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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT03003520
Other study ID # MEDI4736-DLBCL-001
Secondary ID 2015-005173-20
Status Completed
Phase Phase 2
First received
Last updated
Start date February 28, 2017
Est. completion date April 24, 2022

Study information

Verified date April 2023
Source Celgene
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial Summary

This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical activity, and predictive biomarkers of durvalumab in combination with R-CHOP or R2-CHOP, followed by durvalumab consolidation therapy in previously untreated subjects with high-risk diffuse large B-cell lymphoma (DLBCL). Induction treatment with R-CHOP (± lenalidomide) will last for a total of up to 6 to 8 treatment cycles (21 day cycles), and the total time on study treatment, including durvalumab consolidation, will last up to 12 months. On 05-Sep-2017, the US FDA has issued a Partial Clinical Hold on this study resulting in the discontinuation of enrollment into Arm B (Durvalumab + Lenalidomide + R-CHOP). After the US FDA Partial Clinical Hold, new eligible participants have been enrolled in Arm A (Durvalumab + R-CHOP).


Description:

This research study is conducted in participants with previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Patients with high-risk DLBCL typically have insufficient therapeutic outcomes. Therefore, the addition of novel agents to the currently used induction therapy (R-CHOP) is a rational approach to improve therapeutic outcomes in this disease setting. Based on pre-clinical and clinical observations, it is hypothesized that durvalumab will have activity in DLBCL because the PD 1/PD L1 pathway is involved in the pathophysiology of DLBCL. In particular, the addition of durvalumab may augment the anti-tumor activity of R-CHOP against high-risk DLBCL sub-types. The safety of durvalumab has already been explored. However, as there is limited clinical experience with durvalumab in DLBCL, the study is divided into two stages: - A Safety Run-in Stage to evaluate the safety of the treatment combinations until at least 10 subjects are included in each of the two treatment arms - An Expansion Stage to analyze the clinical activity of the treatment combinations Results posted following Primary Outcome Completion date are based on a database cut-off of August 2, 2018.


Recruitment information / eligibility

Status Completed
Enrollment 46
Est. completion date April 24, 2022
Est. primary completion date April 24, 2022
Accepts healthy volunteers No
Gender All
Age group 18 Years and older
Eligibility Inclusion Criteria: 1. CD20+Diffuse Large B-Cell Lymphoma. 2. Ann Arbor stage 3 or 4 or stage 2 with bulky disease 3. High or high-intermediate disease risk. 4. No prior anti-lymphoma treatment. 5. Subject is willing and able to undergo biopsy. 6. Investigator considers R-CHOP immunochemotherapy appropriate. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 8. Adequate hematology laboratory results (absolute neutrophil count = 1.5 * 10^9/L, platelet count = 75 * 10^9/L, hemoglobin = 10.0 g/dL). 9. Adequate biochemistry laboratory results (aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) = 3.0 * upper limit of normal; bilirubin = 2.0 mg/dL; creatinine clearance of = 40 mL/min). 10. Bi-dimensionally measurable disease (> 2.0 cm). 11. Subject is using effective contraception. Exclusion Criteria: 1. Diagnosis of lymphoma other than Diffuse Large B-Cell Lymphoma. 2. Composite lymphoma or transformed lymphoma. 3. Primary or secondary Central Nervous System involvement by lymphoma. 4. Seropositive or active viral infection with hepatitis B virus, human immunodeficiency virus or hepatitis C virus. 5. History of other malignancies, unless disease-free for = 5 years. 6. Left ventricular ejection fraction < 50%. 7. Peripheral neuropathy = Grade 2. 8. Prior use of lenalidomide, or monoclonal antibodies against CTLA-4, PD-1, or PD-L1. 9. High risk of developing thromboembolic events, who are unwilling to take venous thromboembolism prophylaxis. 10. Active or prior documented autoimmune or inflammatory disorders within the past 3 years. 11. Current or prior use of immunosuppressive medication within 28 days before start of treatment.

Study Design


Intervention

Drug:
Durvalumab
Durvalumab was supplied in single use vials as a liquid solution containing 500 mg (nominal) of durvalumab at a concentration of 50 mg/mL to be infused by intravenous (IV) injection. Day 1 of each treatment cycle (Induction Period and Consolidation Period) started with the administration of IV durvalumab followed by a 2-hour observation period post infusion.
Rituximab
Subsequent to durvalumab infusion, rituximab was administered by IV. Rituximab administration could be split over 2 consecutive days according to local clinical practice. Rapid infusion of rituximab was not allowed in this clinical study.
Doxorubicin
A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab.
Vincristine
A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab.
Cyclophosphamide
A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab.
Prednisone
Prednisone was administered as an IV infusion or by mouth (PO) on Day 1, followed by PO administration on Days 2-5 of each cycle. Prednisone could be given prior to other drugs of the CHOP therapy. It was administered after lenalidomide dosing in the R2-CHOP treatment arm.
Lenalidomide
Lenalidomide was administered orally in capsule form on Days 1-14 of the DUR+R2-CHOP treatment arm only.

Locations

Country Name City State
Austria Innsbruck Medical University Department of Internal Medicine Innsbruck
Austria Landeskrankenhaus Salzburg Salzburg
Austria Local Institution - 101 Vienna
Austria Medical University of Vienna Internalmedicine 1, Hematology Vienna
Austria Hanusch Krankenhaus Wien
Denmark Aarhus Sygehus Arhus C
Denmark Rigshospitalet, Kobenhavns Universitet - Centre for Clinical Intervention Research - The Copenhagen Copenhagen
Denmark Odense Universitetshospital Odense C
Estonia (North Estonia Medical Centre) - Onkoloogia-ja Hematoloogiakliinik Tallinn
Estonia Tartu University Hospital Tartu
United Kingdom University Hospital Birmingham Birmingham
United Kingdom Royal Marsden Hospital London
United Kingdom Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine Oxford
United States Roswell Park Cancer Institute Buffalo New York
United States Mid Ohio Oncology Hematology Inc Columbus Ohio
United States Parkview Research Center Fort Wayne Indiana
United States Banner MD Anderson Cancer Center Gilbert Arizona
United States Mayo Clinic Rochester Minnesota
United States University of Rochester Medical Center Rochester New York
United States Swedish Cancer Institute Seattle Washington

Sponsors (1)

Lead Sponsor Collaborator
Celgene

Countries where clinical trial is conducted

United States,  Austria,  Denmark,  Estonia,  United Kingdom, 

Outcome

Type Measure Description Time frame Safety issue
Primary Percentage of Participants Who Achieved a Complete Response (CR) at the End of Induction Therapy The primary efficacy analysis evaluated the complete response rate (CRR) at the end of the induction therapy in the efficacy evaluable population in a comparative manner against historical control. The response to treatment was assessed according to the 2014 International Working Group (IWG) Response Criteria for Non-Hodgkin's Lymphoma (NHL) (Cheson, 2014). CR was defined as a complete metabolic response and radiographic evidence showing target nodes/nodal masses regressed to = 1.5 cm in longest diameter, no new lesions, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. Clopper-Pearson two-sided 95% confidence interval is reported. Null hypothesis for the primary endpoint was rejected if the lower limit of the confidence interval for the complete response rate at the completion of the induction therapy in the efficacy evaluable population is above 55%. From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period).
Secondary Percentage of Participants Who Responded During Induction and Continued Into Consolidation Therapy (Database Cutoff Date: 02-Aug-2018) The percentage of participants who achieved a partial response (PR) or complete response (CR) at the end of Induction and continued into consolidation period in the efficacy evaluable population in a comparative manner against historical control. The response to treatment was assessed according to the 2014 International Working Group (IWG) Response Criteria for Non-Hodgkin's Lymphoma (NHL) (Cheson, 2014). CR was defined in outcome #1. PR was defined as a partial metabolic response and radiographic evidence showing = 50% decrease in sum of perpendicular diameters (SPD) of up to 6 target measurable nodes and extranodal sites, no new lesions, spleen must have regressed > 50% in length beyond normal, and residual bone marrow involvement improved from baseline. Clopper-Pearson two-sided 95% confidence interval is reported. Null hypothesis was rejected if the lower limit of the confidence interval for the rate of subjects who continue consolidation therapy out of all subjects. From first dose of study drug to completion of at least one cycle in the Consolidation Period (Day 1 up to Week 52)
Secondary Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) CD8 T-Cell Density Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period).
Secondary Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Total Percentage Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period).
Secondary Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Percentage of Tumor Cells Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period).
Secondary Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for the Interferon Gamma Score (IFNG-Score) From Ribonucleic Acid (RNA)-Sequencing Data Data in the analysis include all participants who received durvalumab, irrespective of the study arm in which they enrolled, because the selected biomarkers have been associated with response in other anti-PD1 or anti-PDL1 studies, such as durvalumab. IHC analysis was performed on the baseline tumor biopsy to quantify CD8 T-cell density. Participants with 'high' values, i.e. above the threshold defined as the median value of 774 cells/mm^2 found in commercial DLBCL samples using matched analytical methods, were predicted to be responders to treatment with durvalumab. The definition of a complete response was that used in the primary outcome. Biomarker biopsies: Days -28 to Day -1. Clinical response: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period).
Secondary Participants With Treatment Emergent Adverse Events (TEAE) An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen during a study. A serious AE is any AE occurring at any dose that: • Results in death; • Is life-threatening; • Requires or prolongs existing inpatient hospitalization; • Results in persistent or significant disability/incapacity; • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to study drug and graded the severity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, Version 4.03): - Grade 1 = Mild (no limitation in activity or intervention); - Grade 2 = Moderate (some limitation in activity; no/minimal medical intervention required); - Grade 3 = Severe (marked limitation in activity; medical intervention required, hospitalization possible); - Grade 4 = Life-threatening; - Grade 5 = Death. Relation to IP is determined by the investigator. From the date of the first dose of study drug to within 90 days after the last dose of durvalumab or 28 days after the last dose of any investigational product (IP) whichever is greater. (Up to approximately 72 weeks)
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