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Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors (ESSENTIAL)

Primary Purpose

Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Selinexor
Sponsored by
University of Utah
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Primary Myelofibrosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female subject aged ≥ 18 years.
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
  • Diagnosis of primary myelofibrosis (PMF), post-essential thrombocytosis (PET-MF) or post-polycythemia vera (PPV-MF).
  • Life expectancy ≥ 6 months.
  • Prior treatment with ruxolitinib or any experimental JAK1/2 inhibitor with any one or more of the following:

    a. Inadequate response after being on ≥ 3 months of treatment defined by: i. Palpable spleen ≥ 10 cm below the left subcostal margin on physical examination at the screening visit OR ii. Palpable spleen ≥ 5cm below the left subcostal margin on physical examination at the screening visit AND active symptoms of MF at the screening visit defined presence of 1 symptom score of ≥ 5 or two symptom scores each of ≥ 3 using the Screening Symptoms Form (Appendix 6) b. Intolerant to ruxolitinib and/or other JAK1/2 inhibitors due to any grade ≥ 3 non-hematologic AEs of or any grade ≥ 2 AEs requiring treatment discontinuation AND palpable spleen ≥ 5cm below the left subcostal margin on physical examination at the screening visit.

  • Adequate organ function as defined as:

    • Hematologic (≤ 7 days prior to C1D1):

      • Total white blood cell (WBC) count ≥ 1000/mm3
      • Absolute neutrophil count (ANC) ≥ 500/mm3
      • Hemoglobin ≥ 7 g/dL
      • Platelet count ≥ 30,000/mm3

For patients receiving transfusion and growth factor support, the following delays must be observed between the last administration and hematologic laboratory screening assessments:

• For hematopoietic growth factor support (including erythropoietin, darbepoetin, granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF], and platelet stimulators [e.g., eltrombopag, romiplostim, or interleukin-11]): at least 2 weeks.

Growth factor support, RBC and/or platelet transfusions are allowed as clinically indicated per institutional guidelines during the study.

  • Hepatic (≤ 28 days prior to C1D1):

    • Total bilirubin < 1.5 × ULN except in patients with indirect hyperbilirubinemia due to hemolysis or with Gilbert's syndrome where total bilirubin should be < 5 × ULN
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 × ULN.
  • Renal (within 28 days prior to C1D1):

    • Estimated creatinine clearance (CrCl) ≥ 20 mL/min using the Cockcroft and Gault formula [(140-Age) × Mass (kg)/(72 × creatinine mg/dL), multiply by 0.85 if the patient is female] OR

      • Female patients of childbearing potential must have a negative serum pregnancy test (≤ 3 days prior to C1D1).
      • Female patients of childbearing potential must agree to use 2 methods of contraception throughout the study and for 3 months following the last dose of study treatment (including 1 highly effective and 1 effective method of contraception as defined in section 7.4)
      • Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential.
      • Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior treatments including ruxolitinib or other experimental agents unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
      • Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines.

Exclusion Criteria:

  • Prior exposure to a SINE compound, including selinexor.
  • BSA < 1.4 m2 at baseline, calculated by the Dubois or Mosteller methods.
  • Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals ≤ 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled infection ≤ 1 week prior to C1D1 are acceptable.
  • Radiation, chemotherapy, immunotherapy, or any other anticancer therapy (including investigational therapies) ≤ 2 weeks.
  • Ruxolitinib or other JAK1/2 inhibitors ≤ at least 3 days or 5 half-lives prior to C1D1.
  • Major surgery ≤ 4 weeks prior to C1D1.
  • Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus ribonucleic acid (RNA) or hepatitis B virus surface antigen.
  • Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment.
  • Any life-threatening illness, organ system dysfunction, or serious psychiatric, medical, or other conditions/situations which, in the investigator's opinion, could compromise a patient's ability to give informed consent, safety, or compliance with the protocol.
  • Contraindication to any of the required concomitant drugs or supportive treatments.
  • Subjects taking prohibited medications as described in Section 6.3. Following discontinuation of prohibited medications, a washout period is required prior to initiating study treatment (the duration of the washout must be as clinically indicated, e.g. at least five half-lives).
  • Subjects who are breastfeeding and unwilling to stop while on study

Sites / Locations

  • Huntsman Cancer Institute/University of UtahRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Selinexor, all patients

Arm Description

Single Arm Study, all patients will get selinexor

Outcomes

Primary Outcome Measures

Change in spleen volume
To assess the efficacy of selinexor on spleen volume reduction in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Change and percentage change in spleen volume from baseline to EOT as measured by MRI or CT (in applicable patients).

Secondary Outcome Measures

Adverse Events that Occur
To assess the safety/tolerability and further characterize the safety profile of selinexor in PMF, PET-MF, or PPV-MF patients refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Secondary Endpoints: rate of adverse events (AEs) and serious adverse events (SAEs).
Change in symptoms score
Proportion of patients with ≥ 50% reduction of total symptoms score as measured by the MPN-Symptoms Assessment Form (MPN-SAF) from baseline after 6 cycles of treatment. The score will be reported as one mean score of all of the questions in the questionnaire. The higher the score, the worse the symptom.
Overall response
Overall response rate according to the 2013 IWG-MRT consensus criteria for treatment response in primary and secondary MF (post-PV and post-ET).
Overall Survival
Overall survival at 24 months from the initiation of study therapy.

Full Information

First Posted
August 7, 2018
Last Updated
June 30, 2023
Sponsor
University of Utah
Collaborators
Karyopharm Therapeutics Inc
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1. Study Identification

Unique Protocol Identification Number
NCT03627403
Brief Title
Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors
Acronym
ESSENTIAL
Official Title
A Phase II Study to Evaluate the Efficacy and Safety of Selinexor in Patients With Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
May 10, 2019 (Actual)
Primary Completion Date
March 14, 2024 (Anticipated)
Study Completion Date
March 14, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Utah
Collaborators
Karyopharm Therapeutics Inc

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a phase II, open label, prospective, single-arm study evaluating the efficacy and safety of selinexor in patients with PMF or secondary MF (PPV-MF or PET-MF) who are refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Primary Myelofibrosis, Post-essential Thrombocythemia Myelofibrosis, Post-polycythemia Vera Myelofibrosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Open label, non-randomized, prospective, single-arm study
Masking
None (Open Label)
Allocation
N/A
Enrollment
56 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Selinexor, all patients
Arm Type
Experimental
Arm Description
Single Arm Study, all patients will get selinexor
Intervention Type
Drug
Intervention Name(s)
Selinexor
Intervention Description
Selinexor will be administered orally at a dose of 80 mg once weekly until IWG-MR disease progression, intolerable toxicity, or no clinical benefit per treating physician's discretion whichever occurs first. For patients enrolled after Protocol v7, Selinexor will be administered by oral route beginning at 40mg once weekly. . Prior to protocol version 7, the starting dose of sSelinexor was 60 mg and 80 mg once weekly.
Primary Outcome Measure Information:
Title
Change in spleen volume
Description
To assess the efficacy of selinexor on spleen volume reduction in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Change and percentage change in spleen volume from baseline to EOT as measured by MRI or CT (in applicable patients).
Time Frame
Up to 6 months
Secondary Outcome Measure Information:
Title
Adverse Events that Occur
Description
To assess the safety/tolerability and further characterize the safety profile of selinexor in PMF, PET-MF, or PPV-MF patients refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors. Secondary Endpoints: rate of adverse events (AEs) and serious adverse events (SAEs).
Time Frame
Up to 6 months
Title
Change in symptoms score
Description
Proportion of patients with ≥ 50% reduction of total symptoms score as measured by the MPN-Symptoms Assessment Form (MPN-SAF) from baseline after 6 cycles of treatment. The score will be reported as one mean score of all of the questions in the questionnaire. The higher the score, the worse the symptom.
Time Frame
Up to 6 months
Title
Overall response
Description
Overall response rate according to the 2013 IWG-MRT consensus criteria for treatment response in primary and secondary MF (post-PV and post-ET).
Time Frame
Up to 6 months
Title
Overall Survival
Description
Overall survival at 24 months from the initiation of study therapy.
Time Frame
Up to 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male or female subject aged ≥ 18 years. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 Diagnosis of primary myelofibrosis (PMF), post-essential thrombocytosis (PET-MF) or post-polycythemia vera (PPV-MF). Life expectancy ≥ 6 months. Prior treatment with ruxolitinib or any experimental JAK1/2 inhibitor with any one or more of the following: a. Inadequate response after being on ≥ 3 months of treatment defined by: i. Palpable spleen ≥ 10 cm below the left subcostal margin on physical examination at the screening visit OR ii. Palpable spleen ≥ 5cm below the left subcostal margin on physical examination at the screening visit AND active symptoms of MF at the screening visit defined presence of 1 symptom score of ≥ 5 or two symptom scores each of ≥ 3 using the Screening Symptoms Form (Appendix 6) b. Intolerant to ruxolitinib and/or other JAK1/2 inhibitors due to any grade ≥ 3 non-hematologic AEs of or any grade ≥ 2 AEs requiring treatment discontinuation AND palpable spleen ≥ 5cm below the left subcostal margin on physical examination at the screening visit. Adequate organ function as defined as: Hematologic (≤ 28 days prior to C1D1): Total white blood cell (WBC) count ≥ 1000/mm3 Absolute neutrophil count (ANC) ≥ 500/mm3 Hemoglobin ≥ 7 g/dL Platelet count ≥ 30,000/mm3 For patients receiving transfusion and growth factor support, the following delays must be observed between the last administration and hematologic laboratory screening assessments: • For hematopoietic growth factor support (including erythropoietin, darbepoetin, granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage-colony stimulating factor [GM-CSF], and platelet stimulators [e.g., eltrombopag, romiplostim, or interleukin-11]): at least 2 weeks. Growth factor support, RBC and/or platelet transfusions are allowed as clinically indicated per institutional guidelines during the study. Hepatic (≤ 28 days prior to C1D1): Total bilirubin < 1.5 × ULN except in patients with indirect hyperbilirubinemia due to hemolysis or with Gilbert's syndrome where total bilirubin should be < 5 × ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 × ULN. Renal (within 28 days prior to C1D1): Estimated creatinine clearance (CrCl) ≥ 20 mL/min using the Cockcroft and Gault formula [(140-Age) × Mass (kg)/(72 × creatinine mg/dL), multiply by 0.85 if the patient is female] OR Female patients of childbearing potential must have a negative serum pregnancy test (≤ 3 days prior to C1D1). Female patients of childbearing potential must agree to use 2 methods of contraception throughout the study and for 3 months following the last dose of study treatment (including 1 highly effective and 1 effective method of contraception as defined in section 7.4) Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. Recovery to baseline or ≤ Grade 1 CTCAE v5.0 from toxicities related to any prior treatments including ruxolitinib or other experimental agents unless AE(s) are clinically nonsignificant and/or stable on supportive therapy. Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines. Exclusion Criteria: Prior exposure to a SINE compound, including selinexor. BSA < 1.4 m2 at baseline, calculated by the Dubois or Mosteller methods. Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals ≤ 1 week prior to C1D1. Patients on prophylactic antibiotics or with a controlled infection ≤ 1 week prior to C1D1 are acceptable. Radiation, chemotherapy, immunotherapy, or any other anticancer therapy (including investigational therapies) ≤ 2 weeks. Ruxolitinib or other JAK1/2 inhibitors ≤ at least 3 days or 5 half-lives prior to C1D1. Major surgery ≤ 4 weeks prior to C1D1. Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus ribonucleic acid (RNA) or hepatitis B virus surface antigen. Any active gastrointestinal dysfunction interfering with the patient's ability to swallow tablets, or any active gastrointestinal dysfunction that could interfere with absorption of study treatment. Any life-threatening illness, organ system dysfunction, or serious psychiatric, medical, or other conditions/situations which, in the investigator's opinion, could compromise a patient's ability to give informed consent, safety, or compliance with the protocol. Contraindication to any of the required concomitant drugs or supportive treatments. Subjects taking prohibited medications as described in Section 6.3. Following discontinuation of prohibited medications, a washout period is required prior to initiating study treatment (the duration of the washout must be as clinically indicated, e.g. at least five half-lives). Subjects who are breastfeeding and unwilling to stop while on study
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Priscilla Blosser, RN
Phone
801-213-6117
Email
Priscilla.blosser@hci.utah.edu
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Srinivas Tantravahi, MD
Organizational Affiliation
University of Utah
Official's Role
Principal Investigator
Facility Information:
Facility Name
Huntsman Cancer Institute/University of Utah
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84112
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Priscilla Blosser, RN
Phone
801-213-6117
Email
Priscilla.blosser@hci.utah.edu

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors

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