Clinical Trials /

Study of Selinexor in Combination With Backbone Treatments or Novel Therapies In Participants With Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL)

NCT04607772

Description:

This is a Phase 1/2, multicenter, open-label study to evaluate the efficacy, and safety of various combinations with selinexor in participants with RR DLBCL. The study will be conducted in two phases: Phase 1 and 2. The Phase 1 of the study will be a standard 3 + 3 dose escalation to determine the maximal tolerated dose (MTD), recommended Phase 2 dose (RP2D) for each treatment arm, and assess the dose limiting toxicities (DLTs). The Phase 2 of the study will be a dose expansion study to assess the efficacy and safety of for RP2D selected at the end of Phase 1 of the study for each treatment arm.

Related Conditions:
  • Diffuse Large B-Cell Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Selinexor in Combination With Backbone Treatments or Novel Therapies In Participants With Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL)
  • Official Title: A Multicenter, Phase 1/2 Study of Selinexor in Combination With Backbone Treatments or Novel Therapies in Patients With Relapsed or Refractory (RR) Diffuse Large B-Cell Lymphoma (DLBCL)

Clinical Trial IDs

  • ORG STUDY ID: XPORT-DLBCL-025
  • NCT ID: NCT04607772

Conditions

  • Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Interventions

DrugSynonymsArms
SelinexorKPT-330Arm A: Selinexor with Bendamustine and Rituximab (S-BR))
RituximabArm A: Selinexor with Bendamustine and Rituximab (S-BR))
BendamustineArm A: Selinexor with Bendamustine and Rituximab (S-BR))
Polatuzumab VedotinArm B: Selinexor with Polatuzumab Vedotin and Rituximab (S-PR)
IbrutinibArm E: Selinexor with Ibrutinib and Rituximab (S-IR)
LenalidomideArm F: Selinexor with Lenalidomide and Rituximab (S-LR)
TafasitamabArm G: Selinexor with Lenalidomide and Tafasitamab (S-LT)
VenetoclaxArm H: Selinexor with Venetoclax (S-V)
GemcitabineArm D: Selinexor, Rituximab, Gemcitabine, Oxaliplatin (S-R-GemOx)
OxaliplatinArm D: Selinexor, Rituximab, Gemcitabine, Oxaliplatin (S-R-GemOx)

Purpose

This is a Phase 1/2, multicenter, open-label study to evaluate the efficacy, and safety of various combinations with selinexor in participants with RR DLBCL. The study will be conducted in two phases: Phase 1 and 2. The Phase 1 of the study will be a standard 3 + 3 dose escalation to determine the maximal tolerated dose (MTD), recommended Phase 2 dose (RP2D) for each treatment arm, and assess the dose limiting toxicities (DLTs). The Phase 2 of the study will be a dose expansion study to assess the efficacy and safety of for RP2D selected at the end of Phase 1 of the study for each treatment arm.

Trial Arms

NameTypeDescriptionInterventions
Arm A: Selinexor with Bendamustine and Rituximab (S-BR))ExperimentalParticipants will receive a dose of 40 or 60 or 80 milligrams (mg) of selinexor oral tablets once weekly on Days 1, 3, and 8 for Cycle 1 up to 6 (each cycle consists of 21 days) during primary treatment and on Days 1, 8, 15, 22 during continuous treatment (each cycle consists of 28 days). Participants will also receive an intravenous (IV) dose of bendamustine 90 milligram per square meter (mg/m^2) on Days 1 and 2 and IV dose of rituximab 375 mg/m^2 on Day 1 during primary treatment.
  • Selinexor
  • Rituximab
  • Bendamustine
Arm B: Selinexor with Polatuzumab Vedotin and Rituximab (S-PR)ExperimentalParticipants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets once weekly on Days 1, 3, and 8 for Cycle 1 up to 6 (each cycle consists of 21 days) during primary treatment and on Days 1, 8, 15, 22 during continuous treatment (each cycle consists of 28 days). Participants will also receive an IV dose of polatuzumab vedotin 1.8 milligram per kilogram (mg/kg) and IV dose of rituximab 375 mg/m^2 on Day 1 during primary treatment.
  • Selinexor
  • Rituximab
  • Polatuzumab Vedotin
ArmC: Selinexor, Polatuzumab Vedotin, Bendamustine, Rituximab (S-PBR)ExperimentalParticipants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets once weekly on Days 1, 3, and 8 for Cycle 1 up to 6 (each cycle consists of 21 days) during primary treatment and on Days 1, 8, 15, 22 during continuous treatment (each cycle consists of 28 days). Participants will also receive an IV dose of polatuzumab vedotin 1.8 mg/kg and IV dose of rituximab 375 mg/m^2 on Day 1, and IV dose of bendamustine 90 mg/m^2 on Days 1 and 2 during primary treatment.
  • Selinexor
  • Rituximab
  • Bendamustine
  • Polatuzumab Vedotin
Arm D: Selinexor, Rituximab, Gemcitabine, Oxaliplatin (S-R-GemOx)ExperimentalParticipants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets once weekly on Days 1 and 3 for Cycle 1 up to 6 (each cycle consists of 14 days ) during primary treatment and on Days 1, 8, 15, 22 during continuous treatment (each cycle consists of 28 days). Participants will also receive an IV dose of rituximab 375 mg/m^2, IV dose of gemcitabine 1000 mg/m^2, and Oxaliplatin IV dose of 100 mg/m^2 on Day 1 during primary treatment.
  • Selinexor
  • Rituximab
  • Gemcitabine
  • Oxaliplatin
Arm E: Selinexor with Ibrutinib and Rituximab (S-IR)ExperimentalParticipants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets once weekly on Days 1, 8, and 15 for Cycle 1 up to 6 during primary and continuous treatment (each cycle consists of 28 days). participants will also receive an IV dose of rituximab 375 mg/m^2 on Day 1, and ibrutinib oral dose of 420 or 560 mg on Day 1 to 28 during primary treatment. Participants will also receive ibrutinib oral dose of 420 mg daily during continuous treatment.
  • Selinexor
  • Rituximab
  • Ibrutinib
Arm F: Selinexor with Lenalidomide and Rituximab (S-LR)ExperimentalParticipants will receive a dose of 40 or 60 mg of selinexor oral tablets once weekly on Days 1, 8, and 15 for Cycle 1 up to 6 during primary and continuous treatment (each cycle consists of 28 days). Participants will also receive an IV dose of rituximab 375 mg/m^2 on Day 1, and lenalidomide oral dose of 20 mg once daily on Days 1 to 21 during primary treatment. Participants will also receive lenalidomide oral dose of 20 mg on Days 1 to 21 during the continuous treatment.
  • Selinexor
  • Rituximab
  • Lenalidomide
Arm G: Selinexor with Lenalidomide and Tafasitamab (S-LT)ExperimentalParticipants will receive a dose of 40 or 60 mg of selinexor oral tablets once weekly on Days 1, 8, and 15 for Cycle 1 up to 3 during primary treatment and Days 1, 8, 15, and 22 during continuous treatment (each cycle consists of 28 days per cycle). During the primary treatment (Cycle 1 to 12), participants will also receive lenalidomide oral dose of 25 mg once daily on Days 1 to 21, tafasitamab IV dose of 12 mg/kg on Days 1, 8, 15, and 22 for Cycle 1 to 3 and Days 1 and 15 for Cycle 4 to 12. Participants will also receive an IV dose of tafasitamab 12 mg/kg during the continuous treatment on Days 1 and 15.
  • Selinexor
  • Lenalidomide
  • Tafasitamab
Arm H: Selinexor with Venetoclax (S-V)ExperimentalParticipants will receive 40 or 60 or 80 mg of selinexor oral tablets once weekly on Days 1, 8 and 15 for Cycle 1 up to 6 of primary and continuous with treatment duration (28 days per cycle). Participants who receive 40 and 60 mg of selinexor during primary treatment will also receive oral dose of venetoclax 200 mg on Days 1 to 7 then 400 mg on Days 8 to 28 for cycle 1; 400 mg daily for Cycle 2 to 6 (each cycle=28 days). Participants who receive 60 and 80 mg of selinexor during primary treatment will also receive venetoclax 400 mg orally on Days 1 to 7 then 600 mg on Days 8 to 28 for Cycle 1; 600 mg daily for Cycle 2 to 6 (each cycle=28 days). Participants who receive 80 mg selinexor during primary treatment will also receive venetoclax 400 mg orally on Days 1 to 7, then 600 mg from Days 8 to 14, then 800 mg from Day 15 to 28 for Cycle 1; 800 mg daily for Cycle 2 to 6 (each cycle=28 days). Participants during continuous treatment will also receive venetoclax 400 mg orally daily.
  • Selinexor
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          1. Participants greater than or equal to (≥) 18 years of age.

          2. Pathologically confirmed de novo DLBCL or DLBCL transformed from previously diagnosed
             indolent lymphoma (e.g., follicular lymphoma).

          3. Prior lines of systemic therapy for the treatment of DLBCL:

               -  For Arms A, B, C, E, F, H: Participants must have received at least 1 but no more
                  than 3 prior lines of systemic therapy for the treatment of DLBCL.

               -  For Arm D (S-R-GemOx) participants must have received at least 1 but not more
                  than 2 lines of systemic therapy (Documentation to be provided).

               -  For Arm G (S-LT) participants must have received only 1 line of systemic therapy

          4. Positron emission tomography (PET) positive measurable disease per the Lugano
             Classification 2014, having at least 1 node with longest diameter (LDi) greater than
             (>) 1.5 centimetres (cm) or 1 extranodal lesion with LDi >1 cm.

          5. Adequate bone marrow function.

          6. Circulating lymphocytes less than or equal to (≤) 50 * 109/L.

          7. Adequate liver and kidney function.

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

          9. An estimated life expectancy of >6 months at Screening.

         10. Participants with primary refractory disease defined as no response or relapse within
             6 months after ending first-line treatment will be allowed on study (up to 20
             percentage [%] of enrolled participants in each Phase).

         11. Male participants and female participants of childbearing potential must agree to use
             highly effective methods of contraception: Male participants must agree not to donate
             sperm.

         12. Participants with active hepatitis B Virus (HBV) are eligible if antiviral therapy for
             hepatitis B has been given for >8 weeks and viral load is <100 international units per
             milliliter (IU/mL); participants with hepatitis C Virus (HCV) are eligible if viral
             load is negative; participants with human immunodeficiency virus (HIV) are eligible if
             cluster of differentiation 4 (CD4+) T-cell counts ≥350 cells per microliter
             (cells/μL), viral load is negative and no history of acquired immunodeficiency
             syndrome (AIDS)-defining opportunistic infections in the last year.

        Exclusion Criteria:

          1. DLBCL with mucosa-associated lymphoid tissue (MALT) lymphoma; composite lymphoma
             (Hodgkin lymphoma + NHL); Gray zone lymphoma; DLBCL transformed from Chronic
             Lymphocytic Leukemia (Richter Syndrome); Primary mediastinal large B-cell lymphoma
             (PMBCL); T-cell rich large B-cell lymphoma.

          2. Participants with high grade lymphoma with c-MYC, B-cell lymphoma 2 (BCL-2) and/or
             BCL-6 rearrangements are excluded from the Phase 1 portion of the study only.

          3. Previous treatment with selinexor or other XPO1 inhibitors.

          4. 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 Cycle 1 Day 1 (C1D1). Low dose steroids <30 mg prednisone
             (or equivalent) are permitted; and palliative radiotherapy.

          5. Received strong cytochrome P450 3A (CYP3A) inhibitors ≤7 days prior to Day 1 dosing or
             strong CYP3A inducers ≤14 days prior to Day 1 dosing.

          6. Major surgery <14 days of C1D1.

          7. Autologous stem cell transplant (SCT) <100 days or allogeneic SCT <180 days prior to
             C1D1 or active graft-versus-host disease after allogeneic SCT (or cannot discontinue
             graft versus host disease [GVHD] treatment or prophylaxis).

          8. Prior chimeric antigen receptor T cell (CAR-T cell) infusion at any time (Phase 1
             only); prior CAR-T cell infusion ≤120 days prior to C1D1 (Phase 2 only).

             The following are Arm Specific exclusion criteria:

          9. Arm B (S-PR): Serum total bilirubin >1.5 * ULN, Neuropathy Grade ≥2 (CTCAE, v5.0).

         10. Arm C (S-PBR): Serum total bilirubin >1.5 * ULN, Neuropathy Grade ≥2 (CTCAE, v5.0).

         11. Arm D (S-R-GemOx): Neuropathy Grade 2≥ (CTCAE, v5.0) interstitial lung disease or
             pulmonary fibrosis.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Maximum Tolerated Dose (MTD)
Time Frame:Within the first cycle (maximum 28 days) of treatment
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Phase 1: Overall Response Rate per the Lugano Classification 2014
Time Frame:Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a complete response (CR) or partial response (PR) (up to 6 months)
Safety Issue:
Description:
Measure:Phase 1: Disease Control Rate (DCR) per Lugano Classification 2014
Time Frame:Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a CR or PR or stable disease (SD) (up to 6 months)
Safety Issue:
Description:
Measure:Phase 1: Duration of Response (DOR) per Lugano Classification 2014
Time Frame:Time from the first response of PR or CR until disease progression (up to 12 months)
Safety Issue:
Description:
Measure:Phase 1: Overall Response Rate (ORR) per the Modified Lugano Classification
Time Frame:Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a CR or PR (up to 6 months)
Safety Issue:
Description:
Measure:Phase 1: Number of Participants With Adverse Events (AEs) by Occurrence, Nature, and Severity
Time Frame:From start of study drug administration up to 30 days after last dose of study treatment (up to 24 months)
Safety Issue:
Description:
Measure:Phase 2: Overall Response Rate per the Modified Lugano Classification
Time Frame:Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a complete response (CR) or partial response (PR) (up to 6 months)
Safety Issue:
Description:
Measure:Phase 2: Disease Control Rate (DCR) per Lugano Classification 2014
Time Frame:Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a CR or PR or stable disease (SD) (up to 6 months)
Safety Issue:
Description:
Measure:Phase 2: Duration of Response (DOR) per Lugano Classification 2014
Time Frame:Time from the first response of PR or CR until disease progression or death (up to 12 months)
Safety Issue:
Description:
Measure:Phase 2: Number of Participants With AEs by Occurrence, Nature, and Severity
Time Frame:From start of study drug administration up to 30 days after last dose of study treatment (up to 24 months)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Karyopharm Therapeutics Inc

Trial Keywords

  • Karyopharm
  • Diffuse Large B-Cell Lymphoma
  • DLBCL
  • KPT-330
  • Selinexor
  • Bendamustine
  • Rituximab
  • Polatuzumab Vedotin
  • Gemcitabine
  • Oxaliplatin
  • Ibrutinib
  • Lenalidomide
  • Tafasitamab
  • Venetoclax

Last Updated

October 26, 2020