Clinical Trials /

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

NCT04442022

Description:

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. The 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. The 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.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
  • Double-Hit Lymphoma
  • Transformed Non-Hodgkin Lymphoma
  • Triple-Hit Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: A Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) With or Without Selinexor in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma
  • Official Title: A Phase 2/3, Multicenter Randomized Study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) With or Without Selinexor in Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma (RR DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: XPORT-DLBCL-030
  • SECONDARY ID: 2020-000605-84
  • NCT ID: NCT04442022

Conditions

  • Relapsed/Refractory Diffuse Large B-cell Lymphoma

Interventions

DrugSynonymsArms
Selinexor (combination therapy)Phase 2: Selinexor 40 mg + R-GDP
Selinexor (combination therapy)Phase 2: Selinexor 60 mg + R-GDP
Selinexor (combination therapy)Phase 3: Selinexor (Selected Dose) + R-GDP followed by Placebo
Placebo matching for Selinexor (combination therapy)Phase 3: Placebo + R-GDP followed by Placebo
Rituximab (combination therapy)Phase 2: Selinexor 40 mg + R-GDP
Rituximab (combination therapy)Phase 2: R-GDP
Gemcitabine (combination therapy)Phase 2: R-GDP
Dexamethasone (combination therapy)Phase 2: R-GDP
Cisplatin (combination therapy)Phase 2: R-GDP
Selinexor (continuous therapy)Phase 2: Selinexor 40 mg + R-GDP
Placebo matching for Selinexor (continuous therapy)Phase 3: Placebo + R-GDP followed by Placebo

Purpose

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. The 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. The 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.

Trial Arms

NameTypeDescriptionInterventions
Phase 2: Selinexor 40 mg + R-GDPExperimentalPatients with RR DLBCL will receive combination therapy of selinexor 40 mg orally at Day 1, and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by single-agent continuous therapy with selinexor 60 mg orally once weekly (QW) for each 28-day cycle until progressive disease (PD) or unacceptable toxicity.
  • Selinexor (combination therapy)
  • Rituximab (combination therapy)
  • Gemcitabine (combination therapy)
  • Dexamethasone (combination therapy)
  • Cisplatin (combination therapy)
  • Selinexor (continuous therapy)
Phase 2: Selinexor 60 mg + R-GDPExperimentalPatients with RR DLBCL will receive combination therapy of selinexor 60 mg orally at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by single-agent continuous therapy with selinexor 60 mg orally QW for each 28-day cycle until PD or unacceptable toxicity.
  • Selinexor (combination therapy)
  • Rituximab (combination therapy)
  • Gemcitabine (combination therapy)
  • Dexamethasone (combination therapy)
  • Cisplatin (combination therapy)
  • Selinexor (continuous therapy)
Phase 2: R-GDPActive ComparatorPatients with RR DLBCL will receive R-GDP on specified days (Days 1, 2, 3, 4, and 8) for each 21-day cycle for up to 6 cycles.
  • Rituximab (combination therapy)
  • Gemcitabine (combination therapy)
  • Dexamethasone (combination therapy)
  • Cisplatin (combination therapy)
Phase 3: Selinexor (Selected Dose) + R-GDP followed by Selinexor 60 mgExperimentalPatients with RR DLBCL will receive combination therapy of selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by selinexor 60 mg orally QW for each 28-day cycle until PD or unacceptable toxicity.
  • Selinexor (combination therapy)
  • Rituximab (combination therapy)
  • Gemcitabine (combination therapy)
  • Dexamethasone (combination therapy)
  • Cisplatin (combination therapy)
  • Selinexor (continuous therapy)
Phase 3: Selinexor (Selected Dose) + R-GDP followed by PlaceboExperimentalPatients with RR DLBCL will receive combination therapy of selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by matching placebo for selinexor orally QW for each 28-day cycle until PD or unacceptable toxicity.
  • Selinexor (combination therapy)
  • Rituximab (combination therapy)
  • Gemcitabine (combination therapy)
  • Dexamethasone (combination therapy)
  • Cisplatin (combination therapy)
  • Placebo matching for Selinexor (continuous therapy)
Phase 3: Placebo + R-GDP followed by PlaceboPlacebo ComparatorPatients with RR DLBCL will receive combination therapy of placebo matching for selinexor (selected dose from Phase 2) at Day 1 and Day 8 of each 21-day cycle for up to 6 cycles in combination with R-GDP followed by matching placebo for selinexor orally QW for each 28-day cycle until PD or unacceptable toxicity.
  • Placebo matching for Selinexor (combination therapy)
  • Rituximab (combination therapy)
  • Gemcitabine (combination therapy)
  • Dexamethasone (combination therapy)
  • Cisplatin (combination therapy)
  • Placebo matching for Selinexor (continuous therapy)

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 2: Overall Response Rate (ORR): Based on Lugano Criteria 2014
Time Frame:From date of initial randomization to the date of disease progression or initiating a new DLBCL treatment (maximum of 5 years from randomization)
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Phase 2: Progression-free Survival (PFS): Based on Lugano Criteria 2014
Time Frame:From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 2: Overall Survival (OS)
Time Frame:From date of initial randomization until death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 3: Overall Response Rate (ORR): Based on Lugano Criteria 2014
Time Frame:From date of initial randomization to the date of disease progression or initiating a new DLBCL treatment (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 3: Overall Survival (OS)
Time Frame:From date of initial randomization until death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 2: Overall Response Rate at the End of Combination Therapy (ORR-EoC): Based on Lugano Criteria 2014
Time Frame:From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Safety Issue:
Description:
Measure:Phase 2: Overall Response Rate at the End of Combination Therapy (ORR-EoC): Based on Modified Lugano Criteria
Time Frame:From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Safety Issue:
Description:
Measure:Phase 2: Duration of Response (DOR): Based on Lugano Criteria 2014
Time Frame:From time of first response until disease progression or death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 2: Progression-free Survival (PFS): Based on Modified Lugano Criteria
Time Frame:From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 2: Number of Patients with Adverse Events (AEs)
Time Frame:Up to 30 days after last dose of study drug (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 3: Overall Response Rate at the End of Combination Therapy (ORR-EoC): Based on Lugano Criteria 2014
Time Frame:From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Safety Issue:
Description:
Measure:Phase 3: Overall Response Rate at the End of Combination Therapy (ORR-EoC): Based on Modified Lugano Criteria
Time Frame:From C1D1 (Cycles 1 up to 6; 21 days per cycle) up to 28 days after EoC therapy
Safety Issue:
Description:
Measure:Phase 3: Duration of Response (DOR): Based on Lugano Criteria 2014
Time Frame:From time of first response until disease progression or death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 3: Progression-free Survival (PFS): Based on Modified Lugano Criteria
Time Frame:From date of initial randomization to the date of disease progression or death (maximum of 5 years from randomization)
Safety Issue:
Description:
Measure:Phase 3: Number of Patients with Adverse Events (AEs)
Time Frame:Up to 30 days after last dose of study drug (maximum of 5 years from randomization)
Safety Issue:
Description:

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Karyopharm Therapeutics Inc

Trial Keywords

  • Relapsed/Refractory DLBCL
  • Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP)
  • Selinexor
  • Karyopharm
  • KCP-330
  • XPOVIO
  • DLBCL
  • XPORT-DLBCL-030
  • R-GDP

Last Updated

November 30, 2020