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 the disease control rate (DCR…
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Brief title
Condition
- Lymphomas NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy:
Objective disease response assessment will be made according to the revised
criteria for response assessment of lymphoma (Cheson, 2014). The data used for
primary statistical analysis will be provided by the central imaging
laboratory.
The primary endpoint of ORR will be assessed as the ORR of selinexor 60 mg
compared to a minimally effective lower threshold level of ORR of 15%.
* The ORR is defined as the proportion of patients who achieve either CR or PR.
* Progression is defined as the first occurrence of PD per the revised response
criteria. Clinical disease progression in the absence of formal criteria for
PD should be radiographically confirmed whenever possible and must be
comprehensively documented by the treating physician. Patients who have
clinical disease progression in the absence of formal criteria for PD or
radiographical confirmation will be censored at the time of last non-PD
adequate response assessment.
* DOR is defined as the duration of time from first occurrence of CR or PR
until the first date that disease progression is objectively documented
* DCR is defined as the proportion of patients who achieve CR, PR, or SD for a
minimum of 4 weeks, following randomization/enrollment (i.e., ORR + SD)
* PFS is defined as the duration of time from randomization/enrollment until
progression or death due to any cause. A sensitivity analysis will also be
performed for PFS where death will be included if it may be reasonably
attributed to the patient*s underlying DLBCL.
* OS is defined as the duration of time from randomization/enrollment until
death due to any cause. A sensitivity analysis will also be performed for OS
where death will be included if it may be reasonably attributed to the
patient*s underlying DLBCL.
* Each patient*s TTP on selinexor compared with the TTP of his/her most recent
prior therapy. TTP is defined as the duration of time from the date of
randomization/enrollment until the date of progression.
Safety:
The safety and tolerability of selinexor will be evaluated by means of adverse
event (AE) reports, Eastern Cooperative Oncology Group (ECOG) performance
status, physical examinations, electrocardiograms (ECGs), ophthalmic
examinations, concomitant medications, vital signs, and laboratory safety
evaluations.
PK and PDn Assessments:
PK and PDn will be determined at various times following administration of
selinexor.
PK endpoints to be evaluated will include maximum plasma concentration (Cmax)
and time-to-peak plasma concentration.
The PDn endpoints will include:
* Each patient*s DLBCL molecular subtype (GCB or non-GCB) using gene expression
and/or protein profiling, DNA sequencing, and FISH
* Changes in transcripts, or levels, or activation of relevant oncogenes,
phenotype-related proteins, and XPO1 targets
Secondary outcome
See above
Background summary
DLBCL is an aggressive cancer with a median survival of less than 6 months
without treatment. With current immunochemotherapy, 60 to 65% of patients are
progression-free at 2 years, and ~30% of patients with DLBCL are disease-free
at 10 years following initial diagnosis. The remaining patients have a poor
prognosis with disease resistant to available agents, including high-dose
chemotherapy with stem cell transplantation. A very clear unmet medical need
persists for patients with R/R DLBCL.
Selinexor is an orally bioavailable SINE compound that specifically blocks
exportin 1 (XPO1). In Phase 1 studies including patients with heavily
pretreated DLBCL, single agent oral selinexor showed an overall response rate
(ORR) of 32% (41 evaluable patients). Activity was observed in both the GCB
and non GCB subtypes of DLBCL. Patients with response had an improved overall
survival (OS) versus those who had stable disease (SD) or PD (Karyopharm Oral
Lymphoma Presentation, 2015 International Conference on Malignant Lymphoma).
The current study is designed to confirm selinexor activity with R/R DLBCL in
patients who have had at least 2 but no more than 5 previous systemic regimens
and are not eligible for high dose chemotherapy with stem cell rescue at the
time of study entry.
A pre-planned interim futility analysis (that included a total of 63 patients
enrolled on protocol Version 6.0 prior to 01 November 2016 who were eligible
for response evaluation) found the 60 mg dose to have a significantly lower AE
burden with reduced discontinuations due to toxicities, while providing a
central review adjudicated ORR (~28%) equivalent to the higher dose, but with a
longer duration of response (DOR) and longer OS. Based on these results, the
100 mg Arm will be discontinued as of protocol Version 7.0 and the study will
be completed with a single 60 mg Arm based on Food and Drug Administration
feedback provided in March 2017.
Study objective
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 the disease control rate (DCR)
* To assess the safety profile of selinexor
Exploratory Efficacy Objectives:
* To determine the median progression-free survival (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 (complete response [CR] or partial
response [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
Exploratory Pharmacokinetic (PK) and Pharmacodynamic (PDn) Objectives:
PK studies:
* To further describe PK properties of selinexor in patients with R/R DLBCL
PDn studies in peripheral blood and/or tumor biopsies:
* To define each patient*s DLBCL molecular subtype, including GCB or non GCB,
using gene-expression profiling, immunophenotyping, deoxyribonucleic acid (DNA)
sequencing, and fluorescence in situ hybridization (FISH) analysis
* To evaluate messenger ribonucleic acid (mRNA), protein levels, and cellular
localization of tumor suppressor and oncogene proteins as well as
microribonucleic acid (miRNA) following treatment with selinexor, in general,
and as related to response
Study design
This is a multicenter, open-label Phase 2b study of the selective inhibitor of
nuclear export (SINE) selinexor (60 mg) given orally to patients with relapsed
and/or refractory (R/R) diffuse large B cell lymphoma (DLBCL) who have no
therapeutic options of demonstrated clinical benefit.
The primary analysis population will include all patients who meet eligibility
criteria and who were assigned to the 60-mg Arm under protocol Version *6.0
(for those enrolled under protocol Version 7.0 or higher, patients must also
receive at least 1 dose of selinexor). This population consists of ~130
patients with R/R DLBCL.
DLBCL histology, DLBCL subtype (germinal center B-cell [GCB] or non-GCB), and
*double hit* DLBCL (DH-DLBCL) status will be confirmed/determined in all
patients.
It is planned that at least 50% of the ~130 patients will have the GCB subtype
of DLBCL. The remaining patients may have DLBCL of either the GCB or the
non-GCB subtype.
Patients will be treated with a fixed milligram dose of 60 mg selinexor orally
twice weekly (BIW).
Study site personnel will provide all scans performed for disease assessment
during the study to the central imaging laboratory and all radiology reports to
Karyopharm Therapeutics Inc. (Karyopharm).
The central imaging laboratory will review all scans performed for disease
assessment during the study, to independently assess disease response and time
of progressive disease (PD).
Patients should remain on study treatment until the assessment of PD from the
central imaging laboratory has been obtained (unless medically
contraindicated).
* Patients who have PD confirmed by the central imaging laboratory will
discontinue study treatment and be followed for survival.
For patients with progression of disease on imaging assessment, if
disease progression is not clearly unequivocal and/or the patient is
clearly deriving clinical benefit, after discussion with the Karyopharm Medical
Monitor, the Investigator may elect to continue the patient on study and repeat
imaging within 4 to 8 weeks for confirmation or negation of PD.
* Patients who have PD assessed by the treating physician that is not confirmed
by the central imaging laboratory should remain on study treatment (unless
medically contraindicated). If the treating physician decides to discontinue
these patients from study treatment, they will discontinue study treatment and
be followed for survival.
Previous Protocol Versions
Protocol Versions *3.0 required administration of selinexor in conjunction with
lowdose dexamethasone (12 mg with each dose of selinexor). As of Version 4.0,
dexamethasone is no longer required to be given in conjunction with selinexor.
In addition, the inclusion criteria were updated in protocol Version 6.0. In
protocol
Versions 7.0 and higher, the inclusion criteria were further updated and the
high (100 mg) dose Arm was removed. Details for the statistical analysis of the
various protocol populations are provided in the Statistical Methods
subsection.
Intervention
Selinexor will be given at an oral fixed milligram (mg) dose of 60 mg on Days 1
and 3 (e.g., Monday and Wednesday or Tuesday and Thursday, etc.) of Weeks 1 to
4 of each 4 week cycle (total of 8 doses per cycle).
Patients who achieve a partial remission or better will transition to
maintenance dosing. The maintenance dose of selinexor will be 60 mg orally QW.
Patients whose dose has been reduced such that the total weekly dose is <60 mg
will continue on that tolerated dose. If a patient experiences a subsequent
increase in disease burden, or per the discretion of the PI, the dose of
selinexor can be increased to 60 mg orally BIW, after
discussion with the Medical Monitor.
Patients treated under Versions 2.0 to 6.0 of the protocol may have been
randomized to the 100 mg Arm in which selinexor may have been given at an oral
fixed milligram (mg) dose of 100 mg on Days 1 and 3 (e.g., Monday and Wednesday
or Tuesday and Thursday, etc.) of Weeks 1 to 3 (Versions 2.0 to 4.0) or Weeks 1
to 4 (Versions 5.0 and 6.0) of each 4-week cycle (total of 8 doses per cycle).
The 100 mg Arm has been removed in Version 7.0.
Patients randomized to the 100 mg Arm on earlier versions of the protocol and
still on treatment at doses >60 mg BIW (i.e., 120 mg selinexor per week) will
have their dosing regimen immediately decreased to a maximum dose of 120 mg per
week. If, in the opinion of the Investigator, the patient*s dose should not be
immediately reduced, continuation of a dose > 60 mg BIW (> 120 mg per week)
will only be allowed after approval by the Karyopharm Medical Monitor.
Study burden and risks
Very common side effects (*10%): In 100 people receiving selinexor more than 10
people may have:
Nausea
Vomiting
Diarrhea
Decreased appetite
Hyponatremia * low sodium
Dehydration
Vision Blurred
Thrombocytopenia * decrease in platelets, which help your blood clot
Anemia * decrease in red blood cells
Neutropenia * decrease in neutrophils * a specific type of white blood cell
that helps fight infections
Leukopenia * decrease in white blood cells
Fatigue
Weight decrease
Dysgeusia * change in taste
Dizziness
Constipation
Dyspnea * shortness of breath
Asthenia * loss of energy; weakness
Common side effects (*1-10%): In 100 people receiving selinexor about 1 to 10
people may have:
Dry mouth
Blood Creatinine Increased * increase of creatinine in the blood due to a
reduction in kidney function, often related to dehydration
Worsening of pre-existing cataracts
Febrile neutropenia * Fever in the absence of a normal white blood cell
response that may mean you have an infection
Syncope * fainting
Confusion
Pneumonia
Sepsis * potentially life-threatening complication of an infection
Cognitive disorder
Uncommon side effects (>0.1-1%): In 1,000 people receiving selinexor about 1 to
10 people may have:
Altered behavior
Tumor lysis syndrome * potentially a life-threatening side effect caused by the
rapid breakdown of tumor cells and may cause irregular heartbeat, kidney
failure or abnormal blood test results which included elevated uric acid level,
elevated serum potassium and phosphorus levels, and a decreased calcium level
Rare side effects (>0.01-0.1%):In 10,000 people receiving selinexor about 1 to
10 people may have:
Acute cerebellar syndrome * symptoms can include a sudden loss of coordination,
balance, or slurred speech
Serious adverse effects: *3 cases reported as related by the principal
investigator:
Acute kidney injury
Aspartate aminotransferase increased * elevated liver enzyme level
Bacteremia * bacterial infection in the blood
Delirium * state of acute confusion
Encephalopathy * brain disease, damage, or malfunction, which can present
different symptoms that range from mild, such as some memory loss or subtle
personality changes, to severe, such as dementia, seizures, or coma.
General physical health deterioration
Hyperglycemia * elevated blood sugar level
Hypotension * low blood pressure
Pulmonary embolism * pulmonary embolism occurs when a clump of material, most
often a blood clot, gets wedged into an artery in your lungs.
Pyrexia * fever
Septic shock
Upper respiratory tract infection
Wells Avenue 85
Newton MA 02459
US
Wells Avenue 85
Newton MA 02459
US
Listed location countries
Age
Inclusion criteria
Patients, age *18 years, with pathologically confirmed or transformed DLBCL whose disease is R/R, with documented evidence of disease progression (according to the revised criteria for response assessment of lymphoma (Cheson, 2014) and who in the opinion of the Investigator are not candidates for high-dose chemotherapy with autologous stem cell rescue, may be considered for enrollment. If the patient*s most recent systemic anti DLBCL therapy induced a PR or CR, at least 60 days must have elapsed since the end of that therapy; otherwise at least 14 weeks (98 days) must have elapsed since the end of their most recent systemic anti-DLBCL therapy. Patients must have received at least 2 but no more than 5 previous systemic regimens for the treatment of their DLBCL including 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 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 (but no more than 5) previous systemic 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. Patients should have an estimated life expectancy of more than 3 months at study entry.
Exclusion criteria
Patients with DLBCL with mucosa-associated lymphoid tissue [MALT] lymphoma, composite lymphoma (Hodgkin*s lymphoma [HL]+ non-Hodgkin*s lymphoma [NHL]), or DLBCL transformed from diseases other than indolent NHL are excluded from this study. Primary mediastinal (thymic) large B-cell lymphoma (PMBL) and central nervous system lymphoma are excluded. Patients must not be eligible for high-dose chemotherapy with autologous stem cell transplantation and documentation for ineligibility must be provided. Patients with hemoglobin <10.0 g/dL, a circulating lymphocyte count >50,000/*L, or who have had a red blood cell transfusion within 14 days prior to and including Cycle 1 Day 1 are excluded.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2014-001977-15-NL |
| ClinicalTrials.gov | NCT02227251 |
| CCMO | NL56132.029.16 |