Avelumab 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 (R/R DLBCL)

• Biological: Avelumab
  
  Investigational fully human anti-PD-L1 monoclonal antibody
  Other Name: MSB0010718C
• Biological: Utomilumab
  
  Investigational, fully human IgG2 CD 137/4-1BB agonist
  Other Name: PF-05082566
• Biological: Rituximab
  
  CD20-directed cytolytic antibody
  Other Name: Rituxan
• Other: Azacitidine
  
  Antimetabolite antineoplastic agent and demethylation agent.
  Other Name: Vidaza
• Drug: Bendamustine
  
  Alkylating drug
  Other Name: Treanda
• Drug: Gemcitabine
  
  Nucleoside analogue
  Other Name: Gemzar
• Drug: Oxaliplatin
  
  Platinum-based drug
  Other Name: Eloxatin

• Experimental: Phase 1b Arm A
  
  avelumab/utomilumab/rituximab
  Interventions:
  

  • Biological: Avelumab
  • Biological: Utomilumab
  • Biological: Rituximab
• Experimental: Phase 1b Arm B
  
  avelumab/utomilumab/azacitidine
  Interventions:
  

  • Biological: Avelumab
  • Biological: Utomilumab
  • Other: Azacitidine
• Experimental: Phase 1b Arm C
  
  avelumab/rituximab/bendamustine
  Interventions:
  

  • Biological: Avelumab
  • Biological: Rituximab
  • Drug: Bendamustine
• Experimental: Phase 3 Arm D (selected from Phase 1b)
  
  Selected regimen from Phase 1b component which may be i) avelumab/utomilumab/rituximab OR ii) avelumab/rituximab/azacitidine OR iii) avelumab/rituximab/bendamustine
  Interventions:
  

  • Biological: Avelumab
  • Biological: Utomilumab
  • Biological: Rituximab
  • Other: Azacitidine
  • Drug: Bendamustine
• Active Comparator: Phase 3 Arm E
  
  Investigator's Choice of either rituximab/bendamustine or rituximab/gemcitabine/oxaliplatin
  Interventions:
  

  • Biological: Rituximab
  • Drug: Bendamustine
  • Drug: Gemcitabine
  • Drug: Oxaliplatin

Key Inclusion Criteria:

-Any of the following as defined by the WHO, 2016 lymphoid neoplasm classifications and histologically confirmed:

• Diffuse large B-cell lymphoma (DLBCL), Not Otherwise Specified (NOS): Germinal center B-cell type (GCB), Activated B-cell type (ABC)
• High-grade B-cell lymphoma (HGBCL) NOS
• HGBCL with MYC and BCL2 and/or BCL6 rearrangements
• T-cell histocyte-rich large B-cell lymphoma
• EBV+ DLBCL, NOS
• HHV8+ DLBCL, NOS

Relapsed or refractory disease 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. Patients who are ineligible for intensive second line chemotherapy, must have received at least one prior rituximab-containing combination chemotherapy regimen.

• Baseline measurable disease with at least 1 bi dimensional lesion with longest diameter (LDi) >1.5cm on CT scan which is FDG avid on PET scan.
• A biopsy (archived or Screening/recent) will be collected at Screening.
• At least 18years of age (or ?20 years in Japan).
• Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1.

Key Exclusion Criteria:

• Active central nervous system (CNS) lymphoma.
• Prior organ transplantation including prior allogeneic SCT.
• 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).