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 Hematological Malignancies
1. Written informed consent in accordance with federal, local,and institutional
2. Age ≥18 years
3. Patients with malignancies that are refractory to or who are intolerant of
established therapy known to provide clinical benefit for their condition. Patients
must not be candidates for anti-tumor regimens known to provide clinical benefit.
4. Histologically confirmed diagnosis, and evidence of disease progression, of Multiple
Myeloma (MM), Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia (CLL), or
Waldenstrom's Macroglobulinemia (WM) as described below:
Multiple Myeloma (MM): Symptomatic disease previously treated with ≥3 prior regimens
(lines of therapy) that included at least one of each of the following: an alkylating
agent, an immunomodulatory drug, a proteasome inhibitor,and a steroid. Patients must
have measurable disease asdefined by at least one of the following:
- Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA myeloma,
by quantitative IgA
- Urinary M-protein excretion at least 200 mg/24 hours
- Serum Free Light Chain (SFLC) whereby the involved light chain measures ≥ 10
mg/dL and with an abnormal ratio
Non-Hodgkin's Lymphoma (NHL): Advanced indolent or aggressive NHL according to the
WHO1 classification,having been treated with ≥2 prior regimens including rituximab
(for B cell NHL only), an alkylating agent, and steroids. Patients with cutaneous T
cell lymphoma (CTCL) or Peripheral T Cell Leukemia (PTCL) are excluded from the
Chronic Lymphocytic Leukemia (CLL): advanced, relapsed CLL after having received
fludarabine (if appropriate), an alkylating agent, and rituximab as part of one or
more of their previous regimens.
Waldenström's Macroglobulinemia (WM): relapsed WM after at least 2 prior regimens
(lines of therapy) that included at least one proteasome inhibitor and at least one
Dose Expansion Cohort Group 1: Approximately 24 eligible patients with MM, NHL,CLL,
and WM will be enrolled into the dose expansion cohort.
Group 2: Approximately 24 eligible patients with acute myeloid leukemia (AML, any
subtype) or acute lymphoblastic leukemia (ALL). Patients with AML or ALL are eligible
only for enrollment into this dose expansion cohort and not in the dose escalation
AML: patients diagnosed with any subtype of AML(including acute biphenotypic and
mixed lineage) relapsed following treatment with at least one antileukemia regimen
including (unless contraindicated) an anthracycline and cytosine arabinoside (AraC).
Patients ineligible for standard induction therapy should be relapsed after at least
one prior anti-leukemia regimen. Patients with acute promyelocytic leukemia (APL) are
eligible following relapse on all-trans retinoic acid and arsenic trioxide.
ALL: patients diagnosed with any subtype of ALL following treatment with at least one
5. All patients on this study must have evidence of progressive disease on study entry.
There is no upper limit on the number of prior treatments provided all
inclusion/exclusion criteria are met.
6. Dose Escalation Phase: Eastern Cooperative Oncology Group (ECOG) Performance Status
of 0-1.Dose Expansion Phase: Eastern Cooperative Oncology Group (ECOG) Performance
Status of 0-2 (Appendix 1).
7. Patients receiving hematopoietic growth factor support including erythropoietin,
darbepoetin, G-CSF, GM-CSF, and platelet stimulators can continue to do so, but must
be transfusion independent for at least 3 weeks prior to registration in the dose
escalation phase of the study.
Transfusions are permitted in the dose expansion phase of the study. Screening
absolute neutrophil count (ANC)should be independent of growth factor support for at
least 1 week prior to registration for all patients except those with AML or ALL.
8. Adequate hematopoietic function (excluding patients with acute leukemia) within 14
days prior to C1D1: total white blood cell (WBC) count ≥1,500/mm3, absolute
neutrophil count (ANC) ≥800/mm3, hemoglobin (Hb) ≥8.0gm/dL, and platelet count
≥30,000/mm3. Screening ANC should be independent of growth factor support for >1 week
for all patients except those with acute leukemia (AML or ALL). Patients in Group 2
with acute leukemia should meet other inclusion/exclusion criteria but are not
required to meet these hematopoietic function criteria.
9. Adequate hepatic function within 14 days prior to C1D1: bilirubin <2 times the upper
limit of normal (ULN), asparate aminotransferase (AST) <2.5 times ULN and alanine
aminotransferase (ALT) <2.5 times ULN. In the case of known(radiological and/or
biopsy documented) liver metastasis, AST <5.0 times ULN and ALT <5.0 times ULN is
10. Adequate renal function within 14 days prior to C1D1:estimated creatinine clearance
of ≥ 30 mL/min, calculated using the formula of Cockroft and Gault (140-Age) •
Mass(kg)/(72 • creatinine mg/dL); multiply by 0.85 if female.
11. 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. For CLL and NHL palliative steroids for disease related symptoms are allowed
up to 3 days prior to starting therapy. For AML or ALL patients a minimum of 2 weeks
since last therapy, provided that patients have recovered from all adverse effects
are allowed. Hydroxyurea may be continued until 72 hours prior to first dose and at
least 24 hours before the baseline bonemarrow aspiration is performed;
3. Patients with active graft versus host disease after allogeneic stem cell
transplantation. At least 6 months must have elapsed since completion of allogeneic
stem cell transplantation;
4. Major surgery within four weeks before Day 1;
5. Unstable cardiovascular function:
- symptomatic ischemia, or
- uncontrolled clinically significant conduction abnormalities (ie: 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;
6. Uncontrolled active infection requiring systemic antibiotics,antivirals, or
antifungals within one week prior to first dose;
7. Known to be HIV seropositive;
8. Known active hepatitis A, B, or C infection; or known to be positive for HCV RNA or
HBsAg (HBV surface antigen);
9. 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
months. Patient with acute leukemia with blasts in their cerebrospinal fluid (CSF)
without CNS symptom may be included.
10. Patients with significantly diseased or obstructed gastrointestinal tract or
uncontrolled vomiting or diarrhea.
11. Grade ≥2 peripheral neuropathy at baseline (within 14 days prior to cycle 1 day 1).
12. History of seizures, movement disorders or cerebrovascular accident within the past 5
years prior to cycle 1 day 1.
13. Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased
14. In the opinion of the investigator, patients who are significantly below their ideal
15. Serious psychiatric or medical conditions that could interfere with treatment;
16. Participation in an investigational anti-cancer study within 3 weeks prior to Cycle 1
17. Concurrent therapy with approved or investigational anticancer therapeutic.