Selinexor in Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors

Study Overview
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Brief Summary
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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.

Official Title
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A Phase II Study to Evaluate the Efficacy and Safety of Selinexor in Patients With Myelofibrosis Refractory or Intolerant to JAK1/2 Inhibitors

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

Intervention / Treatment
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* Drug: Selinexor


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open label, non-randomized, prospective, single-arm study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selinexor, all patients<br>Single Arm Study, all patients will get selinexor | Drug: Selinexor<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | Up to 6 months | 
| 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. | Up to 6 months | 
| 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). | Up to 6 months | 
| Overall Survival | Overall survival at 24 months from the initiation of study therapy. | Up to 24 months |