Safety and Efficacy of Blinatumomab in Adults With Newly Diagnosed High-risk Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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A phase 2, multicenter, open-label, single arm clinical trial in adults with newly diagnosed aggressive high-risk DLBCL.

Detailed Description
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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.

Official Title
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20150288 A Phase 2 Open-label Study Investigating the Safety and Efficacy of Blinatumomab After Frontline R-Chemotherapy in Adult Subjects With Newly Diagnosed High-risk Diffuse Large B-Cell Lymphoma (DLBCL)

Conditions
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High-risk Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: Blinatumomab
* Drug: Investigator's Choice Chemotherapy
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subject has provided informed consent prior to initiation of any study-specific activities/procedures Age ≥ 18 at time of informed consent Subject must have untreated histologically proven high-risk DLBCL defined by atleast one of the following: International Prognostic Index (IPI) for Diffuse Large B-cell Lymphoma 3 to 5 (representing high intermedidate - high ratings), Double-hit or higher or double protein expression Eastern Cooperative Oncology Group performance status ≤ 2. Subject meets the criteria per investigator's institution to receive standard of care (SOC) rituximab-chemotherapy (ie, R-CHOP [14 or 21] or R-DA-EPOCH or R-CHOEP) of 6 cycles. Subjects may be enrolled on study prior to cycle 1 or cycle 2 of SOC R-chemotherapy Adequate organ and bone marrow function determined within 14 days prior to enrollment defined as: Hematological: Absolute neutrophil count ≥1*10^9/L; Platelet count ≥75*10^9/L;Hemoglobin ≥8g/dL Renal: Creatinine clearance ≥50mL/min; Hepatic: Aspartate aminotransferase/Alanine aminotransferase <3*upper limit of normal (ULN); Total bilirubin <2*ULN (unless Gilbert's Disease or if liver involvement with lymphoma) Subject must have completed 6 cycles of SOC R-chemotherapy and achieved CR, PR or stable disease by PET/CT performed 3 weeks (± 3 days) after cycle 6 of SOC R-chemotherapy. Subjects with progressive disease (PD) are not eligible for treatment with blinatumomab and will end the study. Exclusion Criteria: Clinically relevant central nervous system (CNS) pathology requiring treatment such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, and psychosis Evidence of CNS involvement with DLBCL at disease evaluation obtained prior to starting blinatumomab Current autoimmune disease or history of autoimmune disease with potential of CNS involvement Subject has active infection requiring systemic therapy Prior anti-CD19 therapies Known infection with HIV or chronic infection with hepatitis B virus or hepatitis C virus History of other malignancy within the past 3 years with the following exceptions: Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician Adequately treated non-melanoma skin cancer or lentigo malignancy without evidence of disease Adequately treated cervical carcinoma in situ without evidence of disease Adequately treated breast ductal carcinoma in situ without evidence of disease Prostatic intraepithelial neoplasia without evidence of prostate cancer Adequately treated urothelial papillary non-invasive carcinoma or carcinoma in situ Subject has known hypersensitivity to immunoglobulins or any of the products or components to be administered during dosing. Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the subject's and investigator's knowledge. History/evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion. Females who are pregnant or breastfeeding or planning to become pregnant or breastfeed while receiving blinatumomab and for an additional 48 hours after the last treatment dose of blinatumomab. Currently receiving treatment in another investigational device or drug study or less than 30 days since ending treatment on another investigational device or drug study. Other investigational procedures while participating in this study are excluded.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Blinatumomab<br>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<br>* Blinatumomab monotherapy was supplied in single-use sterile glass injection vials and administered as an IV infusion.<br>* Other names: BlinCyto;Drug: Investigator's Choice Chemotherapy<br>* 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).<br>Drug: Dexamethasone<br>* 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).<br>* Other names: corticosteroid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 |