Selinexor in Advanced Liposarcoma
- Registration Number
- NCT02606461
- Lead Sponsor
- Karyopharm Therapeutics Inc
- Brief Summary
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
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* selinexor, will be withdrawn from further treatment and followed for survival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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 342
- 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
- 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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- CROSSOVER
- Arm && Interventions
Group Intervention Description Phase 2 Double-blinded: Placebo Followed by Open Label- Selinexor Placebo 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. Phase 3 Double-blinded: Placebo Followed by Open Label- Selinexor Placebo 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. Phase 2 Double-blinded: Selinexor Selinexor 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). Phase 3 Double-blinded: Selinexor Selinexor 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.
- Primary Outcome Measures
Name Time Method Phase 3 Double Blind: Progression-free Survival (PFS) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 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) 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.
Phase 3 Open Label: Progression-free Survival (PFS) as Per RECIST Version 1.1 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) 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.
Phase 2 Double Blind: Progression-free Survival (PFS) as Per RECIST Version 1.1 From date of randomization until the first date of PD or death due to any cause, whichever occurred first (up to 57 months) 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.
Phase 2 Open Label: Progression-free Survival (PFS) as Per RECIST Version 1.1 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) 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.
- Secondary Outcome Measures
Name Time Method Phase 3 Open Label: Overall Survival (OS) From date of randomization in phase 3 open label period until death due to any cause, whichever occurred first (up to 70 months) 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.
Phase 2 Double Blind: Overall Survival (OS) From the date of randomization until death due to any cause, whichever occurred first (up to 70 months) 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.
Phase 2 Open Label: Overall Survival (OS) From date of randomization in the Phase 2 open-label period until death due to any cause, whichever occurred first (up to 70 months) 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.
Phase 3 Double Blind: Time-to-Progression (TTP) as Per RECIST Version 1.1 From date of randomization until the first date of PD or death due to any cause, whichever occurred first (up to 70 months) 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.
Phase 3 Open Label: Time-to-Progression (TTP) as Per RECIST Version 1.1 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) 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.
Phase 2 Double Blind: Time-to-Progression (TTP) as Per RECIST Version 1.1 From date of randomization until the first date of PD or death due to any cause, whichever occurred first (up to 70 months) 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.
Phase 2 Open Label: Time-to-Progression (TTP) as Per RECIST Version 1.1 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) 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.
Phase 3 Double Blind: Overall Response Rate (ORR) From date of randomization until the documentation of CR or PR (up to 70 months) 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.
Phase 3 Open Label: Overall Response Rate (ORR) From date of randomization in the Phase 3 open label period until the documentation of CR or PR (up to 70 months) 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.
Phase 2 Double Blind: Overall Response Rate (ORR) From date of randomization until the documentation of CR or PR (up to 70 months) 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.
Phase 2 Open Label: Overall Response Rate (ORR) From date of randomization in the Phase 2 open-label period until the documentation of CR or PR (up to 70 months) 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.
Phase 3 Double Blind: Duration of Response (DOR) From first occurrence of CR or PR until the first date of PD (up to 70 months) 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.
Phase 3 Double Blind: Progression-free Survival (PFS) as Per Investigator Assessment 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) 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.
Phase 3 Double Blind: Time to Next Treatment (TTNT) Time from randomization to the first new antineoplastic therapy or death due to any cause (up to 70 months) TTNT was defined as time since randomization until the first new antineoplastic therapy or death due to any cause, whichever occurs first.
Phase 2 Double Blind: Time to Next Treatment (TTNT) Time from randomization to the first new antineoplastic therapy or death due to any cause (up to 70 months) TTNT was defined as time since randomization until the first new antineoplastic therapy or death due to any cause, whichever occurs first.
Phase 3 Double Blind: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs From start of study drug administration up to 70 months 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.
Phase 3 Open Label: Number of Participants With TEAEs and Serious TEAEs From start of study drug administration up to 70 months 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.
Phase 2 Double Blind: Number of Participants With TEAEs and Serious TEAEs From start of study drug administration up to 70 months 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.
Phase 2 Open Label: Number of Participants With TEAEs and Serious TEAEs From start of study drug administration up to 70 months 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.
Phase 3 Double Blind: Change From Baseline in Quality-of-life Questionnaire 30 Item (QLQ-C30) Baseline up to Day 1387 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).
Phase 3 Open Label: Change From Baseline in Quality-of-life Questionnaire 30 Item (QLQ-C30) Baseline up to Day 379 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).
Phase 3 Double Blind: Overall Survival (OS) From date of randomization until death due to any cause, whichever occurred first (up to 70 months) 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.
Trial Locations
- Locations (71)
Cedars-Sinai Medical Center
🇺🇸Los Angeles, California, United States
Sarcoma Oncology Center
🇺🇸Santa Monica, California, United States
University of Pittsburgh Medical Center (UPMC)
🇺🇸Pittsburgh, Pennsylvania, United States
MD Anderson
🇺🇸Houston, Texas, United States
Rabin Medical Center
🇮🇱Petach Tikva, Israel
Fred Hutchinson Cancer Research Center
🇺🇸Seattle, Washington, United States
Timone University Hospital
🇫🇷Marseille Cedex 5, France
UZ Brussel
🇧🇪Brussels, Belgium
University of Colorado-Denver
🇺🇸Denver, Colorado, United States
Oregon Health and Science
🇺🇸Portland, Oregon, United States
Duke Institute of Cancer
🇺🇸Durham, North Carolina, United States
Vanderbilt
🇺🇸Nashville, Tennessee, United States
Fox Chase Cancer Center
🇺🇸Philadelphia, Pennsylvania, United States
Northwestern Memorial Hospital
🇺🇸Chicago, Illinois, United States
UCL Saint-Luc
🇧🇪Brussels, Belgium
The Ottawa Hospital Cancer
🇨🇦Ottawa, Ontario, Canada
Princess Margaret Hospital
🇨🇦Toronto, Ontario, Canada
The Royal Marsden NHS Foundation Trust
🇬🇧London, United Kingdom
Institut Curie
🇫🇷Paris, France
James Cancer Center, Ohio State University
🇺🇸Columbus, Ohio, United States
University of California, Los Angeles
🇺🇸Los Angeles, California, United States
Stanford University
🇺🇸Stanford, California, United States
Yale Cancer Center
🇺🇸New Haven, Connecticut, United States
Johns Hopkins
🇺🇸Baltimore, Maryland, United States
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Mayo Clinic Rochester
🇺🇸Rochester, Minnesota, United States
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States
University of Michigan
🇺🇸Ann Arbor, Michigan, United States
Columbia University Medical Center
🇺🇸New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Northwell Health Physicians Partners
🇺🇸New York, New York, United States
University of Pennsylvania
🇺🇸Philadelphia, Pennsylvania, United States
UZ Gent
🇧🇪Ghent, Belgium
Cross Cancer Center - Alberta Health Services
🇨🇦Edmonton, Alberta, Canada
McGill University
🇨🇦Montréal, Quebec, Canada
Oscar Lambret Center
🇫🇷Lille Cedex 307, France
Institut Bergonie
🇫🇷Bordeaux,, France
Centre Leon Berard
🇫🇷Lyon Cedex, France
Institut Régional du Cancer de Montpellier (ICM)
🇫🇷Montpellier, France
Institut Claudius Regaud
🇫🇷Toulouse, France
CLCC Antoine Lacassagne
🇫🇷Nice, France
Institut Gustave Roussy
🇫🇷Villejuif, France
Helios Hospital Berlin-Buch
🇩🇪Berlin, Germany
National Center for Tumor Diseases, Univeristy Hospital Heidelberg
🇩🇪Heidelberg, Germany
University Hospital Mannheim
🇩🇪Mannheim, Germany
Technische Universitaet Dresden Med. Fakultaet Carl Gustav Carus Med. Klinik u. Poliklinik I
🇩🇪Dresden, Germany
Soroka University Medical Center
🇮🇱Be'er Sheva, Israel
Sheba Medical Center
🇮🇱Ramat Gan, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Tel Aviv Sourasky Medical
🇮🇱Tel Aviv, Israel
Istituto Nazionale dei Tumori, Milan
🇮🇹Milano, Italy
Candiolo Cancer Institute
🇮🇹Candiolo, Italy
Assaf Harofe Medical Center
🇮🇱Zerifin, Israel
Policlinico Universitario Campus Biomedico
🇮🇹Roma, Italy
U.O.C. Oncologia Medica Oncology Department
🇮🇹Palermo, Italy
"Germans Trias Pujol" University Hospital
🇪🇸Badalona, Spain
Hospital Universitario Clínico San Carlos
🇪🇸Madrid, Spain
Vall d´hebron University Hospital
🇪🇸Barcelona, Spain
Hospital ICO Bellvitge
🇪🇸Barcelona, Spain
Hospital Universitario Virgen Del Rocio
🇪🇸Sevilla, Spain
Hospital La Fe Valencia
🇪🇸Valencia, Spain
Sahlgrenska Universitetssjukhuset
🇸🇪Göteborg, Sweden
Skane University Hospital
🇸🇪Lund, Sweden
Onkologiska Kliniken
🇸🇪Stockholm, Sweden
University College London Hospitals
🇬🇧London, United Kingdom
Cambridge University Hospitals NHS Foundation Trust
🇬🇧Cambridge, United Kingdom
The Christie
🇬🇧Manchester, United Kingdom
Massachusetts General Hospital
🇺🇸Boston, Massachusetts, United States
Klinik und Poliklinik für Innere Medizin III, Hämatologie und Onkologie Klinikum rechts der Isar der TU Muenchen
🇩🇪Muenchen, Germany
Mayo Clinic
🇺🇸Jacksonville, Florida, United States
Hospital Sant Pau Barcelona
🇪🇸Barcelona, Spain