This Phase I clinical trial studies the side effects and maximum tolerated dose (MTD) of the combination of brentuximab vedotin (BV) and lenalidomide in the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Inclusion Criteria:

• Relapsed or refractory de novo or transformed DLBCL disease following at least one prior systemic therapy (for DLBCL).

• CD30 immunohistochemical staining using the anti-CD30 BerH2 antibody must be available on the most recent biopsy specimen. During dose escalation, patients can be either CD30 positive or CD30 negative. During dose expansion, 15 patients must be CD30 positive and 15 patients must be CD30 negative.

• Post-ASCT or not a candidate for ASCT. Prior allogeneic stem cell transplant is allowed if patient is off all immunosuppressives and has no evidence of active GVHD.

• Prior treatment with brentuximab vedotin is allowed provided the patient did not progress on BV or within 30 days of last dose of BV. Patients must be at least 3 months from the last dose of BV.

• Bidimensional measurable disease of at least 1.5 cm in the greatest transverse diameter as documented by CT or PET/CT.

• At least 18 years of age.

• ECOG performance status ≤ 2

• Bone marrow and organ function as defined below:

  • Absolute neutrophil count (ANC) ≥ 1,000/mcl
  • Platelets ≥ 50,000/mcl
  • Serum bilirubin ≤ 1.5 x institutional upper limit of normal (IULN) OR serum bilirubin ≤ 3.0 x IULN for patients with Gilbert's disease or documented hepatic involvement with NHL
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x IULN OR ALT and AST ≤ 5.0 x IULN for patients with documented hepatic involvement with NHL
  • Creatinine clearance ≥ 60 mL/min/1.73 m2 as calculated by Cockcroft-Gault

• Women of childbearing potential must follow pregnancy testing requirements as outlined in the Revlimid REMS® program material. This is defined as either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of contraception (one highly effective method and one additional effective method AT THE SAME TIME) at least 28 days prior to the start of lenalidomide, for the duration of study participation, and for 28 days following the last doses of brentuximab vedotin and lenalidomide. Women of childbearing potential must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a woman of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.

• All study participants must be registered into the mandatory Revlimid REMS® program and be willing to comply with its requirements. Per standard Revlimid REMS® program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS® program.

• Able to understand and willing to sign an IRB approved written informed consent document (or that of legally authorized representative, if applicable).

Exclusion Criteria:

• Primary mediastinal B-cell lymphoma
• A history of other primary invasive malignancy that has not been in remission for at least 3 years or a current diagnosis of myelodysplastic syndrome (MDS) or an immature leukemia such as acute myeloid leukemia (AML).
• Known active cerebral/meningeal lymphoma.
• Present or history of progressive multifocal leukoencephalopathy (PML).
• NYHA Class III or IV congestive heart failure.
• Active CTCAE version 4.03 grade 3 or higher viral, bacterial, or fungal infection.
• Known to be positive for hepatitis B by surface antigen expression and hepatitis B core antibody.
• Known to have active hepatitis C infection (positive by polymerase chain reaction) or on antiviral therapy for hepatitis C within 6 months prior to the first doses of brentuximab vedotin and lenalidomide.
• Known to be positive for HIV.
• Receiving chemotherapy, radiotherapy, biologics, and/or other antitumor treatment with immunotherapy that is not completed at least 3 weeks prior to study entry, unless underlying disease is progressing on therapy.
• Currently receiving any other investigational agents.
• Known hypersensitivity to any excipient contained in the drug formulation of brentuximab vedotin or lenalidomide.
• Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of starting lenalidomide.
• Receiving immunosuppressive therapy.
• Refractory to prior therapy with brentuximab vedotin (evidence of progression within 30 days of the last dose).
• Prior therapy with lenalidomide.