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Selinexor in Treating Patients with Myelofibrosis Intolerant or Resistant to JAK1 / 2 Inhibitors

Trial Status: Active

This phase II trial studies how well selinexor works in treating patients with myelofibrosis that does not respond to or is intolerant to JAK1 / 2 inhibitors. Drugs used in chemotherapy, such as selinexor, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading.

Inclusion Criteria

  • 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: * Inadequate response after being on >= 3 months of treatment defined by: ** Palpable spleen >= 10 cm below the left subcostal margin on physical examination at the screening visit OR ** Palpable spleen >= 5 cm 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 * Intolerant to ruxolitinib and/or other JAK1/2 inhibitors due to any grade >= 3 non-hematologic adverse events (AEs) of or any grade >= 2 AEs requiring treatment discontinuation AND palpable spleen >= 5 cm below the left subcostal margin on physical examination at the screening visit.
  • Total white blood cell (WBC) count >= 1000/mm^3 (=< 7 days prior to cycle 1 day 1 [C1D1]).
  • Absolute neutrophil count (ANC) >= 500/mm^3 (=< 7 days prior to C1D1).
  • Hemoglobin >= 7 g/dL (=< 7 days prior to C1D1).
  • Platelet count >= 30,000/mm^3 (=< 7 days prior to C1D1).
  • 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, red blood cells (RBC) and/or platelet transfusions are allowed as clinically indicated per institutional guidelines during the study.
  • Total bilirubin < 1.5 x upper limit of normal (ULN) except in patients with indirect hyperbilirubinemia due to hemolysis or Gilbert’s syndrome where total bilirubin should be < 5 ULN (=< 28 days prior to C1D1).
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x ULN (=< 28 days prior to C1D1).
  • Estimated creatinine clearance (CrCl) >= 20 mL/min using the Cockcroft and Gault formula (=< 28 days prior to C1D1).
  • 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).
  • 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 Common Terminology for Adverse Events (CTCAE) version (v) 5.0 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 selective inhibitor of nuclear export (SINE) compound, including selinexor.
  • Body surface area (BSA) < 1.4 m^2 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. 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.

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: ACTIVE
Contact: Srinivas K. Tantravahi
Phone: 801-213-6170

PRIMARY OBJECTIVE:

I. To assess the efficacy of selinexor on spleen volume reduction in subjects with myelofibrosis (primary myelofibrosis [PMF], post-essential thrombocytosis-myelofibrosis [PET-MF], or post-polycythemia vera-myelofibrosis [PPV-MF]) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors.

SECONDARY OBJECTIVES:

I. 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.

II. To further assess the efficacy and clinical activity of selinexor (by means of reduction in symptoms, overall response and overall survival) in subjects with myelofibrosis (PMF, PET-MF, or PPV-MF) refractory or intolerant to ruxolitinib and/or any other experimental JAK1/2 inhibitors.

EXPLORATORY OBJECTIVES:

I. To assess the effects of selinexor on MF bone marrow fibrosis grade.

II. To assess the effects of selinexor on levels of circulating inflammatory cytokines.

III. To assess the effects of selinexor on JAK2 or CALR or MPL mutant allele burden.

IV. To assess the effects of selinexor on genetic mutations by next generation sequencing (NGS).

V. To assess the effects of selinexor on other pharmacodynamic markers.

VI. To explore whether a customized tool can be developed to estimate spleen volume based on magnetic resonance imaging (MRI) or computed tomography (CT) abdomen.

VII. To find predictive marker of selinexor response, from deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) sequencing.

OUTLINE:

Patients receive selinexor orally (PO) once weekly. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, participants are followed up every 3 months until 24 months after treatment initiation.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Huntsman Cancer Institute / University of Utah

Principal Investigator
Srinivas K. Tantravahi

  • Primary ID HCI114354
  • Secondary IDs NCI-2019-01883, ESSENTIAL, IST-302
  • Clinicaltrials.gov ID NCT03627403