E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute Myeloid Leukemia (AML) |
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E.1.1.1 | Medical condition in easily understood language |
Acute Myeloid Leukemia (AML) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 100000004864 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine overall survival (OS) of selinexor as compared to physician’s choice (PC) in patients ≥ 60 years old with relapsed/refractory AML that requires treatment and are ineligible for intensive chemotherapy and/or transplantation. |
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E.2.2 | Secondary objectives of the trial |
• To determine the proportion of patients whose OS is at least 3 months (OS3.0) • To determine the complete remission rate (CRR), including complete remission with full hematologic recovery (CR), and median disease free survival (DFS) for patients who achieve CR • To determine the modified CRR (mCRR), including CR or complete remission with incomplete hematologic recovery (CRi) (including complete remission with incomplete platelet recovery [CRp]), and median DFS for patients who achieve CR or CRi (including CRp) • To determine the overall response rate (ORR) and duration of overall response (DOR), including CR, CRi, morphologic leukemia-free state (MLFS), and partial remission (PR) • To determine the disease control rate (DCR) defined as ORR + stable disease for ≥ 4 weeks (SD), and duration of DCR • To assess the safety and tolerability of selinexor (KPT-330), as compared to physician's choice (PC) • Quality of life and patient reported outcomes (FACT-Leukemia, EQ-5D-5L) (QoL) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
In order for a patient to be included in the study, the patient must meet all the following criteria: 1. Signed, written informed consent in accordance with federal, local, and institutional guidelines 2. Patients age ≥ 60 years with relapsed/refractory AML (defined using WHO criteria) of any type except for acute promyelocytic leukemia (APL; AML M3), after at least one 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. 3. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. 4. Diagnosis of AML (WHO classification definition of ≥ 20% blasts) with the exception of acute promyelocytic leukemia (APL; AML M3); patients must have available archival or recently acquired bone marrow biopsy/aspiration or tumor tissue for central review to be eligible. 5. Relapsed or refractory AML, defined as either: i) recurrence of disease after a complete remission (CR), or ii) failure to achieve CR with initial therapy. 6. All patients must have received at least one prior line of AML therapy given at standard doses and must have progressed after their most recent therapy. Prior therapy must have included an adequate trial of a hypomethylating agent with at least 2 cycles. 7. A period of at least 2 weeks must have elapsed since the last anti-leukemia treatment (with the exception of hydroxyurea) before first dose in this study. 8. Objective, documented evidence of disease progression or failure to respond to a reasonable trial of their most recent previous therapy prior to study entry. 9. Serum biochemical values with the following limits unless due to leukemia: creatinine clearance > 30 cc/min calculated using the Cockcroft and Gault (Cockcroft and Gault 1976) formula or measured; total bilirubin ≤ 2 x upper limit of normal (ULN) (except patients with Gilbert’s syndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of ≤ 3 x ULN); transaminases (AST and ALT) ≤ 2.5 x ULN (except patients with known liver involvement of their AML who must have an AST and ALT ≤ 5 x ULN). 10. Coagulation time (Prothrombin time [PT] and partial thromboplastin time [PTT]) ≤ 1.5 x ULN (PTT elevation for known lupus anticoagulant is allowed). Coagulation may also be measured using thromboplastin time (Quick test) if measurement of PT/PTT is not feasible. 11. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures. 12. Male patients with partners of childbearing potential must agree to use effective contraception during the study period and a period of 3 months after the last dose of study drug. |
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E.4 | Principal exclusion criteria |
A patient will not be included in the study if any of the following criteria are met: 1. Treatment with any investigational agent within three weeks prior to first dose in this study. 2. Presence of central nervous system (CNS) leukemia. 3. Patients with AML M3 or who are 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. 4. Patients whose AML is classified as favorable according to the European LeukemiaNet (ELN) disease risk assessment (Appendix 1). 5. Major surgery within 2 weeks of first dose of study drug. Patients must have recovered from the effects of any surgery performed greater than 2 weeks previously. 6. Patient has a concurrent active malignancy. 7. Unstable cardiovascular function: •symptomatic ischemia, or •uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular (AV) block or asymptomatic left anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded), or •congestive heart failure (CHF) NYHA Class ≥ 3, or •myocardial infarction (MI) within 3 months. 8. Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable. 9. 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). 10. Known human immunodeficiency virus (HIV) infection. 11. Any medical condition which, in the investigator's opinion, could compromise the patient's safety. 12. Patients unable to swallow tablets, or patients with malabsorption syndrome, or any other disease significantly affecting gastrointestinal function
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall survival (OS) is the primary efficacy endpoint of this study. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Two interim analyses will be conducted on the ITT population (see Section 14.2.1.4 of the protocol for further details). The first interim analysis will take place after 31 (25%) OS events have occurred, and will be conducted to assess futility only (non-binding). Futility would be concluded if the p value from the log-rank test is ≥ 0.8084. The second interim analysis will take place after 62 (50%) deaths, and will allow for a conclusion of significant efficacy at an α-level < 0.0015, and stopping for futility (non-binding) at an α-level ≥ 0.2879. |
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E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints will include the following, assessed in hierarchical fashion in the order presented below: • The proportion of patients whose OS is at least 3 months (OS3.0) • The complete remission rate (CRR), including complete remission with full hematologic recovery (CR), and median disease free survival (DFS) for patients who achieve CR • The modified CRR (mCRR), including CR or CRi (including CRp), and median DFS for patients who achieve CR or CRi (including CRp) • The overall response rate (ORR) and duration of overall response (DOR), including CR, CRi, MLFS, and partial remission (PR) • The disease control rate (DCR) defined as ORR + stable disease for ≥ 4 weeks (SD), and duration of DCR • Quality of life and patient reported outcomes (FACT-Leukemia and EQ-5D-5L) (QoL)
The safety and tolerability of selinexor and PC will be evaluated by means of drug-related AE reports, physical examinations, and laboratory safety evaluations.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Physician’s Choice as described in the protocol |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
Denmark |
France |
Germany |
Italy |
Netherlands |
Poland |
Spain |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |