Selinexor in Advanced Liposarcoma

Study Overview
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Brief Summary
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This is a randomized, multicenter, double-blind, placebo-controlled, Phase 2-3 study of patients diagnosed with advanced unresectable dedifferentiated liposarcoma. Approximately 342 total patients will be randomized to study treatment (selinexor or placebo).

Detailed Description
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In the Phase 2 portion of the study, 57 patients were randomized to selinexor (60 mg) or placebo at a 1:1 allocation ratio. In the Phase 3 portion of the study, approximately 285 patients will be randomized to selinexor (60 mg) or placebo with a 2:1 allocation ratio. Patients who progress during the blinded portion of the study will be unblinded and if receiving: placebo, may cross over to open-label selinexor (60mg twice-weekly) selinexor, will be withdrawn from further treatment and followed for survival Study treatment will be given twice-weekly on Day 1 and Day 3 during Weeks 1-6 of each six-week (42 day) cycle until disease progression or intolerability. Treatment will continue until one or more of the following occurs: Disease progression, as defined by RECIST v1.1 Response Criteria Clinical progression, as determined by the treating physician Unacceptable adverse events (AEs) or failure to tolerate study treatment Patient withdrawal Patient discontinuation due to non-compliance

Official Title
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A Phase 2-3, Multicenter, Randomized, Double-blind Study of Selinexor (KPT-330) Versus Placebo in Patients With Advanced Unresectable Dedifferentiated Liposarcoma (DDLS)

Conditions
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Dedifferentiated Liposarcoma

Intervention / Treatment
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* Drug: Selinexor
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥12 years of age Body surface area (BSA) ≥ 1.2 m2 Histologic evidence of DDLS at any time prior to randomization AND current evidence of DDLS requiring treatment Must have measurable disease per RECIST v1.1 Response Criteria Radiologic evidence of disease progression within 6 months prior to randomization. If the patient received other intervening therapy after documented disease progression, further disease progression must be documented after the completion of the intervening therapy Must have had at least 2 prior lines of systemic therapy for liposarcoma (not to exceed 5 prior lines) If patient received any previous systemic therapy, the last dose must have been ≥ 21 days prior to randomization (or ≥ 5 half-lives of that drug, whichever is shorter) with all clinically significant therapy-related toxicities having resolved to ≤ Grade 1 Exclusion Criteria: Patients with pure well-differentiated liposarcoma (WDLS), myxoid/round cell or pleomorphic tumor histologic subtypes Known active hepatitis B (HepB), hepatitis C (HepC) or human immunodeficiency virus (HIV) infection Known central nervous system metastases

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 2 Double-blinded: Selinexor<br>Participants received a fixed blinding dose of 60 milligrams (mg) selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until progressive disease (PD). | Drug: Selinexor<br>* Selinexor 60mg<br>* Other names: KPT-330;|
| Experimental: Phase 3 Double-blinded: Selinexor<br>Participants received a fixed blinding dose of 60 mg selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until PD. | Drug: Selinexor<br>* Selinexor 60mg<br>* Other names: KPT-330;|
| Placebo Comparator: Phase 2 Double-blinded: Placebo Followed by Open Label- Selinexor<br>Participants received a fixed blinding dose of placebo matched to selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until PD in double-blinded treatment period. Participants in the placebo group who had PD during the Phase 2 double-blinded treatment, will be elected to cross over to open-label selinexor. | Drug: Placebo<br> <br> * Other names: sugar pill;|
| Placebo Comparator: Phase 3 Double-blinded: Placebo Followed by Open Label- Selinexor<br>Participants received a fixed blinding dose of placebo matched to selinexor twice-weekly on Day 1 and 3 during each 6-week (42-day) cycle until PD or development of unacceptable toxicity. Participants in the placebo group who had PD during the Phase 3 double-blinded treatment, will be elected to cross over to open-label selinexor. | Drug: Placebo<br> <br> * Other names: sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3 Double Blind: Progression-free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 | PFS was defined as the time from the date of randomization until the first date of Independent Review Committee (IRC)-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the sum of the longest diameter (SLD), taking as reference the smallest sum of the longest diameter (SLD) recorded from baseline or the appearance of 1 or more new lesions. | From the date of randomization until the first date of disease progression, or death due to any cause whichever occurred first (up to 57 months) | 
| Phase 3 Open Label: Progression-free Survival (PFS) as Per RECIST Version 1.1 | PFS was defined as the time from the date of randomization in the Phase 3 open-label period until the first date of IRC-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From the date of randomization in the Phase 3 open label period until the first date of disease progression, or death due to any cause whichever occurred first (up to 57 months) | 
| Phase 2 Double Blind: Progression-free Survival (PFS) as Per RECIST Version 1.1 | PFS was defined as the time from date of randomization until the first date of IRC-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From date of randomization until the first date of PD or death due to any cause, whichever occurred first (up to 57 months) | 
| Phase 2 Open Label: Progression-free Survival (PFS) as Per RECIST Version 1.1 | PFS was defined as the time from date of randomization in the Phase 2 open-label period until the first date of IRC-confirmed PD per RECIST version 1.1, or death due to any cause. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From date of randomization in the Phase 2 open label period until the first date of PD or death due to any cause, whichever occurred first (up to 57 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 3 Double Blind: Overall Survival (OS) | OS was defined as the duration (in months) from the date of randomization to death from any cause. Participants last known to be alive were censored at the date of discontinuation from the study, or database cut date, whichever was earlier. | From date of randomization until death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 3 Open Label: Overall Survival (OS) | OS was defined as the duration (in months) from the date of randomization in the Phase 3 open-label period to death from any cause. Participants last known to be alive were censored at the date of discontinuation from the study, or database cut date, whichever was earlier. | From date of randomization in phase 3 open label period until death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 2 Double Blind: Overall Survival (OS) | OS was defined as the duration (in months) from the date of randomization to death from any cause. Participants last known to be alive were censored at the date of discontinuation from the study, or database cut date, whichever was earlier. | From the date of randomization until death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 2 Open Label: Overall Survival (OS) | OS was defined as the duration (in months) from the date of randomization in the Phase 2 open-label period to death from any cause. Participants last known to be alive were censored at the date of discontinuation from the study, or database cut date, whichever was earlier. | From date of randomization in the Phase 2 open-label period until death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 3 Double Blind: Time-to-Progression (TTP) as Per RECIST Version 1.1 | TTP was defined as the time from date of randomization until ICR-determined PD per RECIST version 1.1, or death due to disease progression, whichever occurred first. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From date of randomization until the first date of PD or death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 3 Open Label: Time-to-Progression (TTP) as Per RECIST Version 1.1 | TTP was defined as the time from date of randomization in the Phase 3 open-label period until ICR-determined PD per RECIST version 1.1, or death due to disease progression, whichever occurred first. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From date of randomization in the Phase 3 open label period until the first date of PD or death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 2 Double Blind: Time-to-Progression (TTP) as Per RECIST Version 1.1 | TTP was defined as the time from date of randomization until ICR-determined PD as per RECIST version 1.1, or death due to disease progression, whichever occurred first. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From date of randomization until the first date of PD or death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 2 Open Label: Time-to-Progression (TTP) as Per RECIST Version 1.1 | TTP was defined as the time from date of randomization in the Phase 2 open-label period until ICR-determined PD per RECIST version 1.1, or death due to disease progression, whichever occurred first. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From date of randomization in the Phase 2 open-label period until the first date of PD or death due to any cause, whichever occurred first (up to 70 months) | 
| Phase 3 Double Blind: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR), per RECIST v.1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of randomization until the documentation of CR or PR (up to 70 months) | 
| Phase 3 Open Label: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieved CR or PR, per RECIST v.1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of randomization in the Phase 3 open label period until the documentation of CR or PR (up to 70 months) | 
| Phase 2 Double Blind: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieved CR or PR, per RECIST v.1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of randomization until the documentation of CR or PR (up to 70 months) | 
| Phase 2 Open Label: Overall Response Rate (ORR) | ORR was defined as the percentage of participants who achieved CR or PR, per RECIST v.1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From date of randomization in the Phase 2 open-label period until the documentation of CR or PR (up to 70 months) | 
| Phase 3 Double Blind: Duration of Response (DOR) | DOR was defined as the time from first occurrence of CR or PR until the first date of PD per RECIST version 1.1 or death. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had reduction in short axis to <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From first occurrence of CR or PR until the first date of PD (up to 70 months) | 
| Phase 3 Double Blind: Progression-free Survival (PFS) as Per Investigator Assessment | PFS was defined as the time from date of randomization until the first date of PD, per RECIST version 1.1, or death due to any cause as defined by the Investigator based on clinical and/or radiologic criteria. PD was defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. | From the date of randomization until the first date of disease progression, or death due to any cause whichever occurred first (up to 70 months) | 
| Phase 3 Double Blind: Time to Next Treatment (TTNT) | TTNT was defined as time since randomization until the first new antineoplastic therapy or death due to any cause, whichever occurs first. | Time from randomization to the first new antineoplastic therapy or death due to any cause (up to 70 months) | 
| Phase 2 Double Blind: Time to Next Treatment (TTNT) | TTNT was defined as time since randomization until the first new antineoplastic therapy or death due to any cause, whichever occurs first. | Time from randomization to the first new antineoplastic therapy or death due to any cause (up to 70 months) | 
| Phase 3 Double Blind: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. A TEAE was defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. | From start of study drug administration up to 70 months | 
| Phase 3 Open Label: Number of Participants With TEAEs and Serious TEAEs | An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. | From start of study drug administration up to 70 months | 
| Phase 2 Double Blind: Number of Participants With TEAEs and Serious TEAEs | An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. | From start of study drug administration up to 70 months | 
| Phase 2 Open Label: Number of Participants With TEAEs and Serious TEAEs | An adverse event was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were defined as those AEs that develop or worsen after the first dose of study drug. TEAEs included both serious and non-serious TEAEs. | From start of study drug administration up to 70 months | 
| Phase 3 Double Blind: Change From Baseline in Quality-of-life Questionnaire 30 Item (QLQ-C30) | The QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of patients with cancer. QLQ-C30 contains 30 questions that include five functional scales (physical, role, emotional, social, and cognitive functioning); three symptom scales (fatigue, nausea/vomiting and pain); six single-item symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties); and global health status/quality of life (QoL). Most questions used a 4-point scale (from 1 'Not at all' to 4 'Very much'); 2 questions used a 7-point scale (from 1 'very poor' to 7 'Excellent'). Scores were averaged and transformed to a 0-100 scale. For the functional scales and the global health status/QoL, a higher score represents a better level of functioning (better health status); for the symptom scales/items, a higher score represents a higher level of symptomatology/problems (worse health status). | Baseline up to Day 1387 | 
| Phase 3 Open Label: Change From Baseline in Quality-of-life Questionnaire 30 Item (QLQ-C30) | The QLQ-C30 is a 30-item questionnaire developed to assess the quality of life of patients with cancer. QLQ-C30 contains 30 questions that include five functional scales (physical, role, emotional, social, and cognitive functioning); three symptom scales (fatigue, nausea/vomiting and pain); six single-item symptom items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties); and global health status/quality of life (QoL). Most questions used a 4-point scale (from 1 'Not at all' to 4 'Very much'); 2 questions used a 7-point scale (from 1 'very poor' to 7 'Excellent'). Scores were averaged and transformed to a 0-100 scale. For the functional scales and the global health status/QoL, a higher score represents a better level of functioning (better health status); for the symptom scales/items, a higher score represents a higher level of symptomatology/problems (worse health status). | Baseline up to Day 379 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced unresectable dedifferentiated liposarcoma, selinexor, KCP-330, Karyopharm, Phase 2 / 3, dedifferentiated liposarcoma, Liposarcoma