The purpose of this Phase 2/3 study is to evaluate efficacy and safety of the combination of selinexor and R-GDP (SR-GDP) in patients with RR DLBCL who are not intended to receive hematopoetic stem cell transplantation (HSCT) or chimeric antigen receptor T cell (CAR-T) therapy. This study consists of 3 arms each in Phase 2 and 3. Phase 2 portion of the study will assess the two doses of selinexor (40 milligram [mg] or 60 mg) in combination with R-GDP, for up to 6 cycles (21-day per cycle), followed by 60 mg selinexor single agent continuous therapy for those who have reached a partial or complete response. Phase 3 portion of the study will evaluate the selected dose of SR-GDP (identified in Phase 2) versus standard R-GDP + matching placebo, for up to 6 cycles (21-day per cycle), followed by placebo or 60 mg selinexor single agent continuous therapy for those who have reached partial or complete response.

Inclusion Criteria:

• Have pathologically confirmed de novo DLBCL or DLBCL transformed from previously diagnosed indolent lymphoma (e.g., follicular lymphoma). Patient with high-grade lymphoma with c-MYC, Bcl2 and/or Bcl6 rearrangements are eligible (only for Phase 2). (Documentation to be provided).

• Have received at least 1 but no more than 3 prior lines of systemic therapy for the treatment of DLBCL with relapsed or refractory disease following their most recent regimen.

  • Salvage chemoimmunotherapy followed by stem cell transplantation will be considered as 1 line of systemic therapy.
  • Maintenance therapy will not be counted as a separate line of systemic therapy.
  • Radiation with curative intent for localized DLBCL will not be counted as 1 line of systemic therapy.

• Positron emission tomography (PET) positive measurable disease with at least 1 node having the longest diameter (LDi) greater than (>) 1.5 centimeter (cm) or 1 extranodal lesion with LDi >1 cm (per the Lugano Criteria 2014). The Deauville 5-point scale (D5PS) score assessed on the FDG PET/CT should be between 3 to 5.

• Not intended for HSCT or CAR-T cell therapy based on objective clinical criteria determined by the treating physician. Patients who cannot receive HSCT due to active disease are allowed on study (up to approximately 15 percent [%] of patients enrolled in each Phase). Documentation on lack of intention to proceed to receive HSCT or CAR-T therapy must be provided by the treating physician.

• Adequate bone marrow function at screening, defined as:

  • Absolute neutrophil count (ANC) ≥1*10^9 per liter (/L).
  • Platelet count ≥100*10^9/L (without platelet transfusion less than [<] 14 days prior to Cycle 1 Day 1 [C1D1]).
  • Hemoglobin ≥8.5 gram per deciliter (g/dL) (without red blood cell transfusion <14 days prior to C1D1).

• Circulating lymphocytes less than or equal to (≤) 50*10^9/L.

• Adequate liver and kidney function, defined as:

  • Aspartate transaminase (AST) or alanine transaminase (ALT) ≤2.5*upper limit of normal (ULN), or ≤5*ULN in cases with known lymphoma involvement in the liver.
  • Serum total bilirubin ≤2*ULN, or ≤5*ULN if due to Gilbert syndrome or in cases with known lymphoma involvement in the liver.
  • Calculated creatinine clearance (CrCl) ≥30 milliliter per minute (mL/min) based on Cockcroft-Gault formula.

• Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

• An estimated life expectancy of >3 months at Screening.

• Patients with primary refractory DLBCL defined as no response or relapse within 6 months after ending first-line treatment, will be allowed in the study.

• Agree to highly effective contraception during the duration of the study with contraception use continuing for 12 months after the last dose of study treatment

• Female patients of childbearing potential must have a negative serum pregnancy test at Screening and agree to use highly effective methods of contraception throughout the study and for 12 months following the last dose of study treatment (except patients with Non-Childbearing potential: Age >50 years and naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy).

• Male patients who are sexually active must use highly effective methods of contraception throughout the study and for 12 months following the last dose of study treatment. Male patients must agree not to donate sperm during the study treatment period and for 12 months following the last dose of study treatment.

Exclusion Criteria:

• DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma, composite lymphoma (Hodgkin's lymphoma + non-Hodgkin's lymphoma [NHL]), DLBCL transformed from diseases other than indolent NHL; primary mediastinal (thymic) large B-cell lymphoma (PMBL); T-cell rich large B-cell lymphoma.

• Previous treatment with selinexor or other XPO1 inhibitors.

• Contraindication to any drug contained in the combination therapy regimen (SR-GDP).

• Known active central nervous system or meningeal involvement by DLBCL at time of Screening.

• Use of any standard or experimental anti-DLBCL therapy (including nonpalliative radiation, chemotherapy, immunotherapy, radio-immunotherapy, or any other anticancer therapy) <21 days prior to C1D1 (prednisone <30 mg or equivalent is permitted; palliative radiation is permitted only if on non-target lesions).

• Any AE, by C1D1, which has not recovered to Grade ≤1 (Common Terminology Criteria for Adverse Events [CTCAE], v.5.0), or returned to baseline, related to the previous DLBCL therapy, except hematological abnormalities (as specified in the inclusion criteria) and alopecia.

• Major surgery <14 days of Cycle 1 Day 1.

• Hematopoietic stem cell transplantation/CAR-T therapy as follows:

  • Autologous stem cell transplant (SCT) <100 days or allogeneic-SCT <180 days prior to C1D1
  • Active graft-versus-host disease (GVHD) after allogeneic SCT (or cannot discontinue GVHD treatment or prophylaxis)
  • CAR-T cell infusion <90 days prior to Cycle 1

• Neuropathy Grade ≥2 (CTCAE, v.5.0).

• Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety, or being compliant with the study procedures.

• Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 7 days prior to first dose of study treatment; however, prophylactic use of these agents is acceptable (including parenteral).

• Patient with active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infections:

  • Patient with active HBV are allowed if antiviral therapy for hepatitis B has been given for >8 weeks and viral load is <100 International units (IU)/mL prior to first dose of study treatment.
  • Patients with known history of HCV or found to be HCV antibody positive on screening, are allowed if there is documentation of negative viral load per institutional standard.
  • Patients with HIV are allowed if they have a negative viral load per institutional standard, and no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections in the last year.

• Inability to swallow tablets, malabsorption syndrome, or any other gastrointestinal (GI) disease or dysfunction that could interfere with absorption of study treatment.

• Breastfeeding or pregnant women.

• Inability or unwillingness to sign an informed consent form (ICF).

• In the opinion of the Investigator, patient who are significantly below their ideal body weight.

• Patients who received a live attenuated vaccine within prior 28 days of the first dose of study treatment.

Phase 2 Portion of the Study: open label; Phase 3 Portion of the Study: double blinded