 percentage of participants | 95% Confidence Interval 0.3 |
Secondary
Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria | 16.7 percentage of participants | 95% Confidence Interval 2.1 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria | 30.0 percentage of participants | 95% Confidence Interval 6.7 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria | 11.1 percentage of participants | 95% Confidence Interval 0.3 |
Secondary
Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria | NA months |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria | 27.0 months |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria | 4.4 months |
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Time frame: 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.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAEs | 12 Participants |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 12 Participants |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAEs | 11 Participants |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAEs | 10 Participants |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 10 Participants |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAEs | 9 Participants |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | TEAEs | 9 Participants |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Grade ≥ 3 TEAEs | 9 Participants |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Grade ≥ 2 TEAEs | 9 Participants |
Secondary
Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria
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.
Time frame: First 12 weeks of blinatumomab treatment
Population: Full Analysis Set: Included all participants who received blinatumomab.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria | 16.7 percentage of participants | 95% Confidence Interval 2.1 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria | 30.0 percentage of participants | 95% Confidence Interval 6.7 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria | 33.3 percentage of participants | 95% Confidence Interval 7.5 |
Secondary
Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria
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.
Time frame: 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.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria | 25.0 percentage of participants | 95% Confidence Interval 5.5 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria | 40.0 percentage of participants | 95% Confidence Interval 12.2 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria | 33.3 percentage of participants | 95% Confidence Interval 7.5 |
Secondary
Overall Survival
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Overall Survival | 9.2 months |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Overall Survival | 7.0 months |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Overall Survival | NA months |
Secondary
Pembrolizumab Minimum Serum Concentration
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Minimum Serum Concentration | Cycle 4 | 34.2 μg/mL | Geometric Coefficient of Variation 29.9 |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Minimum Serum Concentration | Cycle 2 | 13.9 μg/mL | Geometric Coefficient of Variation 25.7 |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Minimum Serum Concentration | Cycle 6 | 50.5 μg/mL | Geometric Coefficient of Variation 23.1 |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Minimum Serum Concentration | Cycle 8 | 62.6 μg/mL | Geometric Coefficient of Variation 27.3 |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Minimum Serum Concentration | Cycle 12 | 53.2 μg/mL | Geometric Coefficient of Variation 15.7 |
Secondary
Pembrolizumab Peak Serum Concentration
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.
Time frame: 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.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Peak Serum Concentration | Cycle 1 | 52.7 μg/mL | Geometric Coefficient of Variation 24.7 |
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Pembrolizumab Peak Serum Concentration | Cycle 8 | 124 μg/mL | Geometric Coefficient of Variation 27.8 |
Secondary
Progression Free Survival by the Revised Response Cheson Criteria
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/Day + Pembrolizumab | Progression Free Survival by the Revised Response Cheson Criteria | 4.2 months | 95% Confidence Interval 0.7 |
| Cohort IIa: Blinatumomab 9/28/56 µg/Day + Pembrolizumab | Progression Free Survival by the Revised Response Cheson Criteria | 1.9 months | 95% Confidence Interval 0.6 |
| Cohort IIIa: Blinatumomab 9/28/112 µg/Day + Pembrolizumab | Progression Free Survival by the Revised Response Cheson Criteria | 2.8 months | 95% Confidence Interval 1.4 |