Recent reports have identified a specific oncogenic mutation L265P of the MYD88 gene in approximately 30% of the patients with the activated B-cell (ABC) type of Diffuse Large B Cell Lymphoma (DLBCL). MYD88 is an initial adapter linker protein in the signaling pathway of the Toll Like Receptors (TLRs), including the endosomal TLRs 7, 8, and 9, for which the ligands are nucleic acids. IMO-8400 is an oligonucleotide specifically designed to inhibit ligand activation of TLRs 7,8, and 9. Recent studies indicate that in the presence of L265P mutation ligand activation of those TLRs results in markedly increased signaling with subsequent increased cell activation, cell survival, and cell proliferation. The scientific rationale for assessing the use of IMO-8400 to treat patients with DLBCL and the L265P mutation is based on laboratory observations that IMO-8400 inhibits ligand-based activation of cells with the mutation and decreases the survival and proliferation of the cell populations responsible for the propagation of the disease.

Eligible subjects will be enrolled and assigned to one of five dose cohorts. Treatment will be administered by subcutaneous injection until progression or intolerable toxicity.

Inclusion Criteria:

• Patients must have a diagnosis of Diffuse Large B Cell Lymphoma (DLBCL) of non-GCB subtype, established according to the World Health Organization (WHO) criteria that has been tested for the MyD88 L265P mutation.

• In addition to the above, key inclusion and exclusion criteria are listed below.

  1. Be at least 18 years of age
  2. Agree to use contraception

Exclusion Criteria:

1. Is nursing or pregnant
2. DLBCL of GCB subtype
3. Has BMI > 34.9 kg/m2
4. Has a positive test for human immunodeficiency virus (HIV-1 or -2) hepatitis C virus (HCV) or hepatitis B surface antigen (HBsAg)
5. Receiving chronic systemic corticosteroid therapy > 20 mg of prednisone daily
6. Being treated with other anti-cancer therapies (approved or investigational)
7. Has an active infection requiring systemic antibiotics
8. Has had surgery requiring general anesthesia within 4 weeks of starting the study
9. Has heart failure of Class III or IV