Metformin in Combination With Standard Induction Therapy for Large B-cell Lymphoma (DLBCL)

Newly diagnosed histologically confirmed CD20 positive previously untreated diffuse large
B-cell lymphoma to receive up to 4-6 cycles (21 day cycles) of:

R-CHOP: Rituximab 375 mg/m2 IV infusion Day 1 Cyclophosphamide 750 mg/m2 IV Day 1
Doxorubicin 50 mg/m2 IV Day 1 Vincristine 1.4 mg/m2 IV Day 1 (cap @ 2mg) Prednisone 100mg PO
daily Days 1-5 Pegfilgrastim 6 mg subcutaneously within 72 if start if cycle Metformin 500
mg PO daily Cycle 1 Days 1-7 Metformin 500 mg PO twice daily Cycle 1 Days 7-21 Metformin 850
mg PO twice daily starting on day 22 and and continuing throughout remainder of cycles plus
22 days post treatment.

Restaging will be done after the 4th cycle is complete. Subjects will be monitored with labs
and physical exams throughout the study.

Inclusion Criteria:

1. Diagnosis of Diffuse Large B-cell Lymphoma (DLBCL) as documented by medical records
and with histology based on criteria established by the World Health Organization

a. subtyping is required for DLBCL

2. No prior therapy for diagnosis of DLBCL

3. Presence of radiographically measurable lymphadenopathy or extranodal lymphoid
malignancy (defined as the presence of equal to or greater than 1 lesion that
measures >1.5 cm in the longest diameter and > 1.0 cm in the longest perpendicular
diameter assessed by CT or MRI) or bone marrow involvement

4. Eastern Cooperative Oncology Group performance score of 0-2

5. Life expectancy of at least 6 months

6. No history of medication dependent diabetes mellitus

7. Required screening laboratory data (within 4 weeks prior to start of study drug) -

Exclusion Criteria:

1. Patients 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

2. Known histological transformation from indolent non-Hodgkins Lymphoma (NHL) or
chronic lymphocytic leukemia (CLL) to an aggressive form of NHL (ie, Richter
transformation)

3. Double or triple hit lymphomas

4. Known active cent4ral nervous system or leptomeningeal lymphoma

5. Presence of known intermediate or high-grade myelodysplastic syndrome

6. History of a non-lymphoid malignancy within the last 3 years (see protocol for
exceptions)

7. Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of
start of study

8. Ongoing, drug-induced liver injury, chronic active Hepatitis C Virus (HCV), chronic
active Hepatitis B Virus (HBV), alcoholic liver disease, non-alcoholic
steatohepatitis, primary biliary cirrhosis, ongoing extrahepatic obstruction caused
by cholelithiasis, cirrhosis of the liver, or portal hypertension.

9. HIV positive

10. Ongoing inflammatory bowel disease

11. Ongoing alcohol or drug addiction

12. Pregnancy

13. History of prior allogeneic bone marrow progenitor cell or solid organ
transplantation.