Selinexor (KPT-330) in Older Patients With Relapsed AML
- Conditions
- Acute Myeloid Leukemia (AML)
- Interventions
- Registration Number
- NCT02088541
- Lead Sponsor
- Karyopharm Therapeutics Inc
- Brief Summary
This is a randomized, multicenter, open-label, phase 2 study of the SINE compound, selinexor given orally versus specified investigator choices (one of three potential salvage therapies). Participants age ≥ 60 years with relapsed or refractory AML of any type except for AML M3, after one prior therapy only, who have never undergone and who are not currently eligible for stem cell transplantation and are currently deemed unfit for intensive chemotherapy.
- Detailed Description
This is a randomized, multicenter, open-label phase 2 study of the SINE compound, selinexor given orally versus restricted investigator choice (i.e., one of three potential salvage therapies).
Participants who have never been transplant eligible, are currently deemed unfit for intensive chemotherapy, ≥ 60 years old, who have AML (except Acute Promyelocytic Leukemia: APL, AML M3) after one prior treatment of either hypomethylating agent or a regimen including Ara-C, and are meeting the inclusion and exclusion criteria will be randomized to receive either oral selinexor or physician's choice (one of three potential treatments: best supportive care (BSC) alone, or BSC + hypomethylating agent, or BSC + low dose Ara-C until disease progression, death or intolerance has occurred.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 317
- Age ≥ 60 years with relapsed or refractory AML of any type except for acute promyelocytic leukemia (APL; AML M3), after at least 1 prior AML therapy , who have never undergone, and who are not currently eligible for, stem cell transplantation, and are currently deemed unfit for intensive chemotherapy.
- Eastern Cooperative Oncology Group (ECOG) ≤ 2.
- Must have available archival or recently acquired bone marrow biopsy/aspiration or tumor tissue for central review to be eligible.
- Relapsed or refractory AML, defined as either: recurrence of disease after a complete remission (CR), or failure to achieve CR with initial therapy.
- Must have received at least 1 prior line of AML therapy given at standard doses and must have progressed after their most recent therapy. Prior therapy must have included: a hypomethylating agent with at least 2 cycles.
- At least 2 weeks must have elapsed since the last anti-leukemia treatment (with the exception of hydroxyurea) before first dose in this study.
- Treatment with any investigational agent within 3 weeks prior to first dose in this study.
- Presence of central nervous system (CNS) leukemia.
- In blast transformation of chronic myeloid leukemia (CML). Prior myelodysplastic syndrome (MDS) is acceptable; prior treatment for MDS does not count as an AML therapy.
- Major surgery within 2 weeks of first dose of study drug. Participants must have recovered from the effects of any surgery performed greater than 2 weeks previously.
- Concurrent active malignancy under treatment.
- Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).
- Known HIV infection.
- Unable to swallow tablets, or participants with malabsorption syndrome, or any other disease significantly affecting gastrointestinal function.
- Participants whose AML is classified as favorable according to the European LeukemiaNet (ELN) disease risk assessment.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Selinexor approximately 55 mg/m^2 (60 to 120 mg based on BSA) Selinexor Participants under protocol versions (PV) less than (\<) 5.0 (those who had one prior line of acute myeloid leukemia (AML) therapy), receive oral selinexor tablets at a dose of approximately 55 mg/m\^2 (milligrams per square meter) (60 to 120 mg based on body surface area \[BSA\]) twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). Selinexor 60 mg (PV <5) (Equivalent to 35 mg/m^2) Selinexor Participants under PV \< 5.0 (those who had one prior line of AML therapy), receive oral selinexor tablets at a fixed dose of 60 mg (equivalent to 35 mg/m\^2), based on BSA, twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). Selinexor 60 mg (PV >=5) (Equivalent to 35 mg/m^2) Selinexor Participants under PV \>= 5 (PV 5: those who had at least one prior line of AML therapy, PV 5.1: who had at least two prior line of AML therapy), receive oral selinexor tablets at a dose of 60 mg (equivalent to 35 mg/m\^2) twice weekly, on Day 1 and 3 of each week of 4-week cycle (28 days per cycle). Physician's Choice 2 (PV >=5) Ara-C Participants under PV \>= 5 (PV 5: those who had at least one prior line of AML therapy, PV 5.1: who had at least two prior line of AML therapy), received BSC along with subcutaneous injection of arabinoside cytosine (Ara-C), 20 mg, twice daily, for 10 days, repeated at 28 to 42 day intervals. Physician's Choice 1 (PV <5) Hydroxyurea Participants under PV \< 5.0 (those who had one prior line of AML therapy) received Best Supportive Care (BSC) which included blood product transfusions, antimicrobials, growth factors as needed, and hydroxyurea.
- Primary Outcome Measures
Name Time Method Overall Survival Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) Overall survival was defined as the time (in days) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact.
- Secondary Outcome Measures
Name Time Method Duration of Disease Control Rate Up to 4 weeks from the date of randomization to the date of progression or recurrence based on IWG criteria Duration of DCR calculated for all participants with DCR. CR: \< 5% myeloblasts in BM, absence of circulating blasts, hematologic recovery (peripheral blood ANC \>1000 cells/microL and platelet count \> 100,000/microL, no need for RBC transfusions), absence of extra medullary disease. PR: No circulating blasts, Neutrophil count \>=1.0 x 10\^9/L, Platelet count \>= 100 x 10\^9/L, \>= 50 % reduction in BM blast to 6% to 25%, or blasts \<= 5% if Auer rods are present. CRp: All criteria for CR except for residual neutropenia (\<1 x 10\^9/L) or thrombocytopenia (\<100 x 10\^9/L), CRi; \< 5% BM blasts with residual neutropenia \[ANC \< 1000 cells/microL\] or thrombocytopenia \[platelets \< 100,000/microL\]. MLFS; morphologic BM blast clearance to \< 5% in a marrow sample in which \<=200 cells enumerated/cellularity is \>= 10%, in absence of blasts with Auer rods, no hematologic recovery required and SD; failure to achieve a response but not meeting criteria for disease progression over period of \> 4 weeks.
Median Disease-Free Survival (DFS) for Participants Who Achieved Complete Remission (CR) Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) DFS for CRR based on IWG criteria, was calculated from the first date of response of CR to the date of progression or recurrence, or date of death if progression or recurrence did not occur. Participants who discontinued prior to disease progression or recurrence or did not progress as of the time of the analysis were censored at the time of last radiologic assessment. CR per IWG 2003 criteria was defined as morphologic presence of \< 5 % myeloblasts in bone marrow, the absence of circulating blasts, hematologic recovery (as evidenced by a peripheral blood ANC \> 1000 cells/microL and platelet count \> 100,000/microL, with no need for RBC transfusions), and the absence of extramedullary disease.
Percentage of Participants With Modified Complete Remission Rate (mCRR) for Those Who Achieved Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (Cri) Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) mCRR was defined as the point estimate of the percentage of participants who had CR, CRi, or CRp. Responses defined as per IWG 2003 response criteria: Morphologic CR:\< 5% myeloblasts in bone marrow, the absence of circulating blasts, hematologic recovery (as evidenced by a peripheral blood ANC \> 1000 cells/microL and platelet count \> 100,000/microL, with no need for RBC transfusions), and the absence of extramedullary disease. Morphologic CRp: All criteria for CR except for residual neutropenia (\<1x10\^9/L) or thrombocytopenia (\<100 x10\^9/L), Cri (\< 5% bone marrow blasts with residual neutropenia \[ANC \< 1000 cells/microL\] or thrombocytopenia \[platelets \< 100,000/microL\]), normal maturation of all cellular components in the bone marrow, no extramedullary disease and transfusion independent.
Median Disease-Free Survival (DFS) for Participants Who Achieved Complete Remission or CR With Incomplete Hematologic Recovery (CRi) or Complete Remission With Incomplete Platelet Recovery (CRp) Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) DFS based on IWG criteria was defined as the duration from start of the complete response achieved until disease progression or death from any cause. Responses defined by IWG 2003 Response Criteria: Morphologic CR: \< 5% myeloblasts in bone marrow, the absence of circulating blasts, hematologic recovery (as evidenced by a peripheral blood ANC \> 1000 cells/microL and platelet count \> 100,000/microL, with no need for RBC transfusions), and the absence of extramedullary disease. Morphologic CRp: All criteria for CR except for residual neutropenia (\<1x10\^9/L) or thrombocytopenia (\<100 x10\^9/L), Cri (\< 5% bone marrow blasts with residual neutropenia \[ANC \< 1000 cells/microL\] or thrombocytopenia \[platelets \< 100,000/microL\]), normal maturation of all cellular components in the bone marrow, no extramedullary disease and transfusion independent.
Percentage of Participants With Overall Survival of at Least 3 Months (OS3.0) From randomization (Day 1) up to 3 months Overall survival was defined as the time (in days) from the date of randomization to the date of death due to any cause. Participants last known to be alive were censored at date of last contact. Analysis was performed using Kaplan-Meier method.
Percentage of Participants With Complete Remission Rate (CRR) for Those Who Achieved Complete Remission (CR) Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) CRR was analyzed using International Working Group (IWG) 2003 criteria, as the difference in the proportions of participants with IWG results of CR. CR per IWG 2003 criteria was defined as morphologic presence of \< 5 percentage (%) myeloblasts in bone marrow, the absence of circulating blasts, hematologic recovery (as evidenced by a peripheral blood absolute neutrophil count (ANC) \> 1000 cells/microliter (microL) and platelet count \> 100,000/microL, with no need for red blood cell (RBC) transfusions), and the absence of extramedullary disease.
Change From Baseline in European Quality of Life-5 Dimension (EQ-5D) Health Questionnaire Visual Analogue Scale (VAS) Baseline, Day 1 of each treatment cycle (a maximum of 20 cycles: 28 days per cycle) up to 30 days after last dose of study drug (final visit) EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: 1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems. EQ-5D-5L is a standardized instrument that measures health-related quality of life for men with prostate cancer. EQ-5D consists of EQ-5D descriptive system and EQ VAS. EQ-5D-5-VAS records participant's self-rated health on a vertical VAS that allows them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable), higher scores indicating a better health state.
Percentage of Participants With Overall Response Rate (ORR) Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) Overall response rate was defined as the point estimate of the percentage of participants who achieved CR (disappearance of all target and non-target lesions), partial response (PR) (\>=30 % decrease in sum of longest diameters of target lesions taking as reference baseline sum longest diameters associated to non-progressive disease response for non-target lesions). CRi; \< 5% BM blasts with residual neutropenia \[ANC \< 1000 cells/microL\] or thrombocytopenia \[platelets \< 100,000/microL\]. CRp; All criteria for CR except for residual neutropenia (\<1x10\^9/L) or thrombocytopenia (\<100 x10\^9/L) and morphologic leukemia-free state (MLFS); morphologic BM blast clearance to \<5% in a marrow sample in which \<=200 cells enumerated or cellularity is ≥10%, in absence of blasts with Auer rods, no hematologic recovery required.
Duration of Response (DOR) Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks) DOR was calculated from date of response of CR, CRi, CRp, MLFS, or PR to date of progression or recurrence based on IWG criteria. CR: \<5% myeloblasts in bone marrow,absence of circulating blasts, hematologic recovery (peripheral blood ANC \>1000 cells/microL, platelet count \> 100,000/microL, no need for RBC transfusions), absence of extramedullary disease. PR: No circulating blasts, neutrophil count \> =1.0 x10\^9/L, platelet count \>= 100 x10\^9/L, \>= 50 % reduction in bone marrow blast to 6% to 25%, or blasts less than or equal to (\<=) 5% if Auer rods are present. CRp: All criteria for CR except for residual neutropenia (\<1x10\^9/L) or thrombocytopenia (\<100 x10\^9/L), CRi; \< 5% bone marrow blasts with residual neutropenia \[ANC \< 1000 cells/microL\] or thrombocytopenia \[platelets \< 100,000/microL\]. MLFS: morphologic bone marrow blast clearance to \< 5% in marrow sample, \<= 200 cells enumerated/cellularity is ≥ 10%, in absence of blasts with Auer rods, no hematologic recovery required.
Percentage of Participants With Disease Control Rate (DCR) Up to 4 weeks from the date of randomization to the date of progression or recurrence based on IWG criteria DCR:Point estimate of % of participants with CR,CRi,CRp,MLFS,PR, or SD for \<=4 weeks.CR:\<5% myeloblasts in bone marrow (BM),absence of circulating blasts,hematologic recovery(peripheral blood ANC \>1000 cells/microL and platelet count \>100,000/microL, no need of RBC transfusions),absence of extramedullary disease. PR:No circulating blasts,Neutrophil count \>=1.0 x10\^9/L, Platelet count \>= 100\*10\^9/L, \>=50% reduction in BM blast to 6% to 25%, or blasts \<=5% if Auer rods are present.CRp:All criteria for CR except for residual neutropenia (\<1\*10\^9/L) or thrombocytopenia(\<100 x10\^9/L),CRi;\< 5% BM blasts with residual neutropenia \[ANC \< 1000 cells/microL\] or thrombocytopenia \[platelets \< 100,000/microL\]. MLFS:morphologic BM blast clearance to \<5% in a marrow sample in which \<=200 cells enumerated or cellularity is ≥10%,in absence of blasts with Auer rods,no hematologic recovery required,SD:failure to achieve a response but not meeting criteria for disease progression over period of \>4 weeks.
Change From Baseline in Quality of Life (QoL) and Patient-Reported Outcomes (Functional Assessment of Cancer Therapy -Leukemia [FACT-Leu] Baseline, Day 1 of each treatment cycle (a maximum of 20 cycles: 28 days per cycle) up to 30 days after last dose of study drug (final visit) QoL was assessed by the FACT-Leu. FACT-Leu combines the General version of the Functional Assessment of Cancer Therapy (FACT-G) with a leukemia-specific sub-scale (17 items). The sub-scales for the FACT-G are Physical Well-Being (7 items), Social/Family Well-Being (7 items), Emotional Well-Being (6 items), and Functional Well-Being (7 items). The trial outcomes index (TOI; total of 31 items) was the primary measurement of interest, comprising the Physical and Functional sub-scales plus the leukemia - specific sub-scale. Each item was rated on a 5-point Likert scale. Range from 0 = (Not at all) to 4 = (Very much); therefore, the TOI had a score ranging from 0 to 124. Higher scores indicated improvement in well being. The QoL assessment was performed at baseline (prior to first dose of study treatment), Day 1 of each cycle on or after the second, and at the final visit.
Trial Locations
- Locations (78)
Jonsson Comprehensive Cancer Center / University of California, Los Angeles
🇺🇸Los Angeles, California, United States
VU University Medical Center
🇳🇱Amsterdam, Netherlands
Colorado Blood Cancer Institute/Sarah Cannon Research Institute
🇺🇸Denver, Colorado, United States
AOU Ospedali Riuniti di Ancona
🇮🇹Ancona, Italy
Aarhus University Hospital
🇩🇰Aarhus, Denmark
Herlev Hospital
🇩🇰Herlev, Denmark
Sutter Oncology & Hematology
🇺🇸Sacramento, California, United States
Winship Cancer Institute / Emory University
🇺🇸Atlanta, Georgia, United States
Yale Cancer Center / Yale University
🇺🇸New Haven, Connecticut, United States
H. Lee Moffitt Cancer Center and Research Institute
🇺🇸Tampa, Florida, United States
Stanford Cancer Institute / Stanford University
🇺🇸Stanford, California, United States
Northwestern University
🇺🇸Chicago, Illinois, United States
University of Chicago Medicine
🇺🇸Chicago, Illinois, United States
University of Kansas Hospital
🇺🇸Kansas City, Kansas, United States
University of Michigan Comprehensive Cancer Center
🇺🇸Ann Arbor, Michigan, United States
Westchester Medical Center / New York Medical College
🇺🇸Hawthorne, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Roswell Park Cancer Institute
🇺🇸Buffalo, New York, United States
Sidney Kimmel Comprehensive Cancer Center / John Hopkins University
🇺🇸Baltimore, Maryland, United States
New York Presbyterian Hospital / Weill Cornell Medical College
🇺🇸New York, New York, United States
Gabrail Cancer Center
🇺🇸Canton, Ohio, United States
Ohio State University Comprehensive Cancer Center
🇺🇸Columbus, Ohio, United States
Milton S. Hershey Medical Center / Penn State
🇺🇸Hershey, Pennsylvania, United States
Texas Transplant Institute/Sarah Cannon Research Institute
🇺🇸San Antonio, Texas, United States
MD Anderson Cancer Center / University of Texas
🇺🇸Houston, Texas, United States
Tennessee Oncology/Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
University of Alberta
🇨🇦Edmonton, Alberta, Canada
Vanderbilt-Ingram Cancer Center / Vanderbilt University
🇺🇸Nashville, Tennessee, United States
Sir Mortimer B. Davis Jewish General Hospital / McGill University
🇨🇦Montreal, Quebec, Canada
Odense University Hospital, Department of Hematology
🇩🇰Odense, Denmark
Department of Haematology, National University Hospital, Rigshospitalet
🇩🇰Copenhagen, Denmark
Centre Hospitalier Lyon
🇫🇷Lyon, France
CHU Bordeaux- Hôpital Haut Lévêque
🇫🇷Bordeaux, France
Hôpital Avicenne
🇫🇷Paris, France
Hopital Saint Louis
🇫🇷Paris, France
Stellvertretende Klinikleiterin Charité, Campus Benjamin Franklin
🇩🇪Berlin, Germany
Institut Universitaire du Cancer Toulouse
🇫🇷Toulouse, France
UNIVERSITÄTSKLINIKUM TU DRESDEN Medizinische Klinik und Poliklinik I,
🇩🇪Dresden, Germany
Ev. Diakonie-Krankenhaus Gemeinnutzige GMBH Medizinische Klinik 2
🇩🇪Bremen, Germany
Sororka MC
🇮🇱Beer Sheva, Israel
Hadassah Medical Center
🇮🇱Jerusalem, Israel
Abteilung Hämatologie, internistische Onkologie und Hämostaseologie
🇩🇪Leipzig, Germany
University Hospital Frankfurt
🇩🇪Frankfurt, Germany
Medizinische Hochschule Hannover (Hannover Medical School) Dept. of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation
🇩🇪Hanover, Germany
UNIVERSITY HOSPITAL OF MÜNSTER Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster
🇩🇪Münster, Germany
Universitätsklinikum Ulm
🇩🇪ULM, Germany
Wolfson Medical Center
🇮🇱Holon, Israel
Rambam Health Care Campus
🇮🇱Haifa, Israel
Tel Aviv Sourasky Medical Centre
🇮🇱Tel Aviv, Israel
AMC, Academisch Medisch Centrum Afdeling Klinische Hematologie
🇳🇱Amsterdam, Netherlands
Chaim Sheba Medical Center
🇮🇱Tel Hashomer, Israel
A.O Spedali Civili di Brescia
🇮🇹Brescia, Italy
AORN Cardarelli / UOSC di Ematologia con TMO
🇮🇹Naples, Italy
Radboud University Medical Center Department of Haematology (476)
🇳🇱Nijmegen, Netherlands
Universitair Medisch Centrum Groningen Department of Haematology
🇳🇱Groningen, Netherlands
Erasmus MC, location Daniel den Hoed
🇳🇱Rotterdam, Netherlands
Isala Kliniecken Zwolle
🇳🇱Zwolle, Netherlands
Wojewódzki Szpital Specjalistyczny im. M. Kopernika, Klinika Hematologii
🇵🇱Lodz, Poland
Samodzielny Publiczny Zakład Opieki Zdrowotnej Ministerstwa Spraw Wewnętrznych
🇵🇱Olsztyn, Poland
Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wrocławiu
🇵🇱Wroclaw, Poland
ICO Badalona
🇪🇸Badalona, Spain
Hospital Universitario de Salamanca Servicio de Hematologia
🇪🇸Salamanca, Spain
Hospital Universitario y Politécnico La Fe
🇪🇸Valencia, Spain
Hospital del Mar
🇪🇸Barcelona, Spain
Northwick Park Hospital
🇬🇧Harrow, England, United Kingdom
Royal Marsden NHS Trust
🇬🇧Sutton, Surrey, United Kingdom
Royal Liverpool University Hospital, Dept of Cellular and Molecular Physiology, Molecular and Clinical Cancer Medicine
🇬🇧Liverpool, Lancashire, United Kingdom
University Hospital Wales
🇬🇧Cardiff, Wales, United Kingdom
Hull and East Yorkshire Hospitals NHS Trust Queens Centre for Oncology and Haematology
🇬🇧Hull, Yorkshire, United Kingdom
Ninewells Hospital and Medical School NHS Tayside
🇬🇧Dundee, United Kingdom
Plymouth Hospitals NHS Trust/Derriford Hospital
🇬🇧Plymouth, United Kingdom
University of Massachusetts Medical School
🇺🇸Worcester, Massachusetts, United States
Instytut Hematologii i Transfuzjologii
🇵🇱Warszawa, Poland
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Rabin Medical Center
🇮🇱Petach Tikva, Israel
Duke Cancer Care
🇺🇸Durham, North Carolina, United States
Tom Baker Cancer Centre
🇨🇦Calgary, Alberta, Canada
University Medical Center Utrecht
🇳🇱Utrecht, Netherlands