Everolimus is an oral mTOR inhibitor with demonstrated preliminary efficacy and safety in diffuse large B-cell lymphoma (DLBCL) in both preclinical and clinical studies. The purpose of this research study is to determine whether Everolimus plus rituximab is safe and effective in participants with relapsed or refractory DLBCL. Everolimus is an investigational drug that works by blocking a special protein that helps cancer cells grow. The safety and effectiveness of Everolimus in the treatment of DLBCL has not yet been fully determined and is still investigational. The other drug in this study, rituximab, is approved by the US Food and Drug Administration (FDA) for use in patients who have diffuse large B-cell lymphoma and certain other types of non-Hodgkin lymphoma. Rituximab is a drug that destroys both normal and cancerous B-cells.

Participants will receive oral Everolimus and intravenous rituximab for DLBCL that has relapsed or been refractory to prior therapy.

• Each treatment cycle lasts 28 days (4 weeks). Everolimus will be taken orally, once daily in the morning.
• Rituximab will be administered by an intravenous (IV) infusion on Days 1, 8, 15 and 22 of Cycle 1. In Cycles 2-6, rituximab will be administered only on Day 1 of each cycle.
• Participants will come into the clinic weekly during the first cycle, then on Day 1 of all cycles thereafter. The following tests and procedures will be performed:
• Weekly During Cycle 1: blood tests
• Day 1 of all Subsequent Cycles: brief physical examination; review of current medications, treatments, symptoms and side effects; vital signs; performance status evaluation; blood tests.
• A full body CT and PET scan to assess the participants tumor will be done within 7 days of completing cycles 2, 4, 6, 9 and 12.

Responding subjects may receive up to 6 cycles of Everolimus plus rituximab, and an additional 6 months of oral Everolimus for participants continuing to respond.

Inclusion Criteria:

• Histologically determined DLBCL that is relapsed or primary refractory after initial therapy
• Greater than 1 prior line of chemotherapy (including an anthracycline unless contraindicated) or immunotherapy. Patients must have relapsed after autologous stem cell transplantation, not be eligible for autologous stem call transplantation in the judgment of the investigator, or refuse autologous stem cell transplantation. Salvage chemotherapy and high dose conditioning for autologous stem cell transplantation count as two separate regimens.
• Measurable disease that has not been previously irradiated on PET-CT of at least 2cm, OR if the patient has had previous radiation to the marker lesion(s), there must be evidence of progression since the radiation. Imaging must be completed no greater than 3 weeks from study enrollment.
• ECOG performance status 0-2
• 18 years of age or older
• Life expectancy of greater than 3 months
• Adequate Organ and marrow function
• Fasting serum cholesterol of 300 mg/dl or less OR 7.75 mmol/L or less AND fasting triglycerides 2.5 x ULN or less

Exclusion Criteria:

• Currently receiving anticancer therapies or who have received anticancer therapies within 3 weeks of the start of the study drug
• Receiving any other investigational agents, or have received investigational agents within 4 weeks of beginning treatment
• Major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
• Known leptomeningeal or brain metastases. Imaging or spinal fluid analysis to exclude CNS involvement is not required, unless there is clinical suspicion by the treating investigator
• Known HIV infection
• Systemic fungal, bacterial, viral, or other infection not controlled
• Prior history of malignancy (except for non-melanoma skin cancer or in situ cervical or breast cancer) unless disease free for at least one year. Patients with prostate cancer are allowed if PSA is less than 1
• Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
• Severely impaired lung function defined as DLCO of <60%
• Uncontrolled diabetes as defined by fasting serum glucose > 1.5 x ULN
• Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of Everolimus
• Active bleeding diathesis
• Female patients who are pregnant or breastfeeding, or adults of reproductive potential who are not using effective birth control methods
• Prior treatment with an mTOR inhibitor
• Known hypersensitivity to murine antibodies,everolimus,other rapamycin
• Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study
• No chronic treatment with systemic corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are permitted

26 patients enrolled, 24 evaluable