Clinical trial NCT04562870: A Study to Evaluate Single Agent Selinexor Versus Physician's Choice in Participants with Previously Treated Myelofibrosis
Official title: A Phase 2, Randomized, Open-Label, Multicenter Study to Evaluate Safety and Efficacy of Single Agent Selinexor Versus Treatment of Physician's Choice in Patients with Previously Treated Myelofibrosis
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Myelofibrosis
Keywords: Myelofibrosis
Selinexor
Total Symptom Score
Spleen Volume Reduction
Anemia response
TSS50
SVR35
SVR25
KPT-330
JAK1
JAK2
XPOVIO
SINE
XPORT-MF-035
Karyopharm
Lead sponsor: Karyopharm Therapeutics Inc
Sponsor class: INDUSTRY
First posted: 2020-09-24
Enrollment: 112
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Percentage of Participants with Spleen Volume Reduction of Greater Than or Equal to (≥) 35 Percent (%) (SVR35)
timeFrame: From Baseline up to Week 24
Secondary outcomes:
measure: Percentage of Participants with Total Symptom Score Reduction of ≥50% (TSS50) Measured by Myelofibrosis Symptom Assessment Form (MFSAF) V4.0, Based on Local Assessment
timeFrame: From Baseline up to Week 24
measure: Percentage of Participants with Spleen Volume Reduction of ≥25% (SVR25)
timeFrame: From Baseline up to Week 24
measure: Overall Survival (OS)
timeFrame: From Baseline up to 12 months after end of treatment (approximately 48 months)]
measure: Percentage of Participants with Anemia Response Assessed by International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
timeFrame: From Baseline up to 28 days after last dose (approximately 48 months)
measure: Duration of Spleen Volume Reduction of ≥35% (SVR35)
timeFrame: From Baseline up to Week 24
measure: Duration of Spleen Volume Reduction of ≥25% (SVR25)
timeFrame: From Baseline up to Week 24
measure: Duration of Total Symptom Score is ≥50% (TSS50) Based on Local Assessment
timeFrame: From Baseline up to Week 24
measure: Overall Response Rate (ORR) Assessed by IWG-MRT
timeFrame: From Baseline up to 28 days after last dose (approximately 48 months)
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs) by Severity Grade ≥3, Serious Adverse event (SAEs), and AEs Leading to Treatment Discontinuation
timeFrame: From first dose of study treatment up to 30 days after end of treatment (approximately 48 months)
measure: Pharmacokinetic (PK) Parameter: Area Under the Plasma Concentration-time Curve (AUC) of Selinexor
timeFrame: 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)
measure: PK Parameter: Maximum Plasma Concentration (Cmax) of Selinexor
timeFrame: 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)
Other outcomes:
Locations:
city: Pasadena
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Aurora
country: United States
facility: Rocky Mountain Cancer Centers, LLP
state: Colorado
city: Niles
country: United States
facility: Illinois Cancer Specialist
state: Illinois
city: Tyler
country: United States
facility: Texas Oncology - Northeast Texas
state: Texas
city: Beijing
country: China
facility: Peking Union Medical College Hospital
state: Beijing
city: Wuhan
country: China
facility: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology
state: Hubei
city: Nantong
country: China
facility: Affiliated Hospital of Nantong University
state: Jiangsu
city: Suzhou
country: China
facility: The Second Affiliated Hospital of Soochow University
state: Jiangsu
city: Suzhou
country: China
facility: Suzhou University -The First Affiliated Hospital
state: Jiangsu
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Hangzhou
country: China
facility: Sir Run Run Shaw Hospital - Zhejiang University School of Medicine
state: Zhejiang
city: Brest
country: France
facility: Institut de Cancéro-Hématologie
state: Bretagne
city: Angers
country: France
facility: Centre Hospitalier Universitaire d'Angers (CHU Angers)
city: Athens
country: Greece
facility: University General Hospital "ATTIKON"
state: Attiki
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS
state: Forlì-Cesena
city: Firenze
country: Italy
facility: Università degli Studi di Firenze - Azienda Ospedaliero - Universitaria Careggi - Dipartimento di medicina sperimentale e clinica
city: Latina
country: Italy
facility: Azienda Unita Sanitaria Locale Latina - Ospedale Santa Maria Goretti
city: Perugia
country: Italy
facility: University of Perugia Department of Medicine Hematology Section
city: Varese
country: Italy
facility: Asst Settelaghi, Ospedale Di Circolo E Fondazione Macchi
city: Katowice
country: Poland
facility: Pratia Onkologia Katowice
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
Study officials:
References: