Selinexor has shown single-agent activity in a current phase I study enrolling patients with
relapsed/refractory AML with durable complete remissions (CR), complete remissions with
incomplete hematologic recovery (CRi), partial remissions (PR), and stable disease (SD)
observed. Furthermore, common toxicities included nausea, fatigue, and anorexia and were
manageable with supportive care agents. Additionally, CLAG chemotherapy has proven activity
in relapsed and refractory AML, and has been shown to be a relatively well tolerated regimen
without significant non-hematologic toxicity. Given the established role of CLAG
chemotherapy, the single agent activity of selinexor, and their non-overlapping toxicities,
the investigators propose a phase I/II open label study of selinexor in combination with CLAG
for the treatment of patients with relapsed/refractory AML.
- Histologically confirmed AML (defined using WHO criteria) with one of the following:
- Primary refractory disease following ≤ 2 cycles of induction chemotherapy, or
- First relapse with no prior unsuccessful salvage chemotherapy, or
- Relapsed or refractory to hypomethylating agent, defined as a lack of response,
disease progression, loss of response, or intolerance as deemed by the study
- Age between 18 and 70 years old.
- ECOG performance status ≤ 3
- Adequate organ function as defined below:
- AST(SGOT), ALT(SGPT), total bilirubin ≤ 2 x IULN except when in the opinion of
treating physician is due to direct involvement of leukemia (eg. hepatic
infiltration or biliary obstruction due to leukemia) or Gilbert's disease
- Creatinine clearance >50 ml/min, calculated using the formula of Cockroft and
Gault: (140-Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply by 0.85 if
- Left ventricular ejection fraction of ≥ 40% by MUGA scan or echocardiogram
- To ensure that no patient will receive a dose of selinexor >70mg/m^2, body surface
area (BSA) calculated by Dubois method must be >1.43 m^2
- Patients should not become pregnant or father a baby while on this study because the
drugs in this study can affect an unborn baby. Women should not breastfeed a baby
while on this study. It is important patients understand the need to use birth control
while on this study. It is not anticipated that female patients enrolling in this
study will be able to conceive. However, in the rare event that this is possible,
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.
- Ability to understand and willingness to sign an IRB approved written informed consent
document (or that of legally authorized representative, if applicable).
- Acute promyelocytic leukemia (AML with t(15;17)(q22;q11) and variants).
- Previous treatment with CLAG or other chemotherapy regimen containing both cladribine
- Colony stimulating factors within 2 weeks of study.
- Active graft versus host disease (GVHD) after allogeneic stem cell transplantation. At
least 2 months must have elapsed since completion of an allogeneic stem cell
- Less than 2 weeks from the completion of any previous cytotoxic chemotherapy (with the
exception of hydroxyurea).
- Concurrent active malignancy under treatment except prostate or breast cancer
undergoing treatment with hormonal therapy.
- Treatment with any investigational agent within three weeks prior to first dose in
- Active CNS involvement with leukemia.
- Unstable cardiovascular function:
- symptomatic ischemia, or
- uncontrolled clinically significant conduction abnormalities (i.e. 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
- A history of allergic reactions attributed to compounds of similar chemical or
biologic composition to KPT-330 or other agents used in the study.
- Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals
within one week prior to first dose. Infections controlled on concurrent
anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional
guidelines is acceptable.
- Any medical condition which, in the investigator's opinion, could compromise the
- Pregnant and/or breastfeeding. Patient must have a negative urine pregnancy test
within 5 days of study entry.
- Unable to swallow tablets, or diagnosed malabsorption syndrome, or any other disease
significantly affecting gastrointestinal function.
- Known active hepatitis B virus (HBV) or C virus (HCV) infection; or known to be
positive for HCV ribonucleic acid (RNA) or HBsAg (HBV surface antigen).
- Known human immunodeficiency virus (HIV) infection.
- Serious psychiatric or medical conditions that could interfere with treatment.