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

• ClinicalTrials.gov Identifier: NCT04442022
• Recruitment Status: Recruiting
• First Posted: June 22, 2020
• Last Update Posted: November 30, 2020
• Sponsor: Karyopharm Therapeutics Inc
• Information provided by (Responsible Party): Karyopharm Therapeutics Inc

Tracking Information

• First Submitted Date: June 10, 2020
• First Posted Date: June 22, 2020
• Last Update Posted Date: November 30, 2020
• Actual Study Start Date: September 3, 2020
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 18, 2020)

• 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) ]
• Phase 3: 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) ]

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 14, 2020)

• 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) ]
• Phase 2: Overall Survival (OS) [ Time Frame: From date of initial randomization until death (maximum of 5 years from randomization) ]
• 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) ]
• Phase 3: Overall Survival (OS) [ Time Frame: From date of initial randomization until death (maximum of 5 years from randomization) ]
• 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 ]
• 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 ]
• 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) ]
• 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) ]
• 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) ]
• 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 ]
• 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 ]
• 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) ]
• 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) ]
• 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) ]

Original Secondary Outcome Measures (submitted: June 18, 2020)

• 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) ]
• Phase 2: Overall Survival (OS) [ Time Frame: From date of initial randomization until death (maximum of 5 years from randomization) ]
• 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) ]
• Phase 3: Overall Survival (OS) [ Time Frame: From date of initial randomization until death (maximum of 5 years from randomization) ]
• 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 ]
• 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 ]
• 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) ]
• 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) ]
• 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) ]
• 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 ]
• 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 ]
• 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) ]
• 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) ]
• Phase 3: Progression-free Survival-2 (PFS-2): Based on Lugano Criteria 2014 [ Time Frame: From date of second randomization to the date of disease progression or death (maximum of 5 years from randomization) ]
• Phase 3: Progression-free Survival-2 (PFS-2): Based on Modified Lugano Criteria [ Time Frame: From date of second randomization to the date of disease progression or death (maximum of 5 years from randomization) ]
• 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) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• 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)
• Brief 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. 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3

Study Design

Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double (Participant, Investigator)
Masking Description:

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

Primary Purpose: Treatment

• Condition: Relapsed/Refractory Diffuse Large B-cell Lymphoma

Intervention

• Drug: Selinexor (combination therapy)
  Dose: 40 mg on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Drug: Selinexor (combination therapy)
  Dose: 60 mg on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Drug: Selinexor (combination therapy)
  Dose: Selected dose of selinexor (from Phase 2) on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Drug: Placebo matching for Selinexor (combination therapy)
  Dose: Placebo matching for selected dose of selinexor (from Phase 2) on Days 1 and 8 of each 21-day cycle for up to 6 cycles; Route of administration: oral
• Drug: Rituximab (combination therapy)
  Dose: 375 milligram per meter square (mg/m^2) on Day 1; Route of administration: intravenous (IV)
• Drug: Rituximab (combination therapy)
  Dose: 375 mg/m^2 on Day 1; Route of administration: IV
• Drug: Gemcitabine (combination therapy)
  Dose: 1000 mg/m^2 on Days 1 and 8; Route of administration: IV
• Drug: Dexamethasone (combination therapy)
  Dose: 40 mg (20 mg if patient is more than 70 years old) on Days 1, 2, 3, and 4; Route of administration: oral or IV
• Drug: Cisplatin (combination therapy)
  Dose: 75 mg/m^2 on Day 1; Route of administration: IV
• Drug: Selinexor (continuous therapy)
  Dose: 60 mg QW for each 28-day cycle until PD; Route of administration: oral
• Drug: Placebo matching for Selinexor (continuous therapy)
  Dose: Placebo matching for 60 mg selinexor QW for each 28-day cycle until PD; Route of administration: oral

Study Arms

• Experimental: Phase 2: Selinexor 40 mg + R-GDP
  Patients 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.
  Interventions:

  • Drug: Selinexor (combination therapy)
  • Drug: Rituximab (combination therapy)
  • Drug: Gemcitabine (combination therapy)
  • Drug: Dexamethasone (combination therapy)
  • Drug: Cisplatin (combination therapy)
  • Drug: Selinexor (continuous therapy)
• Experimental: Phase 2: Selinexor 60 mg + R-GDP
  Patients 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.
  Interventions:

  • Drug: Selinexor (combination therapy)
  • Drug: Rituximab (combination therapy)
  • Drug: Gemcitabine (combination therapy)
  • Drug: Dexamethasone (combination therapy)
  • Drug: Cisplatin (combination therapy)
  • Drug: Selinexor (continuous therapy)
• Active Comparator: Phase 2: R-GDP
  Patients 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.
  Interventions:

  • Drug: Rituximab (combination therapy)
  • Drug: Gemcitabine (combination therapy)
  • Drug: Dexamethasone (combination therapy)
  • Drug: Cisplatin (combination therapy)
• Experimental: Phase 3: Selinexor (Selected Dose) + R-GDP followed by Selinexor 60 mg
  Patients 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.
  Interventions:

  • Drug: Selinexor (combination therapy)
  • Drug: Rituximab (combination therapy)
  • Drug: Gemcitabine (combination therapy)
  • Drug: Dexamethasone (combination therapy)
  • Drug: Cisplatin (combination therapy)
  • Drug: Selinexor (continuous therapy)
• Experimental: Phase 3: Selinexor (Selected Dose) + R-GDP followed by Placebo
  Patients 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.
  Interventions:

  • Drug: Selinexor (combination therapy)
  • Drug: Rituximab (combination therapy)
  • Drug: Gemcitabine (combination therapy)
  • Drug: Dexamethasone (combination therapy)
  • Drug: Cisplatin (combination therapy)
  • Drug: Placebo matching for Selinexor (continuous therapy)
• Placebo Comparator: Phase 3: Placebo + R-GDP followed by Placebo
  Patients 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.
  Interventions:

  • Drug: Placebo matching for Selinexor (combination therapy)
  • Drug: Rituximab (combination therapy)
  • Drug: Gemcitabine (combination therapy)
  • Drug: Dexamethasone (combination therapy)
  • Drug: Cisplatin (combination therapy)
  • Drug: Placebo matching for Selinexor (continuous therapy)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 14, 2020): 501
• Original Estimated Enrollment (submitted: June 18, 2020): 492
• Estimated Study Completion Date: August 2024
• Estimated Primary Completion Date: August 2023 (Final data collection date for primary outcome measure)

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Jatin Shah Chief Medical Officer, MD; (617) 658-0600; jshah@karyopharm.com

Contact: Sharon Shacham Chief Scientific Officer, PhD; (617) 658-0600; sshacham@karyopharm.com

• Listed Location Countries: Australia, Austria, France, Germany, Israel, Italy, Poland, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT04442022
• Other Study ID Numbers: XPORT-DLBCL-030; 2020-000605-84 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Karyopharm Therapeutics Inc
• Study Sponsor: Karyopharm Therapeutics Inc
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Karyopharm Therapeutics Inc
• Verification Date: November 2020