The purpose of this study is to evaluate the safety and tolerability of INCB053914 in combination with INCB050465 in relapsed or refractory diffuse large B-cell lymphoma (DLBCL).

Inclusion Criteria:

• Relapsed or refractory DLBCL, which has been histologically documented, defined as having received at least 2 but no more than 5 prior systemic treatment regimens (eg, an anti-CD20 antibody, an anti-CD20 antibody with or without chemotherapy, or chemotherapy alone) and ineligible for further treatment with standard of care.

• Willing to undergo pretreatment and on-treatment incisional or excisional biopsy of nontarget adenopathy or extranodal lesions. Provision of the most recent, available archived tumor biopsy may satisfy the pretreatment biopsy.

• Measurable disease as defined by the Lugano classification criteria:

  • ≥ 1 measurable nodal lesion (≥ 1.5 cm in longest dimension) or ≥ 1 measurable extranodal lesion (> 1 cm in longest dimension) on CT scan or MRI
  • ≥ 1 PET-avid lesion.

• Eastern Cooperative Oncology Group performance status 0 to 2.

• Willingness to avoid pregnancy or fathering children based on protocol-defined the criteria.

Exclusion Criteria:

• Laboratory values outside the protocol-defined range at screening unless approved by the medical monitor.
• Primary mediastinal (thymic) large B-cell lymphoma or Richter's Syndrome.
• Known brain or central nervous system metastases or history of uncontrolled seizures.
• Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks of the first dose of study treatment.
• Allogeneic stem cell transplant within the last 6 months, or active graft-versus-host disease following allogeneic transplant, or autologous stem cell transplant within the last 3 months before the date of the first dose of study treatment.
• Use of immunosuppressive therapy following allogenic transplant within 28 days of the first dose of study treatment.
• Prior treatment with a PIM inhibitor, selective PI3Kδ inhibitor (eg, idelalisib), or a pan-PI3K inhibitor.
• Receipt of anticancer medications, therapies, or investigational drugs within protocol-defined intervals before the date of the first dose of study treatment.
• Current or previous other malignancy within 3 years of study entry, except cured (or treated with curative intent and no evidence of disease) basal or squamous cell skin cancer, superficial bladder cancer, prostate intraepithelial neoplasm, carcinoma in situ of the cervix, or other noninvasive or indolent malignancy without sponsor approval.
• History of liver function abnormality requiring investigation and/or treatment (eg, due to excessive alcohol or drug-induced liver injury).
• Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, hematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral, or psychiatric disease.
• Chronic or current active infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment, and exposure to a live vaccine within 30 days of study treatment administration.
• Known HIV infection.
• Evidence of HBV or HCV infection.
• History of stroke or intracranial hemorrhage within 6 months of the date of study treatment administration.
• History of clinically significant or uncontrolled cardiac disease.
• Presence of an abnormal ECG that is clinically meaningful. Screening QTc interval > 480 milliseconds is excluded (corrected by Fridericia).
• Any condition that would, in the investigator's judgment, interfere with full participation in the study, including administration of study treatment and attending required study visits; pose a significant risk to the participant; or interfere with interpretation of study data.