a study of durvalumab in combination with r-chop or lenalidomide plus r-chop in previously untreated high-risk diffuse large b-cell lymphoma

Conditions: Lymphoma, Large B-Cell, Diffuse

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).

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.

Keywords: lymphoma diffuse-large b-cell lymphoma durvalumab anti-pd-l1 antibody medi4736 immune checkpoint rituximab cyclophosphamide doxorubicin vincristine prednisone/prednisolone lenalidomide