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

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)

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

Study Overview

• Status: Completed
• Conditions: High-risk Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Blinatumomab; Drug: Investigator's Choice Chemotherapy; Drug: Dexamethasone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Research Site
  • Ontario
    • Sault Ste. Marie, Ontario, Canada, P6B 0A8
      • Research Site
    • Toronto, Ontario, Canada, M5G 2M9
      • Research Site
• France
  • Créteil Cedex, France, 94010
    • Research Site
  • Paris Cedex 10, France, 75475
    • Research Site
• Germany
  • Dresden, Germany, 01307
    • Research Site
  • Ulm, Germany, 89081
    • Research Site
• Spain
  • Madrid, Spain, 28007
    • Research Site
  • Andalucía
    • Sevilla, Andalucía, Spain, 41013
      • Research Site
  • Castilla León
    • Salamanca, Castilla León, Spain, 37007
      • Research Site
  • Cataluña
    • Barcelona, Cataluña, Spain, 08003
      • Research Site
    • L Hospitalet De Llobregat, Cataluña, Spain, 08907
      • Research Site
  • Comunidad Valenciana
    • Valencia, Comunidad Valenciana, Spain, 46026
      • Research Site
  • Galicia
    • A coruña, Galicia, Spain, 15006
      • Research Site
• United Kingdom
  • Bristol, United Kingdom, BS2 8ED
    • Research Site
  • Sheffield, United Kingdom, S10 2JF
    • Research Site
• United States
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Research Site
    • Maywood, Illinois, United States, 60153
      • Research Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Research Site
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • Research Site
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Research Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Research Site
  • Oregon
    • Portland, Oregon, United States, 97213
      • Research Site
  • South Carolina
    • Greenville, South Carolina, United States, 29607
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 100 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Blinatumomab; 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; Blinatumomab monotherapy was supplied in single-use sterile glass injection vials and administered as an IV infusion.; Other Names: AMG103; BlinCyto; Drug: Investigator's Choice Chemotherapy; 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).; Drug: Dexamethasone; 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).; Other Names: corticosteroid

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Amgen

Publications and helpful links

General Publications

• Katz DA, Morris JD, Chu MP, David KA, Thieblemont C, Morley NJ, Khan SS, Viardot A, Martin Garcia-Sancho A, Rodriguez-Garcia G, Bastos-Oreiro M, Lee ST, Kormany W, Chen Y, Wong HL, Anderson AA, Katlinskaya Y, Avilion AA, Dai T, Gonzalez-Barca E. Open-label, phase 2 study of blinatumomab after frontline R-chemotherapy in adults with newly diagnosed, high-risk DLBCL. Leuk Lymphoma. 2022 Sep;63(9):2063-2073. doi: 10.1080/10428194.2022.2064981. Epub 2022 May 3.

Helpful Links

• AmgenTrials clinical trials website

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2017
• Primary Completion (Actual): April 4, 2019
• Study Completion (Actual): October 28, 2019

Study Registration Dates

• First Submitted: December 12, 2016
• First Submitted That Met QC Criteria: January 13, 2017
• First Posted (Estimate): January 18, 2017

Study Record Updates

• Last Update Posted (Actual): September 14, 2020
• Last Update Submitted That Met QC Criteria: August 26, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone; Blinatumomab
• Other Study ID Numbers: 20150288; 2016-002190-35 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: De-identified individual patient data for variables necessary to address the specific research question in an approved data sharing request
• IPD Sharing Time Frame: Data sharing requests relating to this study will be considered beginning 18 months after the study has ended and either 1) the product and indication (or other new use) have been granted marketing authorization in both the US and Europe or 2) clinical development for the product and/or indication discontinues and the data will not be submitted to regulatory authorities. There is no end date for eligibility to submit a data sharing request for this study.
• IPD Sharing Access Criteria: Qualified researchers may submit a request containing the research objectives, the Amgen product(s) and Amgen study/studies in scope, endpoints/outcomes of interest, statistical analysis plan, data requirements, publication plan, and qualifications of the researcher(s). In general, Amgen does not grant external requests for individual patient data for the purpose of re-evaluating safety and efficacy issues already addressed in the product labelling. Requests are reviewed by a committee of internal advisors, and if not approved, may be further arbitrated by a Data Sharing Independent Review Panel. Upon approval, information necessary to address the research question will be provided under the terms of a data sharing agreement. This may include anonymized individual patient data and/or available supporting documents, containing fragments of analysis code where provided in analysis specifications. Further details are available at the link below.
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No