This is a phase 1, open-label, dose-escalation study of fimepinostat (CUDC-907) in patients with relapsed and/or refractory diffuse large B-cell lymphoma (DLBCL), or high-grade B-cell lymphoma (HGBL) with or without MYC and BCL2 alterations. Fimepinostat (CUDC-907) is a multi-targeted agent designed to inhibit phosphoinositide 3-kinase (PI3K)and histone deacetylase (HDAC). The study is designed to assess the safety, the maximum tolerated dose, the recommended phase 2 dose (RP2D), pharmacokinetics and the anti-cancer activity of oral fimepinostat in combination with 1 or more anti-cancer regimens.

Inclusion Criteria:

• Patients ≥ 18 years of age with any of the following: Histopathologically confirmed DLBCL or HGBL (i.e., HGBL with MYC, BCL2, and/or BCL6 rearrangements, HGBL, not otherwise specified [NOS], or DLBCL, NOS) that is refractory to, or has relapsed after, treatment with at least 1 prior regimen. Eligible sub-types include DHL, THL, or DEL, as well as DLBCL or HGBL without MYC and/or BCL2 alterations. Criteria for DHL are concurrent MYC translocation+ and BCL2 translocation+ by fluorescence in situ hybridization (FISH) (same criteria for THL, which also includes BCL6 translocation+ by FISH); criteria for DEL are concurrent overexpression of MYC (≥ 40%) and BCL2 (> 50%) by immunohistochemistry (IHC).
• Measurable disease by CT or PET/CT. MRI acceptable as per protocol.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
• Recovery to Grade 1 or baseline of any toxicity due to prior systemic treatments (excluding alopecia).
• Absolute neutrophil count ≥ 1,000/µL; platelets ≥ 75,000/µL for patients with no bone marrow involvement by malignancy; platelets ≥ 50,000/µL for patients with bone marrow involvement by malignancy.
• Creatinine ≤ 1.5x upper limit of normal (ULN); total bilirubin ≤ 1.5x ULN; AST/ALT ≤ 2.5x ULN.
• Life expectancy of at least 3 months.

Exclusion Criteria:

• Intention to undergo stem cell transplant (SCT) or treatment with chimeric antigen receptor (CAR) T-cell therapy.
• SCT therapy within 100 days prior to starting study treatment.
• Systemic anti-cancer therapy or investigational agent within 3 weeks of study entry, except for nitrosoureas or mitomycin C (6 weeks).
• Other non-cytotoxic anti-cancer therapy or investigational agent within 5 half-lives or 21 days prior to study treatment, whichever is shorter, as long as any drug related toxicities have resolved to Grade 1 or less. Dexamethasone up to 12 mg/d is allowed as supportive therapy and does not exclude participation.
• Contraindication to venetoclax or rituximab.
• Progressive disease during treatment or within 3 months of stopping prior treatment with a BCL2 inhibitor, histone deacetylase (HDAC) inhibitor, or phosphoinositide-3 kinase (PI3k) inhibitor, or prior discontinuation of any of these therapies due to clinically significant toxicity.
• Graft vs. host disease following prior allogeneic transplant within 3 months prior to study treatment.
• Ongoing treatment with chronic immunosuppressants.
• Active CNS lymphoma.
• Known gastrointestinal condition that would interfere with swallowing or the oral absorption or tolerance of fimepinostat.
• Serious infection requiring systemic antibiotic therapy within 14 days prior to study treatment.
• Uncontrolled or severe cardiovascular disease
• Unstable or clinically significant concurrent medical condition.
• Second primary malignancy within 2 years of study entry other than what is specified in the protocol.
• Known HIV positive, hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection.
• Active CMV infection, presence of CMV antigenemia, or evidence of any invasive CMV end organ disease (e.g., CMV colitis).