Treatment with selinexor for patients with relapsed or refractory diffuse large B-cell lymphoma

A Phase 2b Open-label Study of Selinexor (KPT-330) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

This study is testing if a new drug called selinexor can help people with relapsed or hard-to-treat diffuse large B-cell lymphoma when other treatments have failed.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 244 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Karyopharm Therapeutics Inc (Industry-sponsored)
• Drugs / interventions: rituximab, chemotherapy, immunotherapy, radiation
• Locations: 176 sites (Tucson, Arizona and 175 other locations)
• Trial ID: NCT02227251 on ClinicalTrials.gov

What this trial studies

This is a multicenter, open-label Phase 2b study evaluating the efficacy of selinexor (KPT-330) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who have exhausted other treatment options. The study consists of two parts: Part 1 involves administering a fixed dose of 60 mg of selinexor to 130 participants until disease progression or intolerance occurs. Part 2 will randomize approximately 110 participants to receive either 40 mg or 60 mg of selinexor, with stratification based on prior autologous stem cell transplantation. Participants will be monitored until disease progression or death.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with relapsed or refractory DLBCL who have received at least 2 but no more than 5 prior systemic treatments.

Not a fit: Patients who have not been previously treated for DLBCL or those with a performance status greater than 2 may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new therapeutic option for patients with limited treatment alternatives for DLBCL.

How similar studies have performed: Other studies have shown promise with similar approaches using selective inhibitors of nuclear export, but this specific application of selinexor is being evaluated for the first time in this patient population.

Eligibility criteria

Inclusion Criteria (Parts 1 and 2):

* Written informed consent in accordance with federal, local, and institutional guidelines. The participant must provide informed consent prior to the first screening procedure.
* Age greater than or equal to (≥) 18 years.
* ECOG performance status of less than or equal to (≤) 2.
* Participants should have estimated life expectancy of greater than (\>) 3 months at study entry.
* Previously treated, pathologically confirmed de novo DLBCL, or DLBCL transformed from previously diagnosed indolent lymphoma (e.g., follicular lymphoma).
* Participants must have received at least 2 but no more than 5 previous systemic regimens for the treatment of their de novo or transformed DLBCL including (i) at least 1 course of anthracycline-based chemotherapy (unless absolutely contraindicated due to cardiac dysfunction, in which case other active agents such as etoposide, bendamustine, or gemcitabine must have been given) and (ii) at least 1 course of anti-CD20 immunotherapy (e.g., rituximab), unless contraindicated due to severe toxicity. Participants who were considered ineligible for standard multi-agent immunochemotherapy must have received at least 2 and no more than 5 prior treatment regimens including at least 1 course of anti-CD20 antibodies and must be approved by the Medical Monitor. Prior stem cell transplantation is allowed; induction, consolidation, stem cell collection, preparative regimen and transplantation ± maintenance are considered a single line of therapy.
* Female participants of child-bearing potential must have a negative serum pregnancy test at screening and agree to use reliable methods of contraception for 3 months after their last dose of medication. Male participants must use a reliable method of contraception if sexually active with a female of child-bearing potential. For both male and female participants, effective methods of contraception must be used throughout the study and for 3 months following the last dose.

Part 1 additional inclusion criteria:

* For participants whose most recent systemic anti-DLBCL therapy induced a PR or CR, at least 60 days must have elapsed since the end of that therapy. For all other participants, at least 14 weeks (98 days) must have elapsed since the end of their most recent systemic anti-DLBCL therapy. . Palliative localized radiation within the therapy-free interval is allowed. Non-chemotherapy maintenance will not be considered anti DLBCL therapy, and therefore is allowed during the therapy-free interval.
* Documented clinical or radiographic evidence of progressive DLBCL prior to dosing.
* Participants must have measurable disease per the revised criteria for response assessment of lymphoma. Lymph nodes should be considered abnormal if the long axis is \>1.5 centimeter (cm), regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal if its short axis is \>1.0. Lymph nodes ≤1.0 by ≤1.0 will not be considered abnormal for relapse or PD.

Part 2 additional inclusion criteria:

• At least 3 weeks (21 days) must have elapsed since the end of participant's most recent systemic anti-DLBCL therapy (prior to Cycle 1 Day 1). Palliative localized radiation within the therapy-free interval is allowed.Non-chemotherapy maintenance will not be considered anti-DLBCL therapy, and therefore is allowed during the therapy-free interval.

• Adequate hematopoietic function: (i) Hemoglobin ≥10.0 grams per deciliters (g/dL) within 14 days of starting therapy (participant may receive red blood cell \[RBC\] transfusion within 14 days).

(ii) Absolute neutrophil count ≥1000 cells/millimeter (mm\^3) (use of granulocyte growth factors prior to and during the study is acceptable).

(iii) Platelet count ≥100,000/mm\^3 within 14 days of starting therapy (use of platelet growth factors prior to and during the study is acceptable).

* Participants must have measurable disease per the revised criteria for response assessment of lymphoma. Lymph nodes should be considered abnormal if the long axis is \>1.5 cm, regardless of the short axis. Extranodal lesion should be considered abnormal if the long axis is \>1.0 cm.

Exclusion Criteria (Parts 1 and 2):

* Participants who are pregnant or lactating.
* Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
* Participants must not be eligible for high-dose chemotherapy with autologous stem cell transplantation rescue (Investigator must provide detailed documentation for ineligibility).
* Participants who have not recovered to Grade ≤1 clinically significant adverse events, or to their baseline, from their most recent systemic anti-DLBCL therapy.
* Major surgery within 2 weeks of first dose of study treatment.
* Participants with active hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) infections.
* Psychiatric illness or substance use that would prevent the participant from giving informed consent or being compliant with the study procedures.
* Any of the following laboratory abnormalities:

  (i) A circulating lymphocyte count of \>50,000/L. (ii) Hepatic dysfunction: bilirubin \>2.0 times the upper limit of normal (ULN) (except participants with Gilbert's syndrome: total bilirubin of \>3\*ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \>2.5 times ULN. In participants with known liver involvement of their DLBCL, AST and ALT \>5\*ULN.

(iii) Severe renal dysfunction: estimated creatinine clearance of \<30 mL/min, measured in 24-hour urine or calculated using the formula of Cockroft and Gault \[(140-Age)\*Mass (kg)/(72\*creatinine mg/dL); multiply by 0.85 if female\].

* Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the participant's safety.
* Participants with active graft-versus-host disease after allogeneic stem cell transplantation. At least 4 months must have elapsed since completion of allogeneic stem cell transplantation.
* Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals on Cycle 1 Day 1; however, prophylactic use of these agents is acceptable even if parenteral.
* Participants unable to swallow tablets, participants with malabsorption syndrome, or any other gastrointestinal disease or gastrointestinal dysfunction that could interfere with absorption of study treatment.

Part 1 additional exclusion criteria:

* For participants whose most recent systemic anti-DLBCL therapy induced a PR or CR: Radiation, chemotherapy, immunotherapy, radio-immunotherapy, or any other anticancer therapy other than glucocorticoids \<60 days or \<14 weeks prior to Cycle 1 Day 1.
* Known central nervous system lymphoma or meningeal involvement.
* DLBCL with mucosa-associated lymphoid tissue \[MALT\] lymphoma, composite lymphoma (Hodgkin's lymphoma+NHL), or DLBCL transformed from diseases other than indolent NHL.
* Unstable cardiovascular function:

  (i) Symptomatic ischemia, or (ii) Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree atrioventricular block or asymptomatic left anterior fascicular block /right bundle branch block will not be excluded), or (iii) Congestive heart failure of New York Heart Association Class ≥3, or (iv) Myocardial infarction within 3 months.
* Participants with a BSA \<1.4 m\^2 as calculated per Dubois 1916 or Mosteller 1987.
* Any of the following laboratory abnormalities:

  (i) Absolute neutrophil count (ANC) \<1000 cells/mm\^3 or platelet count \<75,000/mm\^3 during screening and on Cycle 1 Day 1. Use of granulocyte-stimulating factors and platelet growth factors prior to and during the study is acceptable.

(ii) Hematopoietic dysfunction: hemoglobin \< 10.0 g/dL within 14 days of and including Cycle 1 Day 1 and/or patients receiving red blood cell (RBC) transfusion within 14 days of and including Cycle 1 Day 1.

* Participants who have been committed to an institution by official or judicial order.
* Participants with dependency on the Sponsor, Investigator or study site.

Part 2 additional exclusion criteria:

* Participants with active HBV, HVC, or HIV infections. Participants with active HBV are allowed if antiviral therapy for hepatitis B has been given for \>8 weeks and viral load is \<100 International units per milliliters (IU/mL) prior to first dose of study treatment. Participants with known history of HCV or found to be HCV antibody positive on screening, are allowed if there is documentation of negative viral load per institutional standard. Participants with HIV who have CD4+T-cell counts ≥350 cells/microliter (mcL), negative viral load per institutional standard, and no history of acquired immune deficiency syndrome (AIDS)-defining opportunistic infections in the last year are allowed.
* Known active central nervous system lymphoma or meningeal involvement. Participants with a history of CNS disease treated into remission may be enrolled.
* DLBCL with MALT lymphoma, composite lymphoma (Hodgkin's lymphoma + NHL), DLBCL arising from CLL (Richter's transformation), or high-grade B-cell lymphoma.
* 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.

Where this trial is running

Tucson, Arizona and 175 other locations

• UACC Arizona — Tucson, Arizona, United States (Completed)
• University of California San Francisco — San Francisco, California, United States (Completed)
• University of California Los Angeles (UCLA) — Santa Monica, California, United States (Completed)
• Boca Raton Cancer Research Medical Center — Plantation, Florida, United States (Completed)
• University of Chicago — Chicago, Illinois, United States (Completed)
• Robert H. Lurie Comprehensive Cancer Center/Northwestern University — Chicago, Illinois, United States (Completed)
• Norton Cancer Institute — Louisville, Kentucky, United States (Completed)
• Dana Farber Cancer Institute — Boston, Massachusetts, United States (Completed)
• Tufts Medical Center — Boston, Massachusetts, United States (Completed)
• Lahey Clinic — Burlington, Massachusetts, United States (Completed)
• University of Massachusetts Medical School — Worcester, Massachusetts, United States (Completed)
• John Theurer Cancer Center at Hackensack University Medical Center — Hackensack, New Jersey, United States (Completed)
• Clinical Research Alliance — Lake Success, New York, United States (Completed)
• New York Presbyterian Hospital/ Cornell Medical College — New York, New York, United States (Completed)
• Stony Brook University Hospital — Stony Brook, New York, United States (Completed)
• Gabrail Cancer Center — Canton, Ohio, United States (Completed)
• Cleveland Clinic Foundation — Cleveland, Ohio, United States (Completed)
• University Hospitals Seidman Cancer Center — Cleveland, Ohio, United States (Completed)
• University of Oklahoma — Oklahoma City, Oklahoma, United States (Completed)
• Greenville Hospital System — Greenville, South Carolina, United States (Completed)
• MD Anderson — Houston, Texas, United States (Completed)
• Swedish Cancer Institute — Seattle, Washington, United States (Completed)
• Virginia Mason Hospital & Medical Center — Seattle, Washington, United States (Completed)
• St. Vincent's Hospital Sydney — Darlinghurst, New South Wales, Australia (Completed)
• Liverpool Hospital, Ingham Institute of Medical Research — Liverpool, New South Wales, Australia (Completed)
• Calvary Mater Newcastle Hospital — Waratah, New South Wales, Australia (Completed)
• Icon Cancer Care — South Brisbane, Queensland, Australia (Completed)
• Royal Adelaide Hospital — Adelaide, South Australia, Australia (Completed)
• Ashford Cancer Centre — Kurralta Park, South Australia, Australia (Completed)
• Monash Medical Centre — Clayton, Victoria, Australia (Completed)
• Epworth Hospital — East Melbourne, Victoria, Australia (Completed)
• St. Vincent's Melbourne — Fitzroy, Victoria, Australia (Completed)
• The Alfred Hospital — Melbourne, Victoria, Australia (Completed)
• Fiona Stanley Hospital — Murdoch, Western Australia, Australia (Completed)
• Medical University of Graz — Graz, Austria (Completed)
• Medizinische Universität Innsbruck für Innere Medizin — Innsbruck, Austria (Completed)
• LKH Leoben Department for Haemato-Oncology — Leoben, Austria (Completed)
• Akh Linz Innere Med III - Zentrum für Hämatologie und med. Onkologie — Linz, Austria (Completed)
• Krankenhaus Barmherzigen Schwestern Linz — Linz, Austria (Completed)
• Krankenhaus der Elisabethinen Linz GmbH — Linz, Austria (Completed)
• Uni. Klinik für Innere Medizin III Universitätsklinikum der PMU LKH Salzburg — Salzburg, Austria (Completed)
• Medical University of Vienna (MUW) Department of Medicine I — Vienna, Austria (Completed)
• Univ. General Hospital Hietzing — Vienna, Austria (Completed)
• Ziekenhuis Netwerk Antwerpen — Antwerpen, Belgium (Completed)
• AZ Sint-Jan — Bruges, Belgium (Completed)
• Institut Jules Bordet — Brussels, Belgium (Completed)
• Cliniques Universitaires Saint-Luc — Brussels, Belgium (Completed)
• UZ Gent — Gent, Belgium (Completed)
• CH Jolimont — La Louviere, Belgium (Completed)
• AZ Delta — Roeselare, Belgium (Completed)

Study contacts

• Study coordinator: Karyopharm Medical Information

Conditions Diffuse Large B-cell Lymphoma; Diffuse large B-cell Lymphoma; DLBCL; Karyopharm; KPT-330; selinexor