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Selinexor (KPT-330) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

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ClinicalTrials.gov Identifier: NCT02227251
Recruitment Status : Active, not recruiting
First Posted : August 28, 2014
Last Update Posted : June 23, 2021
Sponsor:
Information provided by (Responsible Party):
Karyopharm Therapeutics Inc

Tracking Information
First Submitted Date  ICMJE August 12, 2014
First Posted Date  ICMJE August 28, 2014
Last Update Posted Date June 23, 2021
Actual Study Start Date  ICMJE November 2014
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 17, 2021)
  • Part 1: Overall Response Rate (ORR) [ Time Frame: 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 [ Time Frame: 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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 26, 2014)
Objective Response [ Time Frame: One year ]
Assessed according to the revised response criteria based on the Guidelines of the International Working Group (IWG)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 17, 2021)
  • Part 1: Duration of Response (DOR) [ Time Frame: From time of first response until disease progression or death (maximum of 1 year from Part 1 randomization) ]
  • Part 1: Disease Control Rate (DCR) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: From Baseline up to 30 days after last dose (maximum of 1 year from Part 1 randomization) ]
  • Part 2: Duration of response (DOR) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: From Baseline up to 30 days after last dose (maximum of 1 year from Part 2 randomization) ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Selinexor (KPT-330) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Official Title  ICMJE A Phase 2b Open-label Study of Selinexor (KPT-330) in Patients With Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Diffuse Large B-cell Lymphoma
Intervention  ICMJE
  • Drug: Selinexor
    Dose: 60 mg (BIW); Dosage form: film-coated (20 mg each) immediate release tablets; Route of administration: Oral
    Other Name: KPT-330
  • Drug: Selinexor
    Dose: 40 mg (BIW); Dosage form: film-coated (20 mg each) immediate release tablets; Route of administration: Oral
    Other Name: KPT-330
  • Drug: Selinexor
    Dose: 60 mg (BIW) and 60 mg (QW); Dosage form: film-coated (20 mg each) immediate release tablets; Route of administration: Oral
    Other Name: KPT-330
Study Arms  ICMJE
  • Experimental: Part 1: Selinexor 60 mg
    Participants received fixed dose of 60 mg selinexor orally, twice weekly (BIW) on Days 1 and 3 (e.g., Monday and Wednesday or Tuesday and Thursday, etc.) of Weeks 1-4 of each four week (each cycle of 28 days) cycle (total of 8 doses per cycle).
    Intervention: Drug: Selinexor
  • Experimental: Part 2: Arm A-Selinexor 40 mg
    Participants received selinexor 40 mg orally BIW on Days 1 and 3 of each week of 4-week treatment cycles (28 days) until disease progression (total of 8 doses per cycle).
    Intervention: Drug: Selinexor
  • Experimental: Part 2: Arm B-Selinexor 60 mg
    Participants received selinexor 60 mg orally BIW on Days 1 and 3 of each week of 4-week treatment cycles) for 2 cycles (each cycle of 28 days) followed by 60 mg once weekly (QW) in the subsequent cycles until disease progression (total of 8 doses per cycle).
    Intervention: Drug: Selinexor
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: June 17, 2021)
244
Original Estimated Enrollment  ICMJE
 (submitted: August 26, 2014)
200
Estimated Study Completion Date  ICMJE December 2024
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Austria,   Belgium,   Bulgaria,   Canada,   France,   Germany,   Greece,   Hungary,   India,   Israel,   Italy,   Netherlands,   New Zealand,   Poland,   Serbia,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02227251
Other Study ID Numbers  ICMJE KCP-330-009
2014-001977-15 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Responsible Party Karyopharm Therapeutics Inc
Study Sponsor  ICMJE Karyopharm Therapeutics Inc
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Michael Kauffman, MD, PhD Karyopharm Therapeutics Inc
PRS Account Karyopharm Therapeutics Inc
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP