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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Selinexor
* Drug: Hydroxyurea
* Drug: Ara-C


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 60 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selinexor approximately 55 mg/m^2 (60 to 120 mg based on BSA)<br>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). | Drug: Selinexor<br>* Selinexor oral tablet.<br>* Other names: KPT-330;|
| Experimental: Selinexor 60 mg (PV <5) (Equivalent to 35 mg/m^2)<br>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). | Drug: Selinexor<br>* Selinexor oral tablet.<br>* Other names: KPT-330;|
| Experimental: Selinexor 60 mg (PV >=5) (Equivalent to 35 mg/m^2)<br>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). | Drug: Selinexor<br>* Selinexor oral tablet.<br>* Other names: KPT-330;|
| Active Comparator: Physician's Choice 1 (PV <5)<br>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. | Drug: Hydroxyurea<br> <br> * Other names: Hydroxycarbamide;|
| Active Comparator: Physician's Choice 2 (PV >=5)<br>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. | Drug: Ara-C<br>* Ara-C Subcutaneous Injection.<br>* Other names: Depocyt;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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) | 
| 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 | 
| 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 | 
| 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) | 
| 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Relapsed/Refractory Acute Myeloid Leukemia, Acute Myeloid Leukemia, AML, Karyopharm, Selinexor, KPT-330