A Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) With or Without Selinexor in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma

• Status: Recruiting
• Trial end date: 2024-08-01
• Target enrollment: 0
• Participant gender: All

Summary

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.

• Phase: Phase 2/Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Karyopharm Therapeutics Inc
• Treatments: Dexamethasone; Gemcitabine; Rituximab

Criteria

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 2 prior lines of systemic therapy for the treatment of DLBCL (Documentation to be provided).

• 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) (Documentation to be provided).

• 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 10 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 (Documentation to be provided):

• 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 (Documentation to be provided):

• 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 (up to 20% of enrolled patients in each Phase).

• Agree to effective contraception during the duration of the study with contraception use for 14 months for female patients and 11 months for male patients 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 14 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 11 months following the last dose of study treatment. Male patients must agree not to donate sperm during the study treatment period and for 11 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 alopecia.

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

• Autologous stem cell transplant (SCT) <100 days or allogeneic-SCT <180 days prior to C1D1 or active graft-versus-host disease (GVHD) after allogeneic SCT (or cannot discontinue GVHD treatment or prophylaxis) or 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, hepatitis C or HIV infections. Patient with a history of hepatitis B, hepatitis C or HIV are allowed under the following conditions: Patient with active hepatitis B virus (Hep B) 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. Patient with untreated hepatitis C virus (HCV) are allowed if there is documentation of negative viral load per institutional standard. Patient with human immunodeficiency virus (HIV) who have CD4+ T-cell counts ≥350 cells/microliter (µL), negative viral load per institutional standard, and no history of acquired immune deficiency syndrome (AIDS) -defining opportunistic infections in the last year are allowed.

• 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.