A Phase 2 interventional study of Blinatumomab and Investigator's Choice Chemotherapy in High-risk Diffuse Large B-Cell Lymphoma, sponsored by Amgen. Completed at 24 sites in 6 countries. Open to participants aged 18 Years to 100 Years. Per ClinicalTrials.gov, last updated 2020-09-14.
Sponsored by Amgen · Phase 2, Interventional, and Treatment
A phase 2, multicenter, open-label, single arm clinical trial in adults with newly diagnosed aggressive high-risk DLBCL.
The safety profile of blinatumomab after frontline rituximab (R)-chemotherapy, consisting of either R-CHOP (14 or 21) (rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone) or R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin), or R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide), will be determined. The study will consist of a screening period of up to 14 days, a standard of care (SOC) R-chemotherapy run-in period of approximately 21 weeks, a 12 to 16 week blinatumomab treatment period, a 30-day safety follow-up visit, and a long-term follow-up period that begins after the safety follow-up visit is completed until 1 year from the first dose blinatumomab.
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Subject must have untreated histologically proven high-risk DLBCL defined by atleast one of the following:
Adequate organ and bone marrow function determined within 14 days prior to enrollment defined as:
Exclusion Criteria:
History of other malignancy within the past 3 years with the following exceptions:
Blinatumomab was administered as a continuous intravenous (IV) infusion. Cycle 1 was 12 weeks (84 days) in duration with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, 112 µg/day for 6 weeks, followed by a 4-week treatment free time. An optional 4-week Cycle 2 of blinatumomab was available for participants whose disease did not progress, with step dosing of 9 µg/day for 7 days, 28 µg/day for 7 days, and 112 µg/day for 14 days. There was a safety follow-up for 30 days. And a long-term follow-up of up to 8 months for a maximum of 1 year from first dose of blinatumomab or until participant death.
Drug: Blinatumomab · Drug: Investigator's Choice Chemotherapy · Drug: Dexamethasone
Blinatumomab monotherapy was supplied in single-use sterile glass injection vials and administered as an IV infusion.
Also known as: AMG103, BlinCyto
During the run-in period participants received 6 cycles of standard of care rituximab-chemotherapy dosed per investigator's institution standard as follows: * R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,prednisone) * R-DA-EPOCH (rituximab and dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) or * R-CHOEP (rituximab and cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide).
Dexamethasone 20 mg IV: within 1 hour prior to start of treatment in each treatment cycle, and within 1 hour prior to dose-step (increase).
Also known as: corticosteroid
Participants With Treatment-Emergent (Blinatumomab) Adverse Events
Overall incidence and severity of treatment-emergent adverse events occurring during the blinatumomab investigative product (IP) treatment period graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
Time frame: From the start of first infusion of IP to 30 days after the end of last infusion of IP; median (min, max) treatment duration was 56 (16, 84) days
Participants With Treatment-Emergent Adverse Events Related to Blinatumomab Treatment
Overall incidence and severity of treatment-emergent adverse events deemed by investigators to be related to blinatumomab treatment. Severity was graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
Time frame: From the start of first infusion of IP to 30 days after the end of last infusion of IP; median (min, max) treatment duration was 56 (16, 84) days
Overall Objective Response Rate (ORR) Expressed as the Percentage of Participants Achieving Complete Metabolic Response (CMR) and Partial Metabolic Response (PMR) Using Lugano 2014 Criteria During Cycle 1 and During Treatment Period
Tumor response assessment was performed by a central reader according to modified Lugano classification using PET/CT scan. Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete metabolic response (CMR) or partial metabolic response (PMR). CMR: a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PMR: a score 4 (uptake moderately greater than \[\>\] liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline.
Time frame: Cycle 1: Day 78 (3 weeks following end of Cycle 1 IP treatment) Treatment Period: Either the Cycle 1 timeframe or approximately Day 128 (3 weeks after Cycle 2 ended) for participants who completed Cycle 2
Kaplan-Meier Estimates for Duration of Response
Duration of response was calculated only for responders during cycle 1. For participants who had CR or PR on the PET/CT scan at the end of the run-in period, response was measured from the start of blinatumomab treatment. For participants who had stable disease at the end of the run-in period, duration was calculated from documentation of the first assessment of either PR or CR on blinatumomab. Progression was defined as the first diagnosis of progressive metabolic response/progressive disease based on PET/CT scan per central or investigator review during the treatment period or relapse based on clinical tumor assessment during the long-term follow up period. Response duration was calculated until the start of new anti-tumor treatment (excluding any stem cell transplantation), PD, or death, whichever was the earliest event. Participants who did not have new anti-tumor treatment (excluding stem cell transplantation), PD, or death were censored at the last tumor assessment date.
Time frame: The median (range) follow-up time was 11.5 (8.2, 14.5) months
Complete Response Rate Expressed as the Percentage of Participants Achieving Complete Metabolic Response (CMR) Using Lugano 2014 Criteria During Cycle 1 and During Treatment Period
Tumor response assessment was performed by a central reader according to modified Lugano classification using PET/CT scan. CMR: a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology.
Time frame: Cycle 1: Day 78 (3 weeks following end of Cycle 1 IP treatment) Treatment Period: Either the Cycle 1 timeframe or approximately Day 128 (3 weeks after Cycle 2 ended) for participants who completed Cycle 2
Kaplan-Meier Estimates for Overall Survival (OS) From First Dose of Blinatumomab
OS was calculated as the time from the date of first IP infusion until death due to any cause. Participants who are alive at the date that triggers the analysis were censored at the date last known to be alive. Months were calculated as days from the first dose date of blinatumomab to death/censor date, divided by 30.5.
Time frame: The median (range) follow-up time was 12.0 (10.7, 14.5) months.
Kaplan-Meier Estimates for Progression Free Survival (PFS) From First Dose of Blinatumomab
PFS was calculated as the time from the date of first IP infusion until the date of diagnosis of progression of DLBCL or the date of death, whichever was the earliest. The diagnosis of progression of DLBCL was defined as the first diagnosis of progressive metabolic response/progressive disease based on PET/CT scan per central or investigator review during the treatment period or relapse based on clinical tumor assessment during the long-term follow up period. Participants who were alive and did not have progression were censored at the last evaluable non-missing tumor assessment date prior to the analysis trigger date.
Time frame: The median (range) follow-up time was 12.0 (8.2, 14.5)
Percentage of Participants Who Had Hematopoietic Stem Cell Transplantation (HSCT)
Percentage of participants who had HSCT during the Long Term Follow-Up Period.
Time frame: Day 1 up to 14.5 months
Pharmacokinetics (PK) Results for Blinatumomab: Steady-State Concentrations at Week 1, Week 2 and Week 3 for Cycle 1
The steady-state serum concentration (Css), summarized as the observed concentrations collected after at least 10 hours after the start of continuous IV infusion. PK blood samples were analyzed in a central lab.
Time frame: Day 2 at least 24 hours after blinatumomab was started and on Day 9 and Day 16 at least 24 hours after blinatumomab dose was increased in the cycle
Pharmacokinetics (PK) Results for Blinatumomab: Clearance for Cycle 1
PK blood samples were analyzed in a central lab.
Time frame: Day 2 at least 24 hours after blinatumomab was started and on Day 9 and Day 16 at least 24 hours after blinatumomab dose was increased in the cycle
This study was conducted at 12 centers in the European Union (France, Germany, Spain, and the United Kingdom), the United States, and Canada. Of the 54 subjects screened, 47 subjects were enrolled.
| Milestone | Blinatumomab |
|---|---|
| Started | 47 |
| Completed | 30 |
| Not completed | 17 |
| Withdrew: Protocol-specified criteria | 11 |
| Withdrew: Death | 1 |
| Withdrew: Withdrawal by subject | 5 |
| Milestone | Blinatumomab |
|---|---|
| Started | 30 |
| Completed | 28 |
| Not completed | 2 |
| Withdrew: Protocol-specified criteria | 2 |
| Milestone | Blinatumomab |
|---|---|
| Started | 28 |
| Started cycle 1 | 28 |
| Started cycle 2 | 11 |
| Completed | 25 |
| Not completed | 3 |
| Withdrew: Disease progression | 1 |
| Withdrew: Withdrawal by subject | 1 |
| Withdrew: Adverse event | 1 |
| Milestone | Blinatumomab |
|---|---|
| Started | 28 |
| Completed | 26 |
| Not completed | 2 |
| Withdrew: Death | 2 |
Overall incidence and severity of treatment-emergent adverse events occurring during the blinatumomab investigative product (IP) treatment period graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
| Participants | Blinatumomab |
|---|---|
| TEAE | 28 |
| TEAE severity grade >=3 | 11 |
| TEAE severity grade >=4 | 5 |
| Serious TEAE | 7 |
| TEAE leading to interruption of IP | 3 |
| Serious TEAE leading to interruption of IP | 2 |
| TEAE leading to discontinuation of IP | 2 |
| Serious TEAE leading to discontinuation of IP | 1 |
| Fatal TEAEs | 0 |
Overall incidence and severity of treatment-emergent adverse events deemed by investigators to be related to blinatumomab treatment. Severity was graded by investigators according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 and based on the scale: Grade 1 = Mild - transient or mild discomfort; Grade 2 = Moderate - mild to moderate limitation in activity, assistance may be needed; minimal medical intervention required; Grade 3 = Severe - marked limitation in activity, assistance usually required; medical intervention required, hospitalization is possible; Grade 4 = Life threatening - extreme limitation in activity, assistance required; medical intervention, hospitalization or hospice care probable; Grade 5 = death.
| Participants | Blinatumomab |
|---|---|
| Treatment-related TEAE | 23 |
| Related TEAE severity grade >=3 | 9 |
| Related TEAE severity grade >=4 | 3 |
| Related Serious TEAE | 5 |
| Related TEAE leading to interruption of IP | 3 |
| Related Serious TEAE leading to interruption of IP | 2 |
| Related TEAE leading to discontinuation of IP | 2 |
| Related Serious TEAE leading to discon of IP | 1 |
| Related and Fatal TEAEs | 0 |
Tumor response assessment was performed by a central reader according to modified Lugano classification using PET/CT scan. Overall objective response rate (ORR) is the percentage of participants with a best overall response of complete metabolic response (CMR) or partial metabolic response (PMR). CMR: a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology. PMR: a score 4 (uptake moderately greater than \[\>\] liver) or 5 (uptake markedly \>liver and/or new lesions) with reduced uptake compared with baseline and residual mass(es) of any size on PET 5-PS for lymph nodes and extralymphatic sites; no new lesions; and reduced residual uptake in bone marrow compared with baseline.
| percentage of participants | Blinatumomab |
|---|---|
| Cycle 1 | 89.3 (71.8 to 97.7) |
| Entire Treatment Period | 92.9 (76.5 to 99.1) |
Duration of response was calculated only for responders during cycle 1. For participants who had CR or PR on the PET/CT scan at the end of the run-in period, response was measured from the start of blinatumomab treatment. For participants who had stable disease at the end of the run-in period, duration was calculated from documentation of the first assessment of either PR or CR on blinatumomab. Progression was defined as the first diagnosis of progressive metabolic response/progressive disease based on PET/CT scan per central or investigator review during the treatment period or relapse based on clinical tumor assessment during the long-term follow up period. Response duration was calculated until the start of new anti-tumor treatment (excluding any stem cell transplantation), PD, or death, whichever was the earliest event. Participants who did not have new anti-tumor treatment (excluding stem cell transplantation), PD, or death were censored at the last tumor assessment date.
| months | Blinatumomab |
|---|---|
| Kaplan-Meier Estimates for Duration of Response | NA (NA to NA) |
Tumor response assessment was performed by a central reader according to modified Lugano classification using PET/CT scan. CMR: a score of 1 (no uptake above background), 2 (uptake \</=mediastinum), or 3 (uptake \<mediastinum but \</=liver) with/without a residual mass on PET 5-PS, for lymph nodes and extralymphatic sites; no new lesions; no evidence of FDG-avid disease in bone marrow; and normal/IHC-negative bone marrow morphology.
| percentage of participants | Blinatumomab |
|---|---|
| Cycle 1 | 85.7 (67.3 to 96.0) |
| Entire Treatment Period | 89.3 (71.8 to 97.7) |
OS was calculated as the time from the date of first IP infusion until death due to any cause. Participants who are alive at the date that triggers the analysis were censored at the date last known to be alive. Months were calculated as days from the first dose date of blinatumomab to death/censor date, divided by 30.5.
| months | Blinatumomab |
|---|---|
| Kaplan-Meier Estimates for Overall Survival (OS) From First Dose of Blinatumomab | NA (NA to NA) |
PFS was calculated as the time from the date of first IP infusion until the date of diagnosis of progression of DLBCL or the date of death, whichever was the earliest. The diagnosis of progression of DLBCL was defined as the first diagnosis of progressive metabolic response/progressive disease based on PET/CT scan per central or investigator review during the treatment period or relapse based on clinical tumor assessment during the long-term follow up period. Participants who were alive and did not have progression were censored at the last evaluable non-missing tumor assessment date prior to the analysis trigger date.
| months | Blinatumomab |
|---|---|
| Kaplan-Meier Estimates for Progression Free Survival (PFS) From First Dose of Blinatumomab | NA (NA to NA) |
Percentage of participants who had HSCT during the Long Term Follow-Up Period.
| percentage of participants | Blinatumomab |
|---|---|
| Percentage of Participants Who Had Hematopoietic Stem Cell Transplantation (HSCT) | 3.6 (0.1 to 18.3) |
The steady-state serum concentration (Css), summarized as the observed concentrations collected after at least 10 hours after the start of continuous IV infusion. PK blood samples were analyzed in a central lab.
| pg/mL | Blinatumomab |
|---|---|
| Cycle 1 Week 1: 9 mcg/day | 288 ± 289 |
| Cycle 1 Week 2: 28 mcg/day | 795 ± 280 |
| Cycle 1 Week 3: 112 mcg/day | 3160 ± 782 |
PK blood samples were analyzed in a central lab.
| L/Hour | Blinatumomab |
|---|---|
| Pharmacokinetics (PK) Results for Blinatumomab: Clearance for Cycle 1 | 1.61 ± 0.496 |
Collected over Mortality is reported for all enrolled participants from enrollment in the Run-in Period to the end of long-term follow-up. Adverse events are reported from the first dose of blinatumomab through 30 days after last dose; median duration of treatment was 56 days. In addition, serious adverse events related to blinatumomab collected during the long-term follow-up period are reported; median time on follow-up was 12 months.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Blinatumomab | 3/47 (6.4%) | 7/28 (25%) | 26/28 (92.9%) |
| Event | Blinatumomab |
|---|---|
| PyrexiaGeneral disorders | 2/28 |
| NeutropeniaBlood and lymphatic system disorders | 1/28 |
| BacteraemiaInfections and infestations | 1/28 |
| PneumoniaInfections and infestations | 1/28 |
| SepsisInfections and infestations | 1/28 |
| AphasiaNervous system disorders | 1/28 |
| NeurotoxicityNervous system disorders | 1/28 |
| Event | Blinatumomab |
|---|---|
| PyrexiaGeneral disorders | 10/28 |
| TremorNervous system disorders | 10/28 |
| FlushingVascular disorders | 9/28 |
| FatigueGeneral disorders | 8/28 |
| CoughRespiratory, thoracic and mediastinal disorders | 8/28 |
| HeadacheNervous system disorders | 7/28 |
| NauseaGastrointestinal disorders | 5/28 |
| Cytokine release syndromeImmune system disorders | 5/28 |
| ArthralgiaMusculoskeletal and connective tissue disorders | 5/28 |
| Back painMusculoskeletal and connective tissue disorders | 5/28 |
The full analysis set included all participants who received at least 1 dose of blinatumomab.
| Age, Continuous(years) | Blinatumomab |
|---|---|
| Mean | 60.2 ± 11.1 |
| Age, Customized(Participants) | Blinatumomab |
|---|---|
| < 65 years | 18 |
| >=65 years | 10 |
| <75 years | 25 |
| >=75 years | 3 |
| Sex: Female, Male(Participants) | Blinatumomab |
|---|---|
| Female | 18 |
| Male | 10 |
| Ethnicity (NIH/OMB)(Participants) | Blinatumomab |
|---|---|
| Hispanic or Latino | 7 |
| Not Hispanic or Latino | 21 |
| Unknown or Not Reported | 0 |
| Race/Ethnicity, Customized(Participants) | Blinatumomab |
|---|---|
| Asian | 1 |
| Black and African American | 2 |
| Native Hawaiian or Other Pacific Islander | 0 |
| White | 21 |
| Other | 4 |
| Disease Stage at Time of Diagnosis(Participants) | Blinatumomab |
|---|---|
| Stage I | 0 |
| Stage IE | 1 |
| Stage II | 0 |
| Stage III | 5 |
| Stage IV | 22 |
| International Prognostic Index Score at Diagnosis(Participants) | Blinatumomab |
|---|---|
| Score 2 | 2 |
| Score 3 | 17 |
| Score 4 | 7 |
| Score 5 | 2 |
Documents are hosted by the registry — open the source record to download them.
Plan to share: Yes — De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
Supporting information: Study protocol, Sap, Icf, Csr
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