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A Study of Durvalumab in Combination With R-CHOP or Lenalidomide Plus R-CHOP in Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma

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ClinicalTrials.gov Identifier: NCT03003520
Recruitment Status : Active, not recruiting
First Posted : December 28, 2016
Last Update Posted : April 6, 2018
Sponsor:
Information provided by (Responsible Party):
Celgene

Brief Summary:

This Phase 2, two-arm, open-label study is designed to evaluate the safety, clinical activity, predictive biomarkers and pharmacokinetics/ pharmacodynamics of durvalumab in combination with R-CHOP (Arm A) or R2-CHOP (Arm B), followed by durvalumab consolidation therapy in previously untreated subjects with high-risk DLBCL.

Patients with non-ABC subtype (determined by gene expression profiling) will be allocated to Arm A while patients with ABC (activated B-cell type) subtype will be allocated to Arm B. Approximately 120 patients may be enrolled and assigned into the appropriate treatment arms dependent upon their cell of origin status.

Induction treatment with R-CHOP (± Lenalidomide) will last for a total of up to 6 to 8 treatment cycles (21 days cycle), and the total time on study treatment, including durvalumab consolidation, will last up to 12 months.


Condition or disease Intervention/treatment Phase
Lymphoma, Large B-Cell, Diffuse Drug: Durvalumab Drug: Rituximab Drug: Doxorubicin Drug: Vincristine Drug: Cyclophosphamide Drug: Prednisone Drug: Lenalidomide Phase 2

Detailed Description:

This research study is conducted in patients 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 backbone) 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 significantly augment the anti-tumor activity of R-CHOP against high-risk DLBCL subtypes.

There are different subtypes of DLBCL which are distinguished by their Cell of Origin (ABC, GCB, unclassifiable). About a third of DLBCL is of the ABC subtype and as those patients have a worse outcome when treated with R-CHOP, lenalidomide plus R-CHOP (R2-CHOP) will be used for patients with the ABC subtype.

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 for a total of 20 subjects
  • An Expansion Stage to analyze the clinical activity of the treatment combinations in up to 100 additional subjects

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 46 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A PHASE 2, OPEN-LABEL, MULTICENTER STUDY TO EVALUATE THE SAFETY AND CLINICAL ACTIVITY OF DURVALUMAB IN COMBINATION WITH RITUXIMAB, CYCLOPHOSPHAMIDE, DOXORUBICIN, VINCRISTINE, PREDNISONE (R-CHOP) OR WITH LENALIDOMIDE PLUS R CHOP (R2 CHOP) IN SUBJECTS WITH PREVIOUSLY UNTREATED, HIGH RISK DIFFUSE LARGE B CELL LYMPHOMA
Actual Study Start Date : February 28, 2017
Estimated Primary Completion Date : June 22, 2021
Estimated Study Completion Date : July 1, 2024


Arm Intervention/treatment
Experimental: Arm A (non-ABC DLBCL): Durvalumab in combination with R-CHOP
Durvalumab 1125 mg intravenously (IV) on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R-CHOP (IV rituximab, doxorubicin, vincristine, and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5) followed by durvalumab monotherapy for up to a total of 12 months after start of study treatment.
Drug: Durvalumab
Durvalumab
Drug: Rituximab
Rituximab
Drug: Doxorubicin
Doxorubicin
Drug: Vincristine
Vincristine
Drug: Cyclophosphamide
Cyclophosphamide
Drug: Prednisone
Prednisone
Experimental: Arm B (ABC DLBCL): Durvalumab in combination with R2-CHOP
Durvalumab 1125 mg IV on Day 1 of each 21-day cycle in combination with 6 to 8 cycles R2-CHOP (IV rituximab, doxorubicin, vincristine and cyclophosphamide on Day 1; daily oral/IV prednisone/prednisolone from Day 1 to 5; daily oral lenalidomide 15 mg from Day 1 to 14) from Cycle 2 until end of induction therapy (Cycle 6 or Cycle 8), or starting Cycle 1 if ABC subtype is identified prior to Cycle 1 Day 1 (C1D1) followed by durvalumab monotherapy for up to a total of 12 months after start of study treatment.
Drug: Durvalumab
Durvalumab
Drug: Rituximab
Rituximab
Drug: Doxorubicin
Doxorubicin
Drug: Vincristine
Vincristine
Drug: Cyclophosphamide
Cyclophosphamide
Drug: Prednisone
Prednisone
Drug: Lenalidomide
Lenalidomide



Primary Outcome Measures :
  1. Progression Free Survival at 24 months [ Time Frame: Up to 24 months after last patient is enrolled ]
    Subjects who have not experienced disease progression or death within 24 months after start of study treatment


Secondary Outcome Measures :
  1. Treatment-Emergent Adverse Events (AEs) [ Time Frame: Up to 15 months after last patient is enrolled ]
    Number of participants with adverse event

  2. Clinical response to study treatment in biomarker-defined subpopulations [ Time Frame: Up to 24 months after last patient is enrolled ]
    Identification and development of biomarkers predictive of clinical response to study treatment



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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. ECOG performance status of 0-2.
  8. Adequate hematology laboratory results (absolute neutrophil count ≥ 1.5 x 10^9/L, platelet count ≥ 75 x 10^9/L, hemoglobin ≥ 10.0 g/dL).
  9. Adequate biochemistry laboratory results (AST/SGOT and ALT/SGPT ≤ 3.0 x 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03003520


Locations
United States, Arizona
Banner MD Anderson Cancer Center
Gilbert, Arizona, United States, 85234
United States, Indiana
Parkview Research Center
Fort Wayne, Indiana, United States, 46845
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
University of Rochester Medical Center
Rochester, New York, United States, 14642
United States, Ohio
Mid Ohio Oncology Hematology Inc
Columbus, Ohio, United States, 43219
United States, Washington
Swedish Cancer Institute
Seattle, Washington, United States, 98104
Austria
Innsbruck Medical University Dep. of Internal Medicine
Innsbruck, Austria, 6020
Landeskrankenhaus Salzburg
Salzburg, Austria, 5020
Medical University of Vienna Internalmedicine 1, Hematology
Vienna, Austria, 1190
Hanusch Krankenhaus
Wien, Austria, 1140
Denmark
Aarhus Sygehus
Arhus C, Denmark, DK-8000
Rigshospitalet, Kobenhavns Universitet - Centre for Clinical Intervention Research - The Copenhagen
Copenhagen, Denmark, 2100
Odense Universitetshospital
Odense C, Denmark, DK5000
Estonia
(North Estonia Medical Centre) - Onkoloogia-ja Hematoloogiakliinik
Tallinn, Estonia, 13419
Tartu University Hospital
Tartu, Estonia, 51014
United Kingdom
University Hospital Birmingham
Birmingham, United Kingdom, B15 2TH
Royal Marsden Hospital
London, United Kingdom, SW3 6JJ
Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
Oxford, United Kingdom, 0X3 7LE
Sponsors and Collaborators
Celgene
Investigators
Study Director: Oliver Manzke, Medical Doctor Celgene Corporation

Responsible Party: Celgene
ClinicalTrials.gov Identifier: NCT03003520     History of Changes
Other Study ID Numbers: MEDI4736-DLBCL-001
2015-005173-20 ( EudraCT Number )
First Posted: December 28, 2016    Key Record Dates
Last Update Posted: April 6, 2018
Last Verified: April 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Celgene:
Lymphoma
Diffuse-large B-Cell Lymphoma
Durvalumab
Anti-PD-L1 Antibody
MEDI4736
Immune Checkpoint
Rituximab
Cyclophosphamide
Doxorubicin
Vincristine
Prednisone/Prednisolone
Lenalidomide

Additional relevant MeSH terms:
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Cyclophosphamide
Thalidomide
Rituximab
Liposomal doxorubicin
Lenalidomide
Doxorubicin
Prednisone
Vincristine
Prednisolone
Methylprednisolone Hemisuccinate
Antibodies, Monoclonal
Prednisolone acetate
Methylprednisolone acetate
Methylprednisolone
Prednisolone hemisuccinate
Prednisolone phosphate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents