Phase I/II, Study of Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) + Sorafenib in Acute Myeloid Leukemia

Inclusion Criteria

• FLT3-ITD and/or FLT3-D835 mutated patients 18 years of age or older with relapsed/ refractory AML (any number of relapses) including patients who may have been previously exposed to one or more FLT3-inhibitor therapies will be eligible for the phase I portion of this study.
• Phase II FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory patients: Patients should have a diagnosis of AML (de novo or transformed from hematologic malignancies). Patients with high-risk myelodysplastic syndrome (MDS) (defined as having >/= 10% blasts in the bone marrow) or patients with Chronic Myelomonocytic Leukemia (CMML) (having >/= 10% blasts in the bone marrow) may also be eligible after discussion with Principal Investigator (PI). The patients should have one of the following features: 1. Patients with AML should have failed any prior induction therapy or have relapsed after prior therapy. 2. Patients with high-risk MDS or high-risk CMML should have failed any prior therapy for the MDS or CMML. 3. Patients with MDS or CMML who received therapy for the MDS or CMML and progress to AML are eligible at the time of diagnosis of AML regardless any prior therapy for AML. The World Health Organization (WHO) classification will be used for AML.
• Patients must be eligible for one of two cohorts: Cohort 1 (FLT3 and/or FLT3-D835 inhibitor failure cohort) in FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory AML who have failed therapy with up to two prior salvage regimens (SCT or stem cell therapy for patients who previously underwent SCT/stem cell therapy in remission will not be considered a salvage regimen) and have previously been exposed at least one prior FLT3 inhibitor. Cohort 2 (FLT3 inhibitor naive cohort) in FLT3-ITD and/or FLT3-D835 mutated relapsed/refractory who have failed therapy with up to two prior salvage regimens (SCT or stem cell therapy for patients who previously underwent SCT/stem cell therapy in remission will not be considered a salvage regimen) with no prior exposure to any FLT3 inhibitor.
• Age >/=18 years
• Eastern Cooperative Oncology Group (ECOG) Performance Status 3 months at study entry
• Adequate hepatic (serum total bilirubin /= 40%.
• Females must be surgically or biologically sterile or postmenopausal (amenorrheic for at least 12 months) or if of childbearing potential, must have a negative serum or urine pregnancy test within 72 hours before the start of the treatment.
• Women of childbearing potential must agree to use an adequate method of contraception during the study and until 3 months after the last treatment. Males must be surgically or biologically sterile or agree to use an adequate method of contraception during the study until 3 months after the last treatment. Adequate methods of contraception include: Total abstinence when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
• (Continued from Criteria 12) Male sterilization (at least 6 months prior to screening). For female patients on the study, the vasectomized male partner should be the sole partner for that patient Combination of any of the two following (a+b or a+c or b+c) Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate 140 mm Hg systolic or > 90 mm Hg diastolic with or without antihypertensive therapy.
• Uncontrolled infection at the time of enrollment. Infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophyl