I. To estimate safety of KPT-330 (selinexor) in patients with melanoma at the maximum
tolerated dose (MTD) defined by the phase 1 study.
I. To determine the clinical benefit rate (CBR) (complete response, partial response, and
stable disease) of patients with unresectable melanoma.
II. To assess the efficacy at the MTD as measured by progression free survival (PFS) in
patients with melanoma.
I. To validate nuclear transport inhibition resulting from treatment. II. To assess if v-raf
murine sarcoma viral oncogene homolog B1 (BRAF), neuroblastoma RAS viral (v-ras) oncogene
homolog (NRAS), or platelet-derived growth factor receptor, beta polypeptide (PDGFRB)
mutational status impacts response.
III. To assess alteration in signaling pathways as a result of therapy with KPT-330.
IV. To assess immunologic changes resulting from treatment with KPT-330.
Patients receive selinexor orally (PO) twice weekly (BIW). Courses repeat every 4 weeks in
the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 1 year
- Written informed consent in accordance with federal, local, and institutional
- Patients with unresectable melanoma
- Patients must have received a biologic therapy (e.g. interleukin 2) and a BRAF and/or
MEK inhibitor (if tumor contains the V600E or V600K mutation) for 628 metastatic
disease. If patient did not receive such agents, rationale for not treating the
patients with the 629 agent must be cleared with the study PI (ie no V600e/k BRAF
mutation or patient with autoimmunity, thus 630 not eligible for biologic therapy).
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
- Total white blood cell (WBC) count >= 3000/mm^3
- Absolute neutrophil count (ANC) >= 1500/mm^3
- Platelet count >= 100,000/mm^3
- Bilirubin < 2 times the upper limit of normal (ULN) (except patients with Gilbert's
syndrome who must have a total bilirubin of < 3 times ULN)
- Alanine aminotransferase (ALT) < 2.5 times ULN; in the case of known (radiological
and/or biopsy documented) liver metastasis, ALT < 5.0 times ULN is acceptable
- Estimated creatinine clearance of >= 50 mL/min, calculated using the formula of
Cockroft and Gault
- Female patients of child-bearing potential must agree to use dual methods of
contraception and have a negative serum pregnancy test at screening, and male patients
must use an effective barrier method of contraception if sexually active with a female
of child-bearing potential; acceptable methods of contraception are condoms with
contraceptive foam, oral, implantable or injectable contraceptives, contraceptive
patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is
surgically sterilized or post-menopausal; for both male and female patients, effective
methods of contraception must be used throughout the study and for three months
following the last dose
- Patients who are pregnant or lactating
- Radiation, chemotherapy, immunotherapy or any other systemic anticancer therapy =< 2
weeks prior to initiation of therapy
- Major surgery within four weeks before initiation of therapy
- Unstable cardiovascular function:
- Symptomatic ischemia, or
- Uncontrolled clinically significant conduction abnormalities (e.g.: ventricular
tachycardia on antiarrhythmics are excluded and 1st degree atrioventricular (AV)
block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch
block [RBBB] will not be excluded)
- Congestive heart failure (CHF) of New York Heart Association (NYHA) class >= 3,
- Myocardial infarction (MI) within 3 months of initiation of therapy
- Uncontrolled active infection within one week prior to first dose
- Known to be human immunodeficiency virus (HIV) seropositive
- Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C
virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus [HBV] surface antigen)
- Patients with active central nervous system (CNS) malignancy
- Asymptomatic small lesions are not considered active
- Treated lesions may be considered inactive if the patient is able to taper off
steriods without any recurrent neurologic symptoms.
- Patients will be excluded if they have had a major resection of the bowel that could
influence absorption, inflammatory bowel disease, or other gastrointestinal conditions
with increased risk of perforation, history of abdominal fistula, gastrointestinal
perforation within 28 days prior to beginning study treatment
- Grade >= 2 peripheral neuropathy within 14 days prior to initiation of therapy
- History of seizures, movement disorders or cerebrovascular accident within the past 5
- Patients with known macular degeneration or uncontrolled glaucoma
- In the opinion of the investigator, patients who are significantly below their ideal
- Serious psychiatric or medical conditions that could interfere with treatment
- Participation in an investigational anti-cancer study within 3 weeks prior to
initiation of therapy
- Concurrent therapy with approved or investigational anticancer therapeutic