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

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) 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 subtypes.

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

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.