DA-EPOCH-Rituximab/Metformin (RM) for Double Hit Lymphoma
Condition: Diffuse Large B-Cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: Metformin
Intervention description: given in addition to standard of care treatment
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Double Hit DLBCL

Summary:

      Newly diagnosed histologically confirmed c-myc+ de novo DLBCL. Metformin 500 mg daily x 1
      week, then 500 mg twice daily (BID) x 2 weeks, then 850 mg twice daily until 1 month after
      last cycle of chemo-immunotherapy.

      DA-EPOCH-R every 21 days x 4 cycles (CNS prophylaxis single or triple therapy given
      intrathecally each cycle to patients deemed appropriate by treating physician).

      Restage after 4 cycles with CT. Complete remission or partial remission: complete 2 more
      cycles or radiation therapy (XRT) consolidation per physician. Stable or progressive disease
      will go on to salvage therapy off study.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Male or female ≥ 18 years of age

          -  Diagnosis of DLBCL as documented by medical records and with histology based on
             criteria established by the World Health Organization

               -  subtyping is required for DLBCL

               -  c-myc+ defined as presence of c-myc breaks by karyotype/FISH and/or IHC ≥ 40%;
                  this includes double hits (with bcl-2 breaks found using cytogenetics/FISH)
                  and/or double expressors (with bcl-2 protein expression ≥ 70% by IHC); increased
                  copy number in itself is not considered positivity for c-myc

          -  No prior therapy for diagnosis of DLBCL with exception of steroids

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0- 2 (Appendix B)

          -  Life expectancy of at least 6 months

          -  No history of medication dependent diabetes mellitus

          -  No evidence of acute or chronic metabolic acidosis (baseline venous lactate ≤ 4)

        Exclusion Criteria

          -  Patient already on any class of anti-diabetic medication including metformin, insulin
             analogues, sulfonylureas, thiazolidinediones (TZDs) and the incretin-based therapies
             or clear need for therapeutic intervention based on fasting blood glucose

          -  Known histological transformation from indolent non-Hodgkin Lymphoma (iNHL) or chronic
             lymphocytic leukemia (CLL) to an aggressive form of non-Hodgkin's lymphoma (NHL) (ie,
             Richter transformation)

          -  Burkitt and/or precursor lymphoblastic leukemia/lymphoma.

          -  Presence of known intermediate- or high-grade myelodysplastic syndrome

          -  History of an active of treated non-lymphoid malignancy within the last 3 years
             excluding basal cell and squamous cell skin cancers

          -  Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of
             start of study drug.

          -  Subjects who have currently active hepatic or biliary disease (with exception of
             patients with Gilbert's syndrome, asymptomatic gallstones, liver involvement with NHL
             or stable chronic liver disease per investigator assessment)

          -  Renal insufficiency with creatinine > 1.5 x upper limit of normal (ULN) OR creatinine
             clearance of < 45 ml/min as calculated by the Cockcroft-Gault method

          -  CNS or leptomeningeal involvement of lymphoma

          -  HIV positive

          -  Ongoing inflammatory bowel disease

          -  Ongoing alcohol or drug addiction

          -  Pregnancy or breastfeeding

          -  History of prior allogeneic bone marrow progenitor cell or solid organ transplantation
             -