Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)Phase 1HARBOURNCT03340766
Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adults With Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)
A Phase 1 study testing Blinatumomab and Pembrolizumab in people with Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL), run by Amgen at 22 sites in 6 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 100 years
- Conditions the study is for
- Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)
- What is being tested?
- Blinatumomab and Pembrolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 31 participants
- Where
- 22 sitesin 6 countries
- Study dates
- 16 Mar 2018to 14 Aug 2023
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 100 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 9Show fewer
- 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
Who cannot join
- Richter's transformation (DLBCL arising in the setting of prior chronic lymphocytic leukemia) or primary mediastinal B cell lymphoma (PMBCL)
- History or presence of clinically relevant central nervous system pathology such as epilepsy, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
- Has a diagnosis of immunodeficiency or has received systemic steroid therapy (in excess of 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of protocol specified therapy.
- Has undergone prior allogeneic HSCT:
- within the last 5 years OR
- greater than 5 years ago but has active graft versus host disease (GvHD) requiring systemic treatment.
- Has received autologous HSCT within 6 weeks prior to start of treatment.
- Other Exclusion Criteria May Apply.
Trial locations and contacts
22 sites in 6 countries.
22 sites in 6 countries
Australia7 sites
Research Site
Adelaide, South Australia, 5000
Research Site
Darlinghurst, New South Wales, 2010
Research Site
East Melbourne, Victoria, 3002
Research Site
Geelong, Victoria, 3220
Research Site
Melbourne, Victoria, 3004
Research Site
Murdoch, Western Australia, 6150
Research Site
St Leonards, New South Wales, 2065
Spain4 sites
Research Site
Barcelona, Catalonia, 08025
Research Site
Madrid, 28046
Research Site
Salamanca, Castille and León, 37007
Research Site
Santander, Cantabria, 39008
United States3 sites
Research Site
Charleston, South Carolina, 29424
Research Site
Greenville, South Carolina, 29607
Research Site
La Jolla, California, 92093-0960
France3 sites
Research Site
Créteil, 94010
Research Site
Nantes, 44035
Research Site
Pierre-Bénite, 69495
Germany3 sites
Research Site
Heidelberg, 69120
Research Site
Ulm, 89081
Research Site
Würzburg, 97080
Netherlands2 sites
Research Site
Maastricht, 6229 HX
Research Site
Rotterdam, 3015 CN
About this study
Official title: A Phase 1b Open Label Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adult Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
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.
Read the 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.
- Being tested
- Blinatumomab, Pembrolizumab
- Keywords
- DLBCL Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT), Antibodies, Bispecific in combination with PD-1/PD-L1 inhibitor
- Medical subject headings
- Recurrence, Lymphoma, Large B-Cell, Diffuse
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
BlinatumomabDrug
Also called Blincyto, AMG 103, Formerly known as MT103 or bscCD19xCD3
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.
PembrolizumabDrug
Also called Keytruda, MK-3475
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.
| Study group | Role | What they receive |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab | Experimental | Participants received blinatumomab administered as a continuous intravenous infusion (CIVI) for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days then 28 µg/day for the remaining days of treatment.
Starting on Day 15 participants also received 200 mg pembrolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles. Receives: Drug: Blinatumomab; Drug: Pembrolizumab |
| Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab | Experimental | Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 56 µg/day for the remaining days of treatment.
Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. Receives: Drug: Blinatumomab; Drug: Pembrolizumab |
| Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab | Experimental | Participants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 112 µg/day for the remaining days of treatment.
Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. Receives: Drug: Blinatumomab; Drug: Pembrolizumab |
| Expansion Cohort | Experimental | This cohort will test the maximum tolerated dose of blinatumomab in combination with pembrolizumab identified in Part 1 of the study. Receives: Drug: Blinatumomab; Drug: Pembrolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: The DLT evaluation period was 42 days from initiation of pembrolizumab treatment (Day 15 for Cohort Ia and Day 19 for Cohorts IIa and IIIa)
Secondary outcomes (18)
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.
Measured: First 12 weeks of blinatumomab treatment
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.
Measured: First 12 weeks of blinatumomab treatment
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.
Measured: From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
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.
Measured: From study Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
Complete Response Rate During the First 12 Weeks Using the Revised Response 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.
Measured: First 12 weeks of blinatumomab treatment
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.
Measured: First 12 weeks of blinatumomab treatment
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.
Measured: From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
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.
Measured: From Day 1 to 30 days after last dose of either blinatumomab or pembrolizumab administration; the overall median duration of treatment was 87 days.
Progression Free Survival by the Revised Response 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.
Measured: 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).
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.
Measured: 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
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.
Measured: 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 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.
Measured: 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).
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.
Measured: 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).
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.
Measured: Day 2 for 9 µg/day Css (all cohorts), days 10, 15, 22, 29, and 43 for 28 µg/day Css (Cohort Ia), day 10 for 28 µg/day Css (Cohorts IIa and IIIa), and days 19, 26, and 40 for 56 µg/day and 112 µg/day Css (Cohorts IIa and IIIa respectively).
Blinatumomab Clearance
Systemic clearance (CL) was calculated as CL=R0/Css,DN; where R0 is the infusion rate (μg/hr) and Css,DN is the dose normalized average Css.
Measured: Day 2 for 9 µg/day Css (all cohorts), days 10, 15, 22, 29, and 43 for 28 µg/day Css (Cohort Ia), day 10 for 28 µg/day Css (Cohorts IIa and IIIa), and days 19, 26, and 40 for 56 µg/day and 112 µg/day Css (Cohorts IIa and IIIa respectively).
Pembrolizumab Peak 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.
Measured: 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 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.
Measured: Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively).
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.
Measured: 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.
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Nov 2017
- Study start16 Mar 2018
- Primary completion6 Nov 2020
- Study completion14 Aug 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL)Studies of the same condition, open and under way.
- More trials run by AmgenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Enrolment
- 31 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amgen
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Responsible party
- Sponsor
- Investigators
- MD, Study director, Amgen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03340766
- Sponsor's protocol ID
- 20150290
- Other IDs
- 2016-002191-27, PN348, 2016
- Acronym
- HARBOUR
- Status last verified
- Jul 2024
- First submitted
- 23 Oct 2017
- Last updated
- 17 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
- Expanded access
- Available
Study at a glance
From the registry record, last updated by the sponsor on 17 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase 1b Open Label Study Investigating the Safety and Efficacy of Blinatumomab in Combination With Pembrolizumab in Adult Subjects With Relapsed or Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
- ClinicalTrials.gov ID
- NCT03340766
- Acronym / sponsor ID
- HARBOUR / 20150290
- Keywords
- DLBCL Relapsed post-autologous or allogeneic hematopoietic stem cell transplantation (HSCT), Antibodies, Bispecific in combination with PD-1/PD-L1 inhibitor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 31 participants (actual)
- Lead sponsor
- AmgenIndustry (pharma, biotech, devices)
- Collaborators
- Merck Sharp & Dohme LLC
- Study start
- 16 Mar 2018 (actual)
- Primary completion
- 6 Nov 2020 (actual)
- Study completion
- 14 Aug 2023 (actual)
- First posted
- 14 Nov 2017 (actual)
- Results
- Posted 25 Feb 2022
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab | Experimental | Drug: Blinatumomab, Drug: PembrolizumabParticipants received blinatumomab administered as a continuous intravenous infusion (CIVI) for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days then 28 µg/day for the remaining days of treatment. Starting on Day 15 participants also received 200 mg pembrolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) until disease progression or for up to 35 cycles. |
| Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab | Experimental | Drug: Blinatumomab, Drug: PembrolizumabParticipants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 56 µg/day for the remaining days of treatment. Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. |
| Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab | Experimental | Drug: Blinatumomab, Drug: PembrolizumabParticipants received blinatumomab administered as a continuous intravenous infusion for 8 weeks followed by a 28-day treatment-free interval. Participants with stable disease or better may have received a second 28-day consolidation cycle. The starting dose of each cycle was 9 µg/day for the first 7 days, 28 µg/day for 7 days then 112 µg/day for the remaining days of treatment. Starting on Day 19 participants also received 200 mg pembrolizumab administered by IV infusion Q3W until disease progression or for up to 35 cycles. |
| Expansion Cohort | Experimental | Drug: Blinatumomab, Drug: PembrolizumabThis cohort will test the maximum tolerated dose of blinatumomab in combination with pembrolizumab identified in Part 1 of the study. |
Who may qualify
- Ages
- 18 to 100 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (9 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| BlinatumomabAlso: Blincyto, AMG 103, Formerly known as MT103 or bscCD19xCD3Up 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. | Drug | Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab, Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab, Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab, Expansion Cohort |
| PembrolizumabAlso: Keytruda, MK-3475One 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. | Drug | Cohort IIIa: Blinatumomab 9/28/112 µg/day + Pembrolizumab, Cohort IIa: Blinatumomab 9/28/56 µg/day + Pembrolizumab, Cohort Ia: Blinatumomab 9/28 µg/day + Pembrolizumab, Expansion Cohort |
Primary outcome
Number of Participants With Dose Limiting Toxicities (DLTs)
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)
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.
18 secondary outcomes
Objective Response Rate During the First 12 Weeks Using Revised Response Cheson Criteria
Time frame: First 12 weeks of blinatumomab treatment
Cohort IIIa Only: Objective Response Rate During the First 12 Weeks Using the Lugano Classification
Time frame: First 12 weeks of blinatumomab treatment
Objective Response Rate During the Treatment Period Using Revised Response Cheson Criteria
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.
Cohort IIIa Only: Objective Response Rate During the Treatment Period Using the Lugano Classification
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.
Complete Response Rate During the First 12 Weeks Using the Revised Response Cheson Criteria
Time frame: First 12 weeks of blinatumomab treatment
Cohort IIIa Only: Complete Response Rate During the First 12 Weeks Using the Lugano Classification
Time frame: First 12 weeks of blinatumomab treatment
Complete Response Rate During the Treatment Period Using the Revised Response Cheson Criteria
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.
Cohort IIIa Only: Complete Response Rate During the Treatment Period Using the Lugano Classification
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.
Progression Free Survival by the Revised Response Cheson Criteria
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).
Cohort IIIa Only: Progression Free Survival Using the Lugano Classification
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).
Overall Survival
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).
Duration of Response for Participants Who Achieved CR/PR Using the Revised Response Cheson Criteria
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).
Cohort IIIa Only: Duration of Response for Participants Who Achieved CMR/PMR Using the Lugano Classification
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).
Blinatumomab Steady State Concentration (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).
Blinatumomab Clearance
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).
Pembrolizumab Peak Serum Concentration
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).
Pembrolizumab Minimum Serum Concentration
Time frame: Pre-dose on pembrolizumab cycles 2, 4, 6, 8, and 12 (Study days 36, 78, 120, 162, and 246, respectively).
Number of Participants With Treatment-emergent Adverse Events (TEAEs)
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.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- AmgenTrials clinical trials websiteLink provided by the sponsor.
- Individual participant dataSharing planned: Yes. De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
MD study director
Amgen
22 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Blinatumomab and Pembrolizumab in people with Relapsed or Refractory Diffuse Large B Cell Lymphoma (DLBCL), run by Amgen at 22 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 9 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 17 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 22 sites in Australia, Spain, United States, France, Germany and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Dose Limiting Toxicities (DLTs) (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)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Oct 2024.