SELINEXOR for Myelofibrosis

Inclusion criteria

• {"criterion_text":"-A diagnosis of primary MF or post-ET or post-PV MF according to the 2016 WHO classification of MPN, confirmed by the most recent local pathology report.\n-Calculated creatinine clearance (CrCl) >15 mL/min based on the Cockcroft and Gault formula.\n-Patients 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 IU/mL.\n-Patients with untreated hepatitis C virus (HCV) are eligible if there is a documentation of negative viral load per institutional standard.\n-Patients with history of human immunodeficiency virus (HIV) are eligible if they have CD4+ T-cell counts > or = 350 cells/microL, negative viral load per institutional standard, and no history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections in the last year.\n-Female patients 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.\n-Male patients 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 patients must agree not to donate sperm during the study treatment period.\n-Patients must sign written informed consent in accordance with federal, local and institutional guidelines.\n-Previous treatment with JAK inhibitors for at least 6 months.\n-Measurable splenomegaly during the screening period as demonstrated by spleen volume of > or = 450 cm3 by MRI or CT scan\n-Relapsed, refractory or intolerant to JAK inhibitors as defined as meeting one of the criteria below: <35% spleen volume reduction by MRI or CT-scan (from baseline) or b. <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 c. Spleen volume increase >25% from nadir or a return to within 10% of baseline) after any initial response or d. Treatment with JAK inhibitor was complicated by development of 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\n-Patients > or = 18 years of age\n-ECOG < or = 2\n-Platelet count > or = 75 × 10^9/L\n-Absolute neutrophil count (ANC) > or = 1.5 × 10^9/L\n-Serum direct bilirubin < or =1.5 × ULN; AST and ALT < or = 2.5 × ULN"}

Exclusion criteria

• {"criterion_text":"->5% blasts in peripheral blood or >10% blasts in bone marrow (i.e., accelerated phase).\n-Patients with contraindications to use of selinexor or all the drugs intended to be used in the comparative treatment arm.\n-Previous treatment with selinexor or other XPO1 inhibitors.\n-Use of any standard or experimental anti-MF therapy <21 days prior to Cycle 1 Day 1 (hydroxyurea or growth factors are allowed).\n-Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (Example: vomiting, or diarrhea that is CTCAE grade >1).\n-Received strong cytochrome P450 3A (CYP3A) inhibitors < or = 7 days prior to selinexor dosing OR strong CYP3A inducers < or = 14 days prior to selinexor dosing.\n-Major surgery <28 days prior to C1D1.\n-Uncontrolled (i.e., 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).\n-Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety, prevent the patient from giving informed consent, or being compliant with the study procedures.\n-Female patients who are pregnant or lactating."}

Primary endpoints

• {"endpoint_text":"-Rate of Spleen Volume Reduction of > or = 35% (SVR35)","definition_or_measurement_approach":"Spleen volume reduction ≥35% (SVR35); spleen volume measured by MRI or CT scan (spleen volume assessment methods referenced elsewhere in protocol)."}

Secondary endpoints

• {"endpoint_text":"-Rate of Total Symptom Score reduction of > or = 50% (TSS50) in the myelofibrosis symptom assessment form (MFSAF) V4.0, based on local assessment","definition_or_measurement_approach":"TSS50 measured using the myelofibrosis symptom assessment form (MFSAF) V4.0, based on local assessment."}
• {"endpoint_text":"-Rate of Spleen Volume Reduction of > or =25% (SVR25)","definition_or_measurement_approach":"Spleen volume reduction ≥25% (SVR25); spleen volume measurement (e.g., MRI or CT) as per protocol."}
• {"endpoint_text":"-Overall survival (OS)","definition_or_measurement_approach":"Overall survival measured as time from randomization/enrollment to death from any cause."}
• {"endpoint_text":"-Anemia response as defined per the IWG-MRT criteria, based on local assessment • Duration of SVR35 and SVR25 • Duration of TSS50 based on local assessment • ORR (Complete Response [CR] + Partial Response [PR] + Clinical Improvement [CI]) by IWG-MRT criteria, based on local assessment","definition_or_measurement_approach":"Anemia response and ORR assessed per IWG-MRT criteria (local assessment); durations of SVR35, SVR25 and TSS50 measured from response onset to loss of response."}
• {"endpoint_text":"-The occurrence, nature, and severity of AEs","definition_or_measurement_approach":"Adverse events recorded and graded (e.g., CTCAE) to capture occurrence, nature, and severity."}
• {"endpoint_text":"-Population PK derived parameters: • AUC • Cmax","definition_or_measurement_approach":"Population pharmacokinetic parameters including AUC and Cmax derived from collected PK samples."}

Italy

Earliest CTIS Part Ii Submission Date

20-09-2024

Latest Decision Or Authorization Date

04-11-2024

Processing Time Days

45

Number Of Sites

1

Number Of Participants

21

Spain

Earliest CTIS Part Ii Submission Date

20-09-2024

Latest Decision Or Authorization Date

25-10-2024

Processing Time Days

35

Number Of Sites

1

Number Of Participants

7

Primary sponsor

Full Name

Karyopharm Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD (UK) Limited

Responsibilities

Safety Reporting

Name

IQVIA Limited

Responsibilities

PK blood sampling, PD blood sampling, MPN Mutation panel, bone marrow biopsy, aspirate; additional lab/sample handling responsibilities

Name

Datacubed Health Inc.

Responsibilities

use mobile & web platform to collect ePRO data; study configuration in web portal; ePRO deployment & data transfer

Name

4g Clinical LLC

Responsibilities

Operational CRO role (role code 3 provided)

Name

Precision for Medicine (HU) Kft.

Responsibilities

Laboratory/biomarker and related roles (codes 1,12,2,5 provided)

Name

Median Technologies

Responsibilities

Imaging review charter, image management, imaging data reconciliation

Name

Eclinical Solutions LLC

Responsibilities

eClinical systems responsibilities (role code 6 provided)

Name

Stefanini

Responsibilities

IT/service provider role (role code 7 provided)

Third parties

• {"country":"United Kingdom","full_name":"PPD (UK) Limited","duties_or_roles":"Safety Reporting","organisation_type":"Pharmaceutical company"}
• {"country":"Belgium","full_name":"Stefanini","duties_or_roles":"Code 7 (role code provided; specific duty text not listed)","organisation_type":"Pharmaceutical company"}
• {"country":"Hungary","full_name":"Precision for Medicine (HU) Kft.","duties_or_roles":"Codes 1,12,2,5 (roles provided by code; specific duty text not listed)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eclinical Solutions LLC","duties_or_roles":"Code 6 (role code provided; specific duty text not listed)","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Median Technologies","duties_or_roles":"imaging review charter, image management, imaging data reconsiliation","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"PK blood sampling, PD blood sampling, MPN Mutation panel, bonne marrow biopsy, aspirate; and role code 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Datacubed Health Inc.","duties_or_roles":"use mobile&web platform to collect ePRO data; study config in web portal, ePRO deployment&data trans; and role code 7","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"4g Clinical LLC","duties_or_roles":"Code 3 (role code provided; specific duty text not listed)","organisation_type":"Non-Pharmaceutical company"}