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

NCT03003520 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: MEDI4736-DLBCL-0012015-005173-20
• Study Type: interventional
• Target: 46
• Locations: 5 countries
• Sites: 20

Brief 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).

Conditions

Lymphoma, Large B-Cell, Diffuse

Keywords

Lymphoma; Diffuse-large B-Cell Lymphoma; Durvalumab; Anti-PD-L1 Antibody; MEDI4736; Immune Checkpoint; Rituximab; Cyclophosphamide; Doxorubicin; Vincristine; Prednisone/Prednisolone; Lenalidomide

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Percentage of Participants Who Responded During Induction and Continued Into Consolidation Therapy (Database Cutoff Date: 02-Aug-2018)

  From first dose of study drug to completion of at least one cycle in the Consolidation Period (Day 1 up to Week 52)

• Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) CD8 T-Cell Density

  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).

• Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Total Percentage

  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).

• Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Percentage of Tumor Cells

  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).

• 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

  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).

Study Arms (2)

DUR + R-CHOP

EXPERIMENTAL

On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP (IV rituximab 375 mg/m\^2, doxorubicin 50 mg/m\^2, vincristine 1.4 mg/m\^2 (maximum dose of 2.0 mg total), and cyclophosphamide 750 mg/m\^2); Participants also were administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. Induction treatment continued for a total of 6-8 cycles. Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months.

Drug: Durvalumab; Drug: Rituximab; Drug: Doxorubicin; Drug: Vincristine; Drug: Cyclophosphamide; Drug: Prednisone

DUR + R2-CHOP

EXPERIMENTAL

Participants start the study on durvalumab in combination with R-CHOP (as described in Arm DUR + R-CHOP). Based on their DLBCL Cell-of-Origin subtype (test typically done between cycles 1 and 2), participants with ABC subtype continue the study taking durvalumab in combination with R2-CHOP. On Day 1 of each 21-day cycle, participants received durvalumab 1125 mg intravenously (IV) followed by R-CHOP. Participants were also administered daily oral or IV prednisone/prednisolone 100 mg from Day 1 to 5. In addition, a daily oral lenalidomide 15 mg was administered from Day 1 to 14 of each 21-day cycle. Induction treatment continued for a total of 6-8 cycles. Participants who achieve a complete response or partial response continue with consolidation therapy treatment consisting of durvalumab monotherapy 1500 mg by IV on Day 1 of each 28-day cycle for up to a total of 12 months. Enrollment into Arm B was discontinued.

Drug: Durvalumab; Drug: Rituximab; Drug: Doxorubicin; Drug: Vincristine; Drug: Cyclophosphamide; Drug: Prednisone; Drug: Lenalidomide

Interventions

Durvalumab DRUG

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.

Also known as: MEDI4736, IMFINZI™, DUR

DUR + R-CHOP; DUR + R2-CHOP

Rituximab DRUG

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.

Also known as: RITUXAN®

DUR + R-CHOP; DUR + R2-CHOP

Doxorubicin DRUG

A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab.

Also known as: Adriamycin

DUR + R-CHOP; DUR + R2-CHOP

Vincristine DRUG

A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab.

Also known as: leurocristine, Oncovin

DUR + R-CHOP; DUR + R2-CHOP

Cyclophosphamide DRUG

A component of the CHOP therapy administered by IV. CHOP therapy was administered following rituximab.

Also known as: cytophosphane, Cytoxan

DUR + R-CHOP; DUR + R2-CHOP

Prednisone DRUG

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.

Also known as: corticosteroid, prednisolone

DUR + R-CHOP; DUR + R2-CHOP

Lenalidomide DRUG

Lenalidomide was administered orally in capsule form on Days 1-14 of the DUR+R2-CHOP treatment arm only.

Also known as: Revlimid®

DUR + R2-CHOP

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• CD20+Diffuse Large B-Cell Lymphoma.
• Ann Arbor stage 3 or 4 or stage 2 with bulky disease
• High or high-intermediate disease risk.
• No prior anti-lymphoma treatment.
• Subject is willing and able to undergo biopsy.
• Investigator considers R-CHOP immunochemotherapy appropriate.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
• Adequate hematology laboratory results (absolute neutrophil count ≥ 1.5 \* 10\^9/L, platelet count ≥ 75 \* 10\^9/L, hemoglobin ≥ 10.0 g/dL).
• 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).
• Bi-dimensionally measurable disease (\> 2.0 cm).
• Subject is using effective contraception.

You may not qualify if:

• Diagnosis of lymphoma other than Diffuse Large B-Cell Lymphoma.
• Composite lymphoma or transformed lymphoma.
• Primary or secondary Central Nervous System involvement by lymphoma.
• Seropositive or active viral infection with hepatitis B virus, human immunodeficiency virus or hepatitis C virus.
• History of other malignancies, unless disease-free for ≥ 5 years.
• Left ventricular ejection fraction \< 50%.
• Peripheral neuropathy ≥ Grade 2.
• Prior use of lenalidomide, or monoclonal antibodies against CTLA-4, PD-1, or PD-L1.
• High risk of developing thromboembolic events, who are unwilling to take venous thromboembolism prophylaxis.
• Active or prior documented autoimmune or inflammatory disorders within the past 3 years.
• Current or prior use of immunosuppressive medication within 28 days before start of treatment.

Sponsors & Collaborators

• Celgene: lead

Study Sites (20)

Banner MD Anderson Cancer Center

Gilbert, Arizona, 85234, United States

Location

Parkview Research Center

Fort Wayne, Indiana, 46845, United States

Location

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Roswell Park Cancer Institute

Buffalo, New York, 14263, United States

Location

University of Rochester Medical Center

Rochester, New York, 14642, United States

Location

Mid Ohio Oncology Hematology Inc

Columbus, Ohio, 43219, United States

Location

Swedish Cancer Institute

Seattle, Washington, 98104, United States

Location

Innsbruck Medical University Department of Internal Medicine

Innsbruck, 6020, Austria

Location

Landeskrankenhaus Salzburg

Salzburg, 5020, Austria

Location

Hanusch Krankenhaus

Vienna, 1140, Austria

Location

Local Institution - 101

Vienna, 1190, Austria

Location

Medical University of Vienna Internalmedicine 1, Hematology

Vienna, 1190, Austria

Location

Aarhus Sygehus

Arhus C, DK-8000, Denmark

Location

Rigshospitalet, Kobenhavns Universitet - Centre for Clinical Intervention Research - The Copenhagen

Copenhagen, 2100, Denmark

Location

Odense Universitetshospital

Odense C, DK5000, Denmark

Location

(North Estonia Medical Centre) - Onkoloogia-ja Hematoloogiakliinik

Tallinn, 13419, Estonia

Location

Tartu University Hospital

Tartu, 51014, Estonia

Location

University Hospital Birmingham

Birmingham, B15 2TH, United Kingdom

Location

Royal Marsden Hospital

London, SW3 6JJ, United Kingdom

Location

Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine

Oxford, 0X3 7LE, United Kingdom

Location

Related Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse; Lymphoma; Dendritic Cell Sarcoma, Interdigitating

Interventions

durvalumab; Rituximab; Doxorubicin; Vincristine; Cyclophosphamide; Prednisone; Adrenal Cortex Hormones; Prednisolone; Lenalidomide

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Histiocytic Disorders, Malignant; Histiocytosis

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnadienetriols; Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Isoindoles

Limitations and Caveats

After the US FDA Partial Clinical Hold, enrollment of new participants into Arm B was discontinued. If receiving clinical benefit at the discretion of the Investigator, participants could continue treatment in Arm B after being reconsented. Any newly enrolled participant with DLBCL of ABC COO subtype after the US FDA Partial Clinical Hold could continue induction therapy on Arm A after Cycle 1.

Results Point of Contact

• Title: Bristol-Myers Squibb Study Director
• Organization: Bristol-Myers Squibb

Clinical.Trials@bms.com

Please email

Study Officials

• Bristol-Myers Squibb

  Bristol-Myers Squibb

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2016
• First Posted: December 28, 2016
• Study Start: February 28, 2017
• Primary Completion: April 24, 2022
• Study Completion: April 24, 2022
• Last Updated: May 22, 2023
• Results First Posted: September 16, 2019

Record last verified: 2023-04

Locations

ES (2); DK (3); AU (5); GB (3); US (7)