Phase 1B/Phase 3 Multicenter Study of Avelumab (MSB0010718c) in Combination Regimens that Include an Immune Agonist, Epigenetic Modulator, CD20 Antagonist and/or Conventional Chemotherapy in Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)

1. Any of the following as defined by the WHO, 2016 lymphoid neoplasm
classification and histologically confirmed:
- Discussed large B-cell lymphoma (DLBCL), Non Otherwise Specified
(NOS)
- Germinal center B-cell type (GCB)
- Activated B-cell type (ABC)
- High-grade B-cell lymphoma (HGBCL)
- HGBCL with MYC and BCL2 and/or BCL6 rearrangements
- T-cell histocyte-rich large B-cell lymphoma
- EBV+ DLBCL, NOS
- HHV8+ DLBCL, NOS
2.. Documentation that the disease is relapsed or refractory following at least 2 lines (and a maximum of 4 lines) of prior rituximab containing multi-agent chemotherapy which may include an autologous stem cell transplantation unless patients are not considered suitable for intensive second-line chemotherapy or autologous stem cell transplantation. Patients who are ineligible for intensive second line chemotherapy, must have received at least one prior rituximab-containing combination chemotherapy regimen.
3. Patients previously treated with bendamustine must have experienced a response duration 6 months.
4. Documentation of baseline measurable disease with at least 1 bi-dimensional lesion with longest diameter >1.5 cm on CT scan which is fluorodeoxyglucose (FDG) avid on PET scan.
5. A biopsy (archived or Screening/recent) will be collected at Screening.
6. Estimated life expectancy 3 months.
7. At least 18 years of age.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.
9. All adverse events must have resolved to NCI CTCAE v.4.03 Grade 1 (with the exception of alopecia and other Grade 2 AEs not considered medically relevant in the judgment of the Investigator).
10. Patients must have an adequate bone marrow function, including:
a. Absolute neutrophil count (ANC) 1.5 x 109/L;
b. Platelet count 100 x 109/L;
c. Hemoglobin 8 g/dL.
11. Patients must have adequate liver function, including:
a. Total bilirubin level 1.5 × upper limit of normal (ULN);
b. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) 2.5 x ULN.
12. Patients must have an adequate renal function as evidenced by a creatinine clearance 40 mL/min as calculated using the Cockcroft-Gault equation.
13. Serum or urine pregnancy test (for females of childbearing potential) must be negative.
14. Female patients of non-childbearing potential must meet at least 1 of the following criteria:
• Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state;
• Have undergone a documented hysterectomy and/or bilateral oophorectomy;
• Have medically confirmed ovarian failure.
All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential.
15. Must be willing to receive prophylactic granulocyte colony
stimulating factor (G-CSF) in all cycles, for patients >=60 years old
randomized to arm C.
16. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
17. Patients must be willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.

1. Active/symptomatic central nervous system (CNS) lymphoma based on clinical evaluation.
2. Prior organ transplantation including prior allogeneic SCT.
3. Prior therapy with an anti PD-1, anti PD-L1, anti PD-L2, anti CD137, or anti-cytotoxic T lymphocyte associated antigen 4 (CTLA-4) antibody (including ipilimumab, tremelimumab or any other antibody, or drug specifically targeting T-cell co-stimulatory or immune checkpoint pathways).
4. Use of any standard or experimental anti-cancer therapy within 2 weeks to first dose of study treatment, including cytoreductive therapy and radiotherapy, immunotherapy, or cytokine therapy (except for erythropoietin).
5. Use of any non-drug anti-cancer therapy including chimeric antigen receptor (CAR) T-Cell (CAR-T-Cell) therapy.
6. Major surgery within 28 days prior to first dose of study treatment.
7. Diagnosis of any other malignancy 3 years prior to first dose of study treatment, with the exception of: (i) adequately treated basal cell or squamous cell skin cancer, (ii) carcinoma in situ of the breast or cervix, or (iii) low-grade (Gleason 6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration).
8. Known history of testing positive for human immunodeficiency virus ( HIV) or known acquired immunodeficiency syndrome.
9. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen, positive HBV core antibody or HCV ribonucleic acid (RNA) if anti-HCV antibody screening test positive).
10. Active infection requiring systemic therapy.
11. Vaccination within 4 weeks prior to randomization and while on trial is prohibited except for administration of inactivated vaccines.
12. Current use of immunosuppressive medication, EXCEPT for the following:
a. intranasal, inhaled, eye drops, topical steroids, or local steroid injection (eg, intra-articular injection);
b. Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent;
c. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication).
13. Active autoimmune disease that might deteriorate when receiving an immuno-stimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
14. Known anaphylaxis or severe hypersensitivity to rituximab or other monoclonal antibodies, mannitol, or any of the compounds used in this study or to compounds with a similar chemical or biological composition.
15. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke/transient ischemic attack [TIA]/symptomatic pulmonary embolism (<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), unstable angina, congestive heart failure (New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication, other severe acute or chronic medical (including colitis, inflammatory bowel disease, pneumonitis, uncontrolled asthma, or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
16. Known alcohol or drug abuse.
17. Pregnant female patients; breastfeeding female patients; fertile male
patients and female patients of childbearing potential who are unwilling
or unable to use 2 highly effective methods of contraception for a
defined timeframe dependent on study treatment assigned per protocol
and , where applicable, in agreement with local prescribing information
for individual drugs.
18. Patients who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
19. Participation in other studies involving investigational drugs within 4 weeks prior to Cycle 1 Day 1 and/or during study participation.
20. Current use or anticipated need for treatment with drugs that are known strong CYP1A2 inhibitors, including their administration within 10 days prior to patient randomization (ie, ciprofloxacin, fluvoxamine, clinafloxacin, exoxacin, oltipraz, propranolol, rofecoxib, thiabendole and zafirlukast).
21. Current use or anticipated need for treatment with drugs that are known CYP1A2 inducers, including their administration within 10 days prior to patient randomization (ie, omeprazole, phenytoin).