A Study to Evaluate Single Agent Selinexor Versus Physician's Choice in Participants With Previously Treated Myelofibrosis



Sponsor:   Karyopharm Therapeutics Inc


Sommario: This is a Phase 2, multicenter, two-arm, open-label study to evaluate the safety and
efficacy of selinexor versus treatment per physician's choice (PC) in participants with
myelofibrosis (MF) who had at least 6 months of treatment with a Janus kinase (JAK)1/2
inhibitor. Study participants will be randomized in a 1:1 ratio to either receive
selinexor or physicians' choice of treatment.




TIPOLOGIA STUDIO

 
Interventistico



FASE

 
Fase 2




TRATTAMENTO

  
    
  
  • Selinexor
  • Physician's Choice Treatment
    • 






OBIETTIVO PRIMARIO


  
  • Misura: Percentage of Participants with Spleen Volume Reduction of Greater Than or Equal to (≥) 35 Percent (%) (SVR35)
  • Tempo: From Baseline up to Week 24
  • Descrizione: 




OBIETTIVO SECONDARIO


  
  • Misura: Percentage of Participants with Total Symptom Score Reduction of ≥50% (TSS50) Measured by Myelofibrosis Symptom Assessment Form (MFSAF) V4.0, Based on Local Assessment
  • Tempo: From Baseline up to Week 24
  • Descrizione: 
  • Misura: Percentage of Participants with Spleen Volume Reduction of ≥25% (SVR25)
  • Tempo: From Baseline up to Week 24
  • Descrizione: 
  • Misura: Overall Survival (OS)
  • Tempo: From Baseline up to 12 months after end of treatment (approximately 48 months)]
  • Descrizione: 
  • Misura: Percentage of Participants with Anemia Response Assessed by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
  • Tempo: From Baseline up to 28 days after last dose (approximately 48 months)
  • Descrizione: 
  • Misura: Duration of Spleen Volume Reduction of ≥35% (SVR35)
  • Tempo: From Baseline up to Week 24
  • Descrizione: 
  • Misura: Duration of Spleen Volume Reduction of ≥25% (SVR25)
  • Tempo: From Baseline up to Week 24
  • Descrizione: 
  • Misura: Duration of Total Symptom Score is ≥50% (TSS50) Based on Local Assessment
  • Tempo: From Baseline up to Week 24
  • Descrizione: 
  • Misura: Overall Response Rate (ORR) Assessed by IWG-MRT
  • Tempo: From Baseline up to 28 days after last dose (approximately 48 months)
  • Descrizione: 
  • Misura: Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Severity Grade ≥3, Serious Adverse event (SAEs), and AEs Leading to Treatment Discontinuation
  • Tempo: From first dose of study treatment up to 30 days after end of treatment (approximately 48 months)
  • Descrizione: 
  • Misura: Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-time Curve (AUC) of Selinexor
  • Tempo: Cycle 2 Day 1: 1, 2, 4, and 6 hours post-dose; Cycle 2 Day 2: at 24 hours post-dose (each cycle is 28 days)
  • Descrizione: 
  • Misura: PK Parameter: Maximum Plasma Concentration (Cmax) of Selinexor
  • Tempo: Cycle 2 Day 1: 1, 2, 4, and 6 hours post-dose; Cycle 2 Day 2: at 24 hours post-dose (each cycle is 28 days)
  • Descrizione: 




CRITERI DI ELIGIBILITA'


    
             
  • 
        Criteri di inclusione e esclusione
        
    Inclusion Criteria:

  -  A diagnosis of primary MF or post-essential thrombocythemia (ET) or
     post-polycythemia (PV) MF according to the 2016 World Health Organization (WHO)
     classification of myeloproliferative neoplasms (MPN), by the most recent local
     pathology report.

  -  Previous treatment with JAK inhibitors for at least 6 months.

  -  Measurable splenomegaly during the screening period as demonstrated by spleen volume
     of ≥450 centimeter cube (cm^3) by magnetic resonance imaging (MRI) or computerized
     tomography (CT) scan.

  -  Relapsed, Refractory or Intolerant to JAK inhibitors as defined as meeting one of
     the criteria below:

       -  less than (<) 35% spleen volume reduction by MRI or CT-scan (from baseline) or

       -  <50% decrease in spleen size by palpation (from baseline) or an increase of at
          least 3 cm with the spleen at least 5 cm below the left costal margin or

       -  Spleen volume increase greater than (>) 25% from nadir or a return to within
          10% of baseline after any initial response or

       -  Treatment with JAK inhibitor was complicated by development of red blood cells
          (RBC) transfusion requirement (2 units per month for 2 month); or grade 3
          thrombocytopenia, anemia, hematoma/hemorrhage; or grade 2 non-hematologic
          toxicity while on JAK inhibitors

  -  Participants ≥18 years of age.

  -  Eastern Cooperative Oncology Group (ECOG) less than or equal to (≤) 2.

  -  Platelet count ≥75*10^9 per liter (/L).

  -  Absolute neutrophil count (ANC) ≥1.5*10^9/L.

  -  Serum direct bilirubin ≤1.5*upper limit of normal (ULN); aspartate aminotransferase
     (AST) and alanine aminotransferase (ALT) ≤2.5*ULN.

  -  Calculated creatinine clearance (CrCl) >15 milliliter (mL)/minute (min) based on the
     Cockcroft and Gault formula.

  -  Participants with active hepatitis B virus (HBV) are eligible if antiviral therapy
     for hepatitis B has been given for >8 weeks and viral load is <100 International
     Units (IU)/mL.

  -  Participants with untreated hepatitis C virus (HCV) are eligible if there is a
     documentation of negative viral load per institutional standard.

  -  Participants with history of human immunodeficiency virus (HIV) are eligible if they
     have cluster of differentiation 4 (CD4)+ T-cell counts ≥350 cells/microliter (mcL),
     negative viral load per institutional standard, and no history of acquired
     immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year.

  -  Female participants of childbearing potential must have a negative serum pregnancy
     test at screening and agree to use highly effective methods of contraception
     throughout the study and for at least 90 days after the last dose of selinexor, or
     for the duration as stated on the label (SmPC/USPI) for those on the comparator drug
     (physician's choice arm). Childbearing potential excludes: Age >50 years and
     naturally amenorrhoeic for >1 year, or previous bilateral salpingo-oophorectomy, or
     hysterectomy.

  -  Male participants who are sexually active must use highly effective methods of
     contraception throughout the study and for at least 90 days after the last dose of
     selinexor, or for the duration as stated on the label (SmPC/USPI) for those on the
     comparator drug (physician's choice arm). Male participants must agree not to donate
     sperm during the study treatment period.

  -  Participants must sign written informed consent in accordance with federal, local
     and institutional guidelines.

Exclusion Criteria:

  -  >5% blasts in peripheral blood or >10% blasts in bone marrow (i.e., accelerated
     phase).

  -  Previous treatment with selinexor or other exportin 1 (XPO1) inhibitors.

  -  Use of any standard or experimental anti-MF therapy <21 days prior to Cycle 1 Day 1
     (hydroxyurea or growth factors are allowed).

  -  Impairment of gastrointestinal (GI) function or GI disease that could significantly
     alter the absorption of selinexor (Example: vomiting, or diarrhea that is Common
     Terminology Criteria for Adverse Events (CTCAE) grade >1).

  -  Received strong cytochrome P450 3A (CYP3A) inhibitors ≤7 days prior to selinexor
     dosing or strong CYP3A inducers ≤14 days prior to selinexor dosing.

  -  Major surgery <28 days prior to cycle 1 day 1 (C1D1).

  -  Uncontrolled (ie, clinically unstable) infection requiring parenteral antibiotics,
     antivirals, or antifungals within 7 days prior to first dose of study treatment;
     however, prophylactic use of these agents is acceptable (including parenteral).

  -  Any life-threatening illness, medical condition, or organ system dysfunction which,
     in the Investigator's opinion, could compromise the participants safety, prevent the
     participant from giving informed consent, or being compliant with the study
     procedures.

  -  Female participants who are pregnant or lactating.

  -  Participants with contraindications to use of selinexor or all the drugs intended to
     be used in the comparative treatment arm.
    
        
    • 
    




SESSO

  
Tutti




  


ETA' MINIMA



Età Minima: 18 Years

Età Massima: N/A






LUOGO


  
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
Meldola	3173635, 47014
Università degli Studi di Firenze - Azienda Ospedaliero - Universitaria Careggi - Dipartimento di medicina sperimentale e clinica
Florence	3176959, 50134
Azienda Unita Sanitaria Locale Latina - Ospedale Santa Maria Goretti
Latina	3175058, 4100
University of Perugia Department of Medicine Hematology Section
Perugia	3171180, 6132
Asst Settelaghi, Ospedale Di Circolo E Fondazione Macchi
Varese	3164699, 21100