selinexor in myelofibrosis refractory or intolerant to jak1/2 inhibitors

Conditions: Primary Myelofibrosis; Post-essential Thrombocythemia Myelofibrosis; Post-polycythemia Vera Myelofibrosis

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.


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. * patients who are below their ideal body weight and would be unduly impacted by changes in their weight, in the opinion of the investigator, will be excluded * 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