Safety Study of the Selective Inhibitor of Nuclear Export (SINE) KPT-330 in Patients With Advanced Hematological Cancer
Phase: Phase 1
NCT ID: NCT01607892
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 12-485
The purpose of this research study are to find out more information such as: the highest dose of KPT-330 that can be given safely, the side effects it may cause, to examine how the body affects the study drug concentrations in the blood (pharmacokinetics or PK), to examine the effects of this study drug on the body (pharmacodynamics or PDn) and to gain some information on its effectiveness in treating cancer.
Brigham and Women's Hospital, Dana-Farber Cancer Institute
Richard Stone, MD,
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute:
Ilene Galinsky, 617-632-3902,
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. Arm 1 Dose Escalation Phase: 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
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 as defined by at least one of the following:
1. Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA myeloma,
by quantitative IgA; or
2. Urinary M-protein excretion at least 200 mg/24 hours; or
3. 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
WHO 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 this
Chronic Lymphocytic Leukemia (CLL): advanced, relapsed CLL after having received
fludarabine (if medically 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
Arm 1: Dose Expansion Phase:
- Up to 10 patients with MM or WM: Symptomatic disease previously treated with,
and relapsed or refractory to, ≥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 as defined by at least one of the following:
1. Serum M-protein ≥ 0.5 g/dL by serum electrophoresis (SPEP) or for IgA
myeloma, by quantitative IgA; or
2. Urinary M-protein excretion at least 200 mg/24 hours; or
3. Serum Free Light Chain (SFLC) whereby the involved light chain measures ≥
10 mg/dL and with an abnormal ratio.
- Up to 15 patients with relapsed or refractory Diffuse Large B Cell Lymphoma
1. Biopsy-proven aggressive Diffuse Large B-Cell Lymphoma of any genetic
2. Relapsed or refractory to previous therapy for lymphoma.
3. Must have received at least one prior combination chemotherapy regimen.
There is no limit on the number of prior therapies.
4. Patients must have an autologous stem cell transplant if they were eligible
5. Patients must have measurable disease on cross sectional imaging that is at
least 2 cm in the longest diameter.
Arm 2 Dose Escalation and Expansion Phases: Histologically confirmed diagnosis of AML
according to the WHO classification (any subtype except for Acute Promyelocytic
Leukemia (APL)) with disease progression after chemotherapy, or not a chemotherapy
candidate as defined as:
- Refractory disease as defined: Persistent disease after at least two induction
cycles (e.g., 3+7 and 2+5), or at least one high dose arabinoside-C (Ara-C)
containing regimen; or
- Relapsed AML: unlikely to benefit from chemotherapy (second or subsequent
relapse, any relapse patients failing salvage chemotherapy, or patients in first
relapse with less than one year disease free interval; or
- Non-chemotherapy candidates: Previously untreated older adults (> age 60) with
at least one of the following risk factors: age >70 years, antecedent
hematological disease, non-favorable chromosome analysis.
Dose Expansion Cohort Approximately 25 eligible patients with MM or WM (N=10) and
DLBCL (N=15) will be enrolled into the dose expansion cohort in Arm 1 as described
Approximately 24 eligible patients AML as described in the escalation cohort above
will be enrolled into the dose expansion cohort in Arm 2.
Arm 3 Dose Expansion Phase: Histologically confirmed diagnosis of CTCL or PTCL (any
subtype) following treatment with at least two prior therapies.
- PTCL: patients must have relapsed or refractory to at least one prior
chemotherapy regimen, and have relapsed from, or are intolerant to, both
romidepsin and pralatrexate.
- CTCL: patients must extensive disease and have relapsed after at least one prior
chemotherapy regimen as well as from romidepsin.
5. All patients on this study must have evidence of progressive disease on study entry.
Previously untreated patients who are not chemotherapy candidates on Arm 2 may have
advanced disease (without clear progression). 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 (Appendix 1). Dose Expansion Phase: Eastern Cooperative Oncology Group (ECOG)
Performance Status of 0 1 (Appendix 1).
7. Adequate hepatic function within 14 days prior to C1D1: total 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), 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
8. Adequate renal function within 14 days prior to C1D1: estimated creatinine clearance
of ≥ 30 mL/min, calculated using the formula of Cockcroft 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.
10. Arm 1 & 3 only: 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. Elective transfusions are
permitted for transfusion independent patients during the 3-week period prior to
dosing. There are no restrictions on transfusions for enrollment into and during 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
11. Arm 1 & 3 only: 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.
1. Patients who are pregnant or lactating;
2. Radiation, chemotherapy, or immunotherapy or any other anticancer therapy ≤2 weeks
prior to cycle 1 day 1 and mitomycin C and radioimmunotherapy 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 patients in Arm 2, Hydroxyurea may be
given prior to, and during the first cycle of treatment with KPT-330;
3. Patients with active graft versus host disease after allogeneic stem cell
transplantation. At least 3 months must have elapsed since completion of allogeneic
stem cell transplantation except for patients with AML, where at least 2 months must
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 parenteral 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 malignant cells 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 first
dose of study drug;
17. Concurrent therapy with approved or investigational anticancer therapeutic other than
steroids or hydroxyurea as specified above.