Selinexor (KPT-330) in Older Patients With Relapsed AML

Acute Myeloid Leukemia (AML) Clinical Trial

— SOPRA  

Official title:

A Randomized, Open Label, Phase 2 Study of the Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Versus Specified Physician's Choice in Patients ≥ 60 Years Old With Relapsed or Refractory Acute Myeloid Leukemia (AML) Who Are Ineligible for Intensive Chemotherapy and/or Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02088541
• Other study ID #: KCP-330-008
• Status: Completed
• Phase: Phase 2
• Start date: March 2014
• Est. completion date: January 8, 2018

Study information

• Verified date: January 2023
• Source: Karyopharm Therapeutics Inc
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 317
• Est. completion date: January 8, 2018
• Est. primary completion date: January 8, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 60 Years and older

Eligibility

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

Related Conditions & MeSH terms

• Acute Myeloid Leukemia (AML)
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Selinexor
Selinexor oral tablet.
• Hydroxyurea

• Ara-C
Ara-C Subcutaneous Injection.

Locations

Country	Name	City	State
Canada	Tom Baker Cancer Centre	Calgary	Alberta
Canada	University of Alberta	Edmonton	Alberta
Canada	Sir Mortimer B. Davis Jewish General Hospital / McGill University	Montreal	Quebec
Denmark	Aarhus University Hospital	Aarhus
Denmark	Department of Haematology, National University Hospital, Rigshospitalet	Copenhagen
Denmark	Herlev Hospital	Herlev
Denmark	Odense University Hospital, Department of Hematology	Odense
France	CHU Bordeaux- Hôpital Haut Lévêque	Bordeaux
France	Centre Hospitalier Lyon	Lyon
France	Hôpital Avicenne	Paris
France	Hopital Saint Louis	Paris
France	Institut Universitaire du Cancer Toulouse	Toulouse
Germany	Stellvertretende Klinikleiterin Charité, Campus Benjamin Franklin	Berlin
Germany	Ev. Diakonie-Krankenhaus Gemeinnutzige GMBH Medizinische Klinik 2	Bremen
Germany	UNIVERSITÄTSKLINIKUM TU DRESDEN Medizinische Klinik und Poliklinik I,	Dresden
Germany	University Hospital Frankfurt	Frankfurt
Germany	Medizinische Hochschule Hannover (Hannover Medical School) Dept. of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation	Hanover
Germany	Abteilung Hämatologie, internistische Onkologie und Hämostaseologie	Leipzig
Germany	UNIVERSITY HOSPITAL OF MÜNSTER Medizinische Klinik und Poliklinik A, Universitätsklinikum Münster	Münster
Germany	Universitätsklinikum Ulm	ULM
Israel	Sororka MC	Beer Sheva
Israel	Rambam Health Care Campus	Haifa
Israel	Wolfson Medical Center	Holon
Israel	Hadassah Medical Center	Jerusalem
Israel	Rabin Medical Center	Petach Tikva
Israel	Tel Aviv Sourasky Medical Centre	Tel Aviv
Israel	Chaim Sheba Medical Center	Tel Hashomer
Italy	AOU Ospedali Riuniti di Ancona	Ancona
Italy	A.O Spedali Civili di Brescia	Brescia
Italy	AORN Cardarelli / UOSC di Ematologia con TMO	Naples
Netherlands	AMC, Academisch Medisch Centrum Afdeling Klinische Hematologie	Amsterdam
Netherlands	VU University Medical Center	Amsterdam
Netherlands	Universitair Medisch Centrum Groningen Department of Haematology	Groningen
Netherlands	Radboud University Medical Center Department of Haematology (476)	Nijmegen
Netherlands	Erasmus MC, location Daniel den Hoed	Rotterdam
Netherlands	University Medical Center Utrecht	Utrecht
Netherlands	Isala Kliniecken Zwolle	Zwolle
Poland	Wojewódzki Szpital Specjalistyczny im. M. Kopernika, Klinika Hematologii	Lodz
Poland	Samodzielny Publiczny Zaklad Opieki Zdrowotnej Ministerstwa Spraw Wewnetrznych	Olsztyn
Poland	Instytut Hematologii i Transfuzjologii	Warszawa
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1 we Wroclawiu	Wroclaw
Spain	ICO Badalona	Badalona
Spain	Hospital del Mar	Barcelona
Spain	Hospital Universitario de Salamanca Servicio de Hematologia	Salamanca
Spain	Hospital Universitario y Politécnico La Fe	Valencia
United Kingdom	University Hospital Wales	Cardiff	Wales
United Kingdom	Ninewells Hospital and Medical School NHS Tayside	Dundee
United Kingdom	Northwick Park Hospital	Harrow	England
United Kingdom	Hull and East Yorkshire Hospitals NHS Trust Queens Centre for Oncology and Haematology	Hull	Yorkshire
United Kingdom	Royal Liverpool University Hospital, Dept of Cellular and Molecular Physiology, Molecular and Clinical Cancer Medicine	Liverpool	Lancashire
United Kingdom	Plymouth Hospitals NHS Trust/Derriford Hospital	Plymouth
United Kingdom	Royal Marsden NHS Trust	Sutton	Surrey
United States	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan
United States	Winship Cancer Institute / Emory University	Atlanta	Georgia
United States	Sidney Kimmel Comprehensive Cancer Center / John Hopkins University	Baltimore	Maryland
United States	Roswell Park Cancer Institute	Buffalo	New York
United States	Gabrail Cancer Center	Canton	Ohio
United States	Northwestern University	Chicago	Illinois
United States	University of Chicago Medicine	Chicago	Illinois
United States	Ohio State University Comprehensive Cancer Center	Columbus	Ohio
United States	Colorado Blood Cancer Institute/Sarah Cannon Research Institute	Denver	Colorado
United States	Duke Cancer Care	Durham	North Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Westchester Medical Center / New York Medical College	Hawthorne	New York
United States	Milton S. Hershey Medical Center / Penn State	Hershey	Pennsylvania
United States	MD Anderson Cancer Center / University of Texas	Houston	Texas
United States	University of Kansas Hospital	Kansas City	Kansas
United States	Jonsson Comprehensive Cancer Center / University of California, Los Angeles	Los Angeles	California
United States	Tennessee Oncology/Sarah Cannon Research Institute	Nashville	Tennessee
United States	Vanderbilt-Ingram Cancer Center / Vanderbilt University	Nashville	Tennessee
United States	Yale Cancer Center / Yale University	New Haven	Connecticut
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	New York Presbyterian Hospital / Weill Cornell Medical College	New York	New York
United States	Sutter Oncology & Hematology	Sacramento	California
United States	Texas Transplant Institute/Sarah Cannon Research Institute	San Antonio	Texas
United States	Stanford Cancer Institute / Stanford University	Stanford	California
United States	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida
United States	University of Massachusetts Medical School	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Karyopharm Therapeutics Inc

Countries where clinical trial is conducted

United States,  Canada,  Denmark,  France,  Germany,  Israel,  Italy,  Netherlands,  Poland,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall Survival	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	Percentage of Participants With Overall Survival of at Least 3 Months (OS3.0)	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.	From randomization (Day 1) up to 3 months
Secondary	Percentage of Participants With Complete Remission Rate (CRR) for Those Who Achieved Complete Remission (CR)	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	Median Disease-Free Survival (DFS) for Participants Who Achieved Complete Remission (CR)	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	Percentage of Participants With Modified Complete Remission Rate (mCRR) for Those Who Achieved Complete Remission (CR) or Complete Remission With Incomplete Hematologic Recovery (Cri)	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	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)	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	Percentage of Participants With Overall Response Rate (ORR)	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	Duration of Response (DOR)	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.	Baseline until disease progression or discontinuation from the study, or death, whichever occurred first (up to a maximum of approximately 104 weeks)
Secondary	Percentage of Participants With Disease Control Rate (DCR)	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.	Up to 4 weeks from the date of randomization to the date of progression or recurrence based on IWG criteria
Secondary	Duration of Disease Control Rate	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.	Up to 4 weeks from the date of randomization to the date of progression or recurrence based on IWG criteria
Secondary	Change From Baseline in Quality of Life (QoL) and Patient-Reported Outcomes (Functional Assessment of Cancer Therapy -Leukemia [FACT-Leu]	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.	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)
Secondary	Change From Baseline in European Quality of Life-5 Dimension (EQ-5D) Health Questionnaire Visual Analogue Scale (VAS)	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.	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)