Diffuse Large B-cell Lymphoma
Conditions
Keywords
Diffuse large B-cell Lymphoma, DLBCL, Karyopharm, KPT-330, selinexor
Brief summary
A multicenter, open-label Phase 2b study of selinexor (KPT-330) in participants with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who have no therapeutic options of demonstrated clinical benefit.
Detailed description
This is a multicenter, open label, Phase 2b study of the selective inhibitor of nuclear export (SINE) selinexor (40 or 60 milligrams \[mg\]) given orally (PO) to participants with R/R DLBCL). The study is being conducted in 2 parts (Part 1 and Part 2). For Part 1, a fixed 60 mg dose of selinexor is given orally to 130 participants with R/R DLBCL who have no therapeutic options of demonstrated clinical benefit and who meet eligibility criteria and have none of the exclusion criteria will be enrolled to receive selinexor until either disease progression or intolerance has occurred. For Part 2, approximately 110 participants (55 in each arm) are planned to be enrolled. Participants will be randomized (open label) in a 1:1 ratio to either Arm A (40 mg) or Arm B (60 mg) and will be stratified based on history of prior autologous stem cell transplantation (ASCT) versus no prior ASCT. All the participants will be followed until disease progression and/or death.
Interventions
DRUGSelinexor
Dose: 60 mg (BIW); Dosage form: film-coated (20 mg each) immediate release tablets; Route of administration: Oral
Sponsors
Karyopharm Therapeutics Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Overall Response Rate (ORR) | One year | Assessed according to the revised response criteria based on the Guidelines of the International Working Group (IWG). |
| Part 2: Overall Response Rate (ORR) Based on Lugano Criteria | From initial randomization until date of disease progression or death (maximum of 1 year from Part 2 randomization) | Assessed according to the response assessment of lymphoma based on Lugano classification. |
Secondary
| Measure | Time frame |
|---|---|
| Part 1: Duration of Response (DOR) | From time of first response until disease progression or death (maximum of 1 year from Part 1 randomization) |
| Part 1: Disease Control Rate (DCR) | From initial response until disease progression or death (maximum of 1 year from Part 1 randomization) |
| Part 1: Number of Participants with Treatment-emergent Adverse Events (TEAEs) | From Baseline up to 30 days after last dose (maximum of 1 year from Part 1 randomization) |
| Part 1: Number of Participants with Eastern Cooperative Oncology Group (ECOG) Performance Status | From Baseline up to 30 days after last dose (maximum of 1 year from Part 1 randomization) |
| Part 2: Duration of response (DOR) | From time of first response (Part 2) until disease progression or death (maximum of 1 year from Part 2 randomization) |
| Part 2: Disease control rate (DCR) | From initial response (Part 2) until disease progression or death (maximum of 1 year from Part 2 randomization) |
| Part 2: Overall Response Rate (ORR) Based on Modified Lugano Criteria | From initial randomization until date of disease progression or death (maximum of 1 year from Part 2 randomization) |
| Part 2: Number of Participants with Treatment-emergent Adverse Events | From Baseline up to 30 days after last dose (maximum of 1 year from Part 2 randomization) |
| Part 2: Number of Participants with Eastern Cooperative Oncology Group (ECOG) Performance Status | From Baseline up to 30 days after last dose (maximum of 1 year from Part 2 randomization) |
Countries
Australia, Austria, Belgium, Bulgaria, Canada, France, Germany, Greece, Hungary, India, Israel, Italy, Netherlands, New Zealand, Poland, Serbia, Spain, United Kingdom, United States
Outcome results
None listed