Feasibility Study of Induction and Maintenance Avelumab Plus R-CHOP in Patients With Diffuse DLBCL: The AvR-CHOP Study

Inclusion Criteria:

1. Male or Female subjects aged 18 years.
2. Histologically proven CD20-positive diffuse large B cell non-Hodgkin lymphoma (DLBCL) according to the current World Health Organization classification including all morphological variants.
3. No previous treatment for lymphoma including chemotherapy, radiotherapy or other investigational drug.
4. Stage II, III and IV disease (Ann Arbor criteria) (must be able to undergo PET/CT imaging for staging purposes.)
5. Eastern Collaborative Oncology Group performance status 0, or 1, unless attributable to lymphoma in which case patients of performance status 2 are also eligible.
6. Adequate bone marrow function with platelets \> 100x109/l; neutrophils \> 1.5x109/l at the time of study entry unless attributed to bone marrow infiltration by lymphoma.
7. Adequate renal function defined by an estimated creatinine clearance ≥ 30 mL/min according to the Cockcroft-Gault formula (or local institutional standard method)
8. Adequate hepatic function defined by a total bilirubin level ≤ 1.5 × the upper limit of normal (ULN) range and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤ 2.5 × upper limit of institutional normal range unless attributed to lymphoma.
9. Patients must have an acceptable left ventricular ejection fraction (LVEF) i.e. within the local normal range for multigated acquisition scan (MUGA) or ≥ 45% on echocardiogram
10. No concurrent uncontrolled medical condition as determined by the investigator.
11. Life expectancy \> 3 months.
12. Negative blood pregnancy test at screening for women of childbearing potential. Effective contraception for both male and female subjects if the risk of conception exists.
13. Signed written informed consent before any trial-related procedure is undertaken that is not part of the standard patient management.

Exclusion Criteria:

1. T-cell lymphoma, transformed follicular lymphoma, grade 3B Follicular lymphoma.
2. Previous history of treated or non-treated indolent lymphoma. However, patients not previously diagnosed with an indolent lymphoma, who have diffuse large B-cell lymphoma with some small cell infiltration in bone marrow or lymph node may be included after consultation with the sponsor.
3. Central nervous system, meningeal or spinal cord involvement by lymphoma.
4. Prior therapy with any antibody or drug targeting T-cell coregulatory proteins (immune checkpoints) such as PD-1, PD-L1, or cytotoxic T-lymphocyte antigen-4 (CTLA-4).
5. Patients with active autoimmune disease that might deteriorate when receiving an immunostimulatory agent:

i) Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible ii) Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day iii) Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) is acceptable.

f) Subjects with a condition requiring systemic treatment with either corticosteroids (\> 15 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses \> 15 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.

g) Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma) h) Past history of interstitial lung disease. i) Prior organ transplantation, including allogeneic stem-cell transplantation j) Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast.

k) Neurological contra-indication to vincristine (e.g. pre-existing diabetic neuropathy \>grade 1) l) Major surgery for any reason, except diagnostic biopsy, within 4 weeks of enrolment and/or if the subject has not fully recovered from the surgery within 4 weeks of enrolment m) Any other serious active disease, including but not limited to; i) pregnancy or lactation, ii) clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (\< 6 months prior to enrolment), myocardial infarction (\< 6 months prior to enrolment), unstable angina pectoris, congestive heart failure (New York Heart Association Classification Class ≥ II), or serious cardiac arrhythmia requiring medication (including QTc prolongation of \> 470 ms and/or pacemaker) or prior diagnosis of congenital long QT syndrome.

iii) or, uncontrolled active infection, iv) or, uncontrolled diabetes (e.g., hemoglobin A1c ≥ 8%) n) Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS), Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) o) Medical or psychiatric conditions that compromise the patient's ability to give informed consent.