A Phase 2b Open-label, Randomized Two-arm Study Comparing High and Low Doses of Selinexor (KPT-330) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Jason R. Westin
The goal of this clinical research study is to compare 2 doses of KPT-330 when given to patients with (diffuse large B-cell lymphoma) DLBCL. The safety of this drug will also be studied.
Disease Group: Lymphoma
Treatment Agent: KPT-330
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Karyopharm Therapeutics, Inc.
PRIMARY OBJECTIVE • To evaluate the efficacy of selinexor 100 mg (High-Sel) and selinexor 60 mg (Low-Sel) in comparison to a minimally effective lower threshold level of overall response rate (ORR) of 20% and to compare ORR between High-Sel and Low-Sel in patients with relapsed/refractory DLBCL SECONDARY OBJECTIVES • To determine duration of response (DOR) for each dose level • To assess the safety profiles of the High-Sel and Low-Sel regimens • To compare the disease control rate (DCR) of patients with relapsed/refractory DLBCL, treated with High-Sel versus Low-Sel EXPLORATORY EFFICACY OBJECTIVES • To make a preliminary comparison of the median progression-free survival (PFS) and median overall survival (OS) of patients with relapsed/refractory DLBCL, treated with High-Sel versus Low-Sel • To make a preliminary comparison of PFS, ORR, DOR, DCR, QoL and OS obtained with High-Sel versus Low-Sel, and with combined High-Sel and Low-Sel, in patients with germinal center B-cell (GCB) versus non-germinal center (non-GCB) DLBCL • To compare Quality of Life (QoL) in patients treated with High-Sel versus Low-Sel using 1) the Functional Assessment of Cancer Therapy – Lymphoma (FACT-Lym) questionnaire and 2) the EQ-5D-5L Health Questionnaire • To make a preliminary comparison of PFS, ORR, DOR, DCR, QoL, and OS of High-Sel versus Low-Sel in patients with “double hit” DLBCL (DH-DLBCL) including translocations identified by cytogenetic analysis during study screening or overexpression of both MYC and BCL2 or BCL6, and in patients with non-DH- DLBCL • To make a preliminary comparison of PFS, ORR, DOR, DCR, QoL, and OS of High-Sel versus Low-Sel in patients with “very good”, “good”, and “poor” Revised International Prognostic Index (R-IPI) • To compare each patient’s time to progression (TTP) on selinexor with the TTP of his/her most recent prior therapy EXPLORATORY PK AND PDn OBJECTIVES PK Studies • To further describe PK properties of selinexor in patients with relapsed/refractory DLBCL treated with High-Sel and Low-Sel PDn Studies in Peripheral Blood and/or Tumor Biopsies • To define each patient’s molecular DLBCL subtype (GCB or non-GCB) using gene-expression profiling. • To evaluate mRNA, protein levels, and cellular localization of tumor suppressor and oncogene proteins as well as miRNA following treatment with selinexor, in general, and as related to response.
IRB Review and Approval Date: 11/26/2014
Recruitment Status: Open
Projected Accrual: 200
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) Eastern Cooperative Oncology Group (ECOG) performance status of </= 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 one 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 one 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 two and no more than five prior treatment regimens including at least one 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) At least 14 weeks must have elapsed since the most recent systemic anti-DLBCL therapy. Palliative localized radiation therapy within 14 weeks is allowed. Non-chemotherapy maintenance therapy within 14 weeks is allowed.
8) Documented clinical or radiographic evidence of progressive DLBCL prior to dosing.
9) Patients must have measurable disease per IWG criteria (Cheson 2007). 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 progressive disease.
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 three 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 three months following the last dose
1) Patients who are pregnant or lactating
2) DLBCL with mucosa-associated lymphoid tissue [MALT] lymphoma, composite lymphoma (HL+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 (CNS) lymphoma or meningeal involvemen
6) Radiation, chemotherapy, immunotherapy, radio-immunotherapy or any other anticancer therapy other than glucocorticoids < 14 weeks prior to Cycle 1 Day 1. Palliative localized irradiation or non-chemotherapy maintenance therapy within 14 weeks is allowed. Patients who have recovered to Grade </=1 or to their baseline from clinically significant adverse effects are allowed.
7) 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
8) Major surgery within 2 weeks of first dose of study drug
9) Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient’s safety
10) Unstable cardiovascular function: * Symptomatic ischemia, or * Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on anti-arrhythmia are excluded; 1st degree AV block or asymptomatic left anterior fascicular block (LAFB)/ right bundle branch block (RBBB) will not be excluded), or * Congestive heart failure (CHF) of NYHA Class >/=3, or * Myocardial infarction (MI) within 3 months
11) Uncontrolled (i.e., clinically unstable) infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; however, prophylactic use of these agents is acceptable even if parenteral
12) Active Hepatitis B or Hepatitis C infection
13) Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study)
14) Patients unable to swallow tablets, patients with malabsorption syndrome, or any other gastrointestinal (GI) disease or GI dysfunction that could interfere with absorption of study treatment
15) Any of the following laboratory abnormalities: Absolute neutrophil count (ANC) <1000 cells/mm^3 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 aspartic 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); Mass (kg)/(72 creatinine mg/dL); multiply by 0.85 if female].
16) Patients with a body surface area (BSA) < 1.4 m^2 as calculated per Dubois 1916 or Mosteller 1987
17) Persons who have been committed to an institution by official or judicial order.
18) Patients with dependency on the sponsor, investigator or study site.
Information and next steps
Jason R. Westin
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