Details

Details

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

IRB KARY1414

CC 14-1340

Hospital Main Campus

Phase Phase 2

Disease Lymphoma, Lymphoma - Diffuse Large B Cell

Drug Selinexor (KPT-330)

Description

Description

Primary Objective
  • To evaluate the efficacy of selinexor 60 mg in comparison to a minimally effective lower threshold level of ORR of 15% in patients with R/R DLBCL
Secondary Objectives
  • To determine DOR
  • To determine DCR
  • To assess the safety profile of selinexor
Exploratory Efficacy Objectives
  • To determine the median PFS and median OS
  • To make a preliminary comparison of PFS, ORR, DOR, DCR, quality of life (QoL), and OS in patients with GCB and non-GCB DLBCL
  • To assess QoL using 1) the Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) questionnaire and 2) the EuroQol 5 dimensions 5 levels (EQ-5D-5L) Health Questionnaire
  • To make a preliminary comparison of PFS, ORR, DOR, DCR, QoL, and OS in patients with DH-DLBCL, including translocations identified by cytogenetic analysis during study screening or overexpression of both MYC and BCL2 or BCL6, and with non-DH- DLBCL
  • To make a preliminary comparison of PFS, ORR, DOR, DCR, QoL, and OS in patients with "very good", "good", and "poor" Revised International Prognostic Index (R-IPI)
  • To make a preliminary comparison of PFS, ORR, DOR, DCR, QoL, and OS based on the response to last prior DLBCL therapy (CR or PR versus all others)
  • To compare each patient's time to progression (TTP) on selinexor with the TTP of the patient's most recent prior therapy
Inclusion Criteria

Inclusion Criteria

  1. Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure.
  2. Age ≥18 years
  3. ECOG performance status of ≤ 2 (Appendix 2)
  4. Patients should have estimated life expectancy of >3 months at study entry
  5. Previously treated, pathologically confirmed de novo DLBCL, or DLBCL transformed from previously diagnosed indolent lymphoma (e.g., follicular lymphoma)
  6. Patients 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. Patients 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.
  7. For patients 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 patients, 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.
  8. Documented clinical or radiographic evidence of progressive DLBCL prior to dosing.
  9. Patients must have measurable disease per the revised criteria for response assessment of lymphoma (Cheson, 2014). Lymph nodes should be considered abnormal if the long axis is > 1.5 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.
  10. Female patients 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 patients must use a reliable method of contraception if sexually active with a female of child-bearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose (see Section 13.5.2.1 Permitted Concomitant Medication - Prevention of Pregnancy for description of acceptable contraceptive methods).
Exclusion Criteria

Exclusion Criteria

  1. Patients who are pregnant or lactating
  2. DLBCL with mucosa-associated lymphoid tissue [MALT] lymphoma, composite lymphoma (Hodgkin's lymphoma +NHL), or DLBCL transformed from diseases other than indolent NHL.
  3. Primary mediastinal (thymic) large B-cell lymphoma (PMBL)
  4. Patients must not be eligible for high-dose chemotherapy with autologous stem cell transplantation rescue (Investigator must provide detailed documentation for ineligibility)
  5. Known central nervous system lymphoma or meningeal involvement
  6. For patients 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 prior to Cycle 1 Day 1
  7. For patients whose most recent systemic anti-DLBCL therapy did not induce a PR or CR: Radiation, chemotherapy, immunotherapy, radio-immunotherapy, or any other anticancer therapy other than glucocorticoids < 14 weeks prior to Cycle 1 Day 1
  8. Patients who have not recovered to Grade ≤ 1 clinically significant AEs, or to their baseline, from their most recent systemic anti-DLBCL therapy
  9. Patients 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
  10. Major surgery within 2 weeks of first dose of study treatment
  11. Any life-threatening illness, medical condition or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety
  12. Unstable cardiovascular function:
    • Symptomatic ischemia, or
    • 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
    • Congestive heart failure of New York Heart Association Class ≥3, or
    • Myocardial infarction within 3 months
  13. Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within 1 week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral
  14. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  15. Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)
  16. Patients unable to swallow tablets, patients with malabsorption syndrome, or any other gastrointestinal disease or gastrointestinal dysfunction that could interfere with absorption of study treatment
  17. Any of the following laboratory abnormalities:
    • Absolute neutrophil count (ANC) <1000 cells/mm3 or platelet count <75,000/mm3 during screening and on C1D1. Use of granulocyte-stimulating factors and platelet growth factors prior to and during the study is acceptable
    • Hepatic dysfunction: bilirubin >2.0 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome: total bilirubin of > 3 x ULN) and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >2.5 times ULN. In patients with known liver involvement of their DLBCL, AST and ALT >5 x ULN.
    • 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) x Mass (kg)/(72 x creatinine mg/dL); multiply by 0.85 if female].
    • 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.
  18. Patients with a BSA < 1.4 m2 as calculated per Dubois 1916 or Mosteller 1987.
  19. Persons who have been committed to an institution by official or judicial order
  20. Patients with dependency on the Sponsor, Investigator or study site