Clinical trial NCT03003520: A Study of Durvalumab in Combination With R-CHOP or Lenalidomide Plus R-CHOP in Previously Untreated High-Risk Diffuse Large B-Cell Lymphoma
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2016-12-28
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed 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.

Eligibility 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. 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.

Primary outcomes:
measure: Percentage of Participants Who Achieved a Complete Response (CR) at the End of Induction Therapy
timeFrame: From first dose of study drug to end of Induction therapy (Day 1 up to Week 26 - maximum duration of Induction Period).
Secondary outcomes:
measure: Percentage of Participants Who Responded During Induction and Continued Into Consolidation Therapy (Database Cutoff Date: 02-Aug-2018)
timeFrame: From first dose of study drug to completion of at least one cycle in the Consolidation Period (Day 1 up to Week 52)
measure: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) CD8 T-Cell Density
timeFrame: 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).
measure: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Total Percentage
timeFrame: 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).
measure: Percentage of Participants Who Achieved a Clinical Response in the Biomarker Subpopulation for Immunohistochemistry (IHC) Programmed Death Ligand - 1 (PDL1) Percentage of Tumor Cells
timeFrame: 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).
measure: 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
timeFrame: 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).
measure: Participants With Treatment Emergent Adverse Events (TEAE)
timeFrame: 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)
Other outcomes:
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: Fort Wayne
country: United States
facility: Parkview Research Center
state: Indiana
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center
state: New York
city: Columbus
country: United States
facility: Mid Ohio Oncology Hematology Inc
state: Ohio
city: Seattle
country: United States
facility: Swedish Cancer Institute
state: Washington
city: Innsbruck
country: Austria
facility: Innsbruck Medical University Department of Internal Medicine
city: Salzburg
country: Austria
facility: Landeskrankenhaus Salzburg
city: Vienna
country: Austria
facility: Local Institution - 101
city: Vienna
country: Austria
facility: Medical University of Vienna Internalmedicine 1, Hematology
city: Wien
country: Austria
facility: Hanusch Krankenhaus
city: Arhus C
country: Denmark
facility: Aarhus Sygehus
city: Copenhagen
country: Denmark
facility: Rigshospitalet, Kobenhavns Universitet - Centre for Clinical Intervention Research - The Copenhagen
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Tallinn
country: Estonia
facility: (North Estonia Medical Centre) - Onkoloogia-ja Hematoloogiakliinik
city: Tartu
country: Estonia
facility: Tartu University Hospital
city: Birmingham
country: United Kingdom
facility: University Hospital Birmingham
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Oxford
country: United Kingdom
facility: Oxford University Hospitals NHS Trust- Churchill Hospital-Oxford Centre for Respiratory Medicine
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: