A Phase I Study of the Safety, Pharmacokinetics and Pharmacodynamics of Escalating Doses of the Selective Inhibitor of Nuclear Export (SINE) KPT- 330 in Patients With Advanced or Metastatic Solid Tumor Malignancies
1. Written informed consent in accordance with federal, local, and institutional
2. Age ≥18 years
3. Patients with advanced or metastatic solid tumors for which no standard therapy is
4. Dose Escalation Phase: Patients have exhausted, or be deemed to not benefit from,
further conventional therapy and have evidence of progressive disease on study entry.
Dose Expansion Phase: Patients must have received at least one prior anticancer
regimen and evidence of progressive disease on study entry.
Both Doses Escalation and Expansion Phases: There is no upper limit on the number of
prior treatments provided all inclusion/exclusion criteria are met.
5. Eastern Cooperative Oncology Group (ECOG)Performance Status of 0-1 (Appendix 1).
6. Adequate hematopoietic function: total white blood cell(WBC)count ≥3000/mm3, absolute
neutrophil count(ANC) ≥1500/mm3, and platelet count ≥100,000/mm3.
7. Adequate hepatic function: bilirubin <2 times the upper limit of normal (ULN) and
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;
8. Adequate renal function: estimated creatinine clearance of ≥50 mL/min, calculated
using the formula of Cockroft and Gault (140-Age) • Mass (kg)/(72 • creatinine
mg/dL);multiply by 0.85 if female.
9. 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 meeting any of the following exclusion criteria are not eligible to enroll in
1. Patients who are pregnant or lactating
2. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤3 weeks
prior to cycle 1 day 1 and mitomycin C and radio-immunotherapy 6 weeks prior to cycle
1 day 1
3. Major surgery within four weeks before Cycle 1 day 1
4. Unstable cardiovascular function:
- symptomatic ischemia, or
- uncontrolled clinically significant conduction abnormalities (eg: ventricular
tachycardia on antiarrhythmics are excluded and 1st degree AV block or
asymptomatic LAFB/RBBB will not be excluded), or
- congestive heart failure (CHF) of NYHA Class ≥3, or
- myocardial infarction (MI) within 3 months of Cycle 1 Day 1 dose;
5. Uncontrolled active infection requiring systemic antibiotics,antivirals, or
antifungals within one week prior to first dose;
6. Known to be HIV seropositive;
7. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or
HBsAg (HBV surface antigen);
8. Patients with active CNS malignancy. Asymptomatic small lesions are not considered
active. Treated lesions may be considered inactive if they are stable for at least 3
9. Patients with significantly diseased or obstructed gastrointestinal tract or
uncontrolled vomiting or diarrhea.
10. Grade ≥2 peripheral neuropathy within 14 days prior to Cycle 1 Day 1.
11. History of seizures, movement disorders or cerebrovascular accident within the past 5
years prior to cycle 1 day 1.
12. Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased
13. In the opinion of the investigator, patients who are significantly below their ideal
14. Serious psychiatric or medical conditions that could interfere with treatment;
15. Participation in an investigational anti-cancer study within 3 weeks prior to Cycle
1 Day 1;
16. Concurrent therapy with approved or investigational anticancer therapeutic.