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

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)

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.

Study Overview

• Status: Suspended
• Conditions: Relapsed or Refractory Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: Selinexor; Drug: Rituximab; Drug: Bendamustine; Drug: Polatuzumab Vedotin; Drug: Gemcitabine; Drug: Oxaliplatin; Drug: Ibrutinib; Drug: Lenalidomide; Drug: Tafasitamab; Drug: Venetoclax

• Study Type: Interventional
• Enrollment (Anticipated): 350
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Tucson, Arizona, United States, 85724
      • University of Arizona
  • California
    • Encinitas, California, United States, 92024
      • California Cancer Associates For Research and Excellence
    • La Jolla, California, United States, 92093
      • UC San Diego Moores Cancer Center
    • Orange, California, United States, 92868
      • University of California Irvine
  • Colorado
    • Aurora, Colorado, United States, 80012
      • US Oncology - Rocky Mountain Cancer Center
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
  • Iowa
    • Des Moines, Iowa, United States, 50309
      • Mission Cancer + Blood
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48021
      • Karmanos Cancer Institute
  • Nebraska
    • Omaha, Nebraska, United States, 68198
      • University of Nebraska Medical Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Comprehensive Cancer Center
  • Oregon
    • Eugene, Oregon, United States, 97401
      • US Oncology - Oncology Associates of Oregon
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Hillman Cancer Center
  • South Carolina
    • Greenville, South Carolina, United States, 29605
      • US Oncology - Prisma Health
  • Texas
    • Austin, Texas, United States, 78705
      • US Oncology - Texas Oncology Austin Midtown
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern
    • Houston, Texas, United States, 77030
      • Baylor Clinic - Mcnair Center
  • Washington
    • Vancouver, Washington, United States, 98684
      • US Oncology - Northwest Cancer Specialists

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Participants greater than or equal to (≥) 18 years of age.
2. Have pathologically confirmed relapsed/refractory (RR) DLBCL, not otherwise specified (NOS).
3. Participants with High Grade B-cell Lymphoma (HGBL) are allowed in Phase 2 only.

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

   • For Arms A, B, C, E, F, G, 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.
5. 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.
6. Adequate bone marrow function at Screening.
7. Circulating lymphocytes less than or equal to (≤) 50 * 109/L.
8. Adequate liver and kidney function.
9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
10. An estimated life expectancy of >6 months at Screening.
11. 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).
12. Male participants, and female participants of childbearing potential must agree to use highly effective methods of contraception during the duration of the study and will continue following the last dose of study treatment for the longest duration stated on the label of each of the given drugs (depending on each arm).
13. Female participants of childbearing potential must have a negative serum pregnancy test at Screening. Female participants of childbearing potential in the S-LR arm and the S-LT arm must have 2 negative pregnancy tests before Lenalidomide treatment (Non-Childbearing potential: Age >50 years and naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or hysterectomy).
14. 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 untreated hepatitis C Virus (HCV) are eligible if viral load is negative per institutional standard; 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. Previous treatment with selinexor or other XPO1 inhibitors.
3. Contraindication to any drug contained in the different treatment arms.
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) and palliative radiotherapy are permitted.
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. Any AE, by Cycle 1 Day 1 (C1D1), which has not recovered to Grade ≤1 (CTCAE, v. 5.0), or returned to baseline, related to the previous DLBCL therapy, except alopecia.
7. Major surgery <14 days of C1D1.
8. 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).
9. 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).
10. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety, or able to comply with the study procedures.
11. 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).
12. Inability to swallow tablets, malabsorption syndrome, or any other GI disease or dysfunction that could interfere with absorption of study treatment.
13. Breastfeeding women or pregnant women.
14. Inability or unwillingness to sign informed consent form.
15. In the opinion of the Investigator, participants who are below their ideal body weight and would be unduly impacted by changes in their weight.

16. Known allergy to any of the drug planned to be given.

    The following are Arm Specific exclusion criteria:

17. Arm B (S-PR): Serum total bilirubin >1.5 * ULN, Neuropathy Grade ≥2 (CTCAE, v5.0).
18. Arm C (S-PBR): Serum total bilirubin >1.5 * ULN, Neuropathy Grade ≥2 (CTCAE, v5.0).
19. Arm D (S-R-GemOx): Neuropathy Grade 2≥ (CTCAE, v5.0) interstitial lung disease or pulmonary fibrosis.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Selinexor with Bendamustine and Rituximab (S-BR)); Participants will receive a dose of 40 or 60 or 80 milligrams (mg) of selinexor oral tablets on Days 1, 3, and 8 for Cycle 1 to 6 (each cycle consists of 21 days) during primary treatment and 60 mg on Days 1, 8, 15, and 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 for Cycle 1 to 6.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Rituximab; Dose: 375 mg/m^2; Drug: Bendamustine; Dose: 90 mg/m^2
Experimental: Arm B: Selinexor with Polatuzumab Vedotin and Rituximab (S-PR); Participants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets on Days 1, 3, and 8 for Cycle 1 to 6 (each cycle consists of 21 days) during primary treatment and 60 mg on Days 1, 8, 15, and 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 for Cycle 1 to 6.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Rituximab; Dose: 375 mg/m^2; Drug: Polatuzumab Vedotin; Dose: 1.8 mg/kg
Experimental: Arm C: Selinexor, Polatuzumab Vedotin, Bendamustine, Rituximab (S-PBR); Participants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets on Days 1, 3, and 8 for Cycle 1 to 6 (each cycle consists of 21 days) during primary treatment and 60 mg on Days 1, 8, 15, and 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 for Cycle 1 to 6.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Rituximab; Dose: 375 mg/m^2; Drug: Bendamustine; Dose: 90 mg/m^2; Drug: Polatuzumab Vedotin; Dose: 1.8 mg/kg
Experimental: Arm D: Selinexor, Rituximab, Gemcitabine, Oxaliplatin (S-R-GemOx); Participants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets on Days 1 and 3 for Cycle 1 to 6 (each cycle consists of 14 days) during primary treatment and 60 mg on Days 1, 8, 15, and 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 for Cycle 1 to 6.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Rituximab; Dose: 375 mg/m^2; Drug: Gemcitabine; Dose: 1000 mg/m^2; Drug: Oxaliplatin; Dose: 100 mg/m^2
Experimental: Arm E: Selinexor with Ibrutinib and Rituximab (S-IR); Participants will receive a dose of 40 or 60 or 80 mg of selinexor oral tablets on Days 1, 8, and 15 for Cycle 1 to 6 during primary treatment and 40 mg (dose level 1) then 60 mg (dose level 2-4) during 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 once daily on Day 1 to 28 during primary treatment for Cycle 1 to 6. Participants will also receive ibrutinib oral dose of 420 mg once daily at all dose levels during continuous treatment.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Rituximab; Dose: 375 mg/m^2; Drug: Ibrutinib; Dose: 420, 560 mg
Experimental: Arm F: Selinexor with Lenalidomide and Rituximab (S-LR); Participants will receive a dose of 40 or 60 mg of selinexor oral tablets on Days 1, 8, and 15 for Cycle 1 to 6 during primary treatment and 40 mg (dose level 1) then 60 mg (dose level 2) during 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 for Cycle 1 to 6. Participants will also receive lenalidomide oral dose of 20 mg on Days 1 to 21 at all dose levels during the continuous treatment.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Rituximab; Dose: 375 mg/m^2; Drug: Lenalidomide; Dose: 20, 25 mg
Experimental: Arm G: Selinexor with Lenalidomide and Tafasitamab (S-LT); Participants will receive a dose of 40 or 60 mg of selinexor oral tablets on Days 1, 8, and 15 for Cycle 1 to 12 during primary treatment and 40 (dose level 1) then 60 mg (dose level 2) during continuous treatment (each cycle consists of 28 days). During the primary treatment, participants will also receive lenalidomide oral dose of 25 mg once daily on Days 1 to 21, and 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 on Days 1 and 15 for all dose levels during the continuous treatment.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Lenalidomide; Dose: 20, 25 mg; Drug: Tafasitamab; Dose: 12 mg/kg
Experimental: Arm H: Selinexor with Venetoclax (S-V); Participants will receive 40 or 60 or 80 mg of selinexor oral tablets on Days 1, 8 and 15 for Cycle 1 to 6 of primary treatment and 40 mg (dose level 1) then 60 mg (dose level 2-5) during continuous treatment (28 days per cycle). Participants who received 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. Participants who received 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. Participants who received 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. Participants during continuous treatment will also receive venetoclax 400 mg orally daily.	Drug: Selinexor; Dose: 40 mg (2 tablets of 20 mg), 60 mg (3 tablets of 20 mg), 80 mg (4 tablets of 20 mg); Other Names: KPT-330; Drug: Venetoclax; Dose: 200, 400, 600, 800 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Phase 1: Maximum Tolerated Dose (MTD)	Within the first cycle (maximum 28 days) of treatment
Phase 1: Recommended Phase 2 Dose (RP2D)	Up to 6 cycles (up to 6 months) of treatment
Phase 2: Overall Response Rate (ORR) per the Lugano Classification 2014	Cycle 1 Day 1 (each cycle consists of maximum 28 days) until a complete response (CR) or partial response (PR) (up to 6 months)

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Karyopharm Therapeutics Inc

Study record dates

Study Major Dates

• Study Start (Actual): November 18, 2020
• Primary Completion (Anticipated): December 1, 2025
• Study Completion (Anticipated): December 1, 2025

Study Registration Dates

• First Submitted: October 26, 2020
• First Submitted That Met QC Criteria: October 26, 2020
• First Posted (Actual): October 29, 2020

Study Record Updates

• Last Update Posted (Estimate): January 25, 2023
• Last Update Submitted That Met QC Criteria: January 24, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: Gemcitabine; DLBCL; Rituximab; Lenalidomide; Ibrutinib; Venetoclax; Bendamustine; Oxaliplatin; Diffuse Large B-Cell Lymphoma; Tafasitamab; Karyopharm; KPT-330; Selinexor; Polatuzumab Vedotin
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Gemcitabine; Lenalidomide; Oxaliplatin; Venetoclax; Bendamustine Hydrochloride; Rituximab
• Other Study ID Numbers: XPORT-DLBCL-025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No