Neoplasms

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Dose escalation of selinexor with fixed doses of daunorubicin and cytarabine.

Induction Therapy may be followed by Consolidation Phase and Maintenance Phase as outlined in the Detailed Description and Intervention Descriptions.

Induction: Oral selinexor on days 1, 3, 8, 10, 15 and 17.

* Dose Level 2: 80 mg twice weekly.
* Dose Level 1 (starting dose): 60 mg twice weekly.
* Dose Level -1: 40 mg twice weekly.

Consolidation: Selinexor same dose as induction (days 1,3,8,10) unless dose limiting toxicity (DLT) dictates a dose reduction.

Maintenance: Selinexor at the same dose as induction on days 1 and 8 a 21 day cycle. They will continue for a maximum of 12 months.

Selinexor

Induction: Daunorubicin 60 mg/m\^2/day (days 1-3).

Consolidation: Daunorubicin 45 mg/m\^2/day (days 1-2).

Induction: Cytarabine 100 mg/m\^2/day (days 1-7).

Consolidation: Cytarabine 100 mg/m\^2/day (continuous infusion on days 1-5).

Kendra Sweet, M.D.

The main purpose of this study is to determine the safety of combining selinexor with daunorubicin and cytarabine. The maximal tolerated dose (MTD) of selinexor with daunorubicin and cytarabine will also be established.

Induction Therapy - Dose escalation of selinexor with Daunorubicin and cytarabine at fixed doses.

Consolidation Phase - Patients who are in complete remission (CR) or complete remission with incomplete count recovery (CRi) by day ≤70 and have recovered from any previous non- hematologic toxicity to baseline or grade ≤1 by day ≤70 following induction chemotherapy may go on to receive consolidation therapy for up to 2 cycles. The consolidation treatment phase will include up to two courses of therapy (28 day cycles) as follows:

Daunorubicin 45mg/m\^2/day (days 1-2) Cytarabine 100mg/m\^2/day (continuous infusion on days 1-5) Selinexor same dose as induction (days 1,3,8,10) unless dose limiting toxicity (DLT) dictates a dose reduction. Selinexor will be given 2 hours prior to daunorubicin on day 1.

A second cycle of consolidation therapy using the same doses as above will be administered, at the investigators discretion, between 28 and 42 days following initiation of the first consolidation treatment, after peripheral blood counts have recovered to CR, CRi levels, and after recovery from any non-hematologic toxicity to baseline or grade ≤1. Dose escalation of Selinexor will not occur during the consolidation phase.

Maintenance Phase - Patients who remain in CR, CRi after up to 2 cycles of consolidation and are not eligible for allogeneic stem cell transplant will be eligible for the maintenance phase of treatment after recovery from any previous non-hematologic toxicity to baseline or grade ≤1. Maintenance therapy will consist of:

Selinexor at the same dose as induction on days 1 and 8 of a 21 day cycle. They will continue for a maximum of 12 months.

Expansion Phase - Once the MTD has been established, there will be an expansion phase to enroll an additional 13 subjects at the MTD to better characterize the safety profile and tolerability.

A Study of Selinexor in Combination With Daunorubicin and Cytarabine for Untreated AML

A Phase 1 Investigator Sponsored Study of Selinexor in Combination With Daunorubicin and Cytarabine in Patients With Previously Untreated Poor-Risk Acute Myeloid Leukemia

MTD / Recommended Phase II Dose (RP2D) of selinexor with daunorubicin and cytarabine. Dose Limiting Toxicity (DLT): Non-hematologic - Any grade 3-4 drug-related non-hematologic toxicity, with the following exceptions: Nausea/vomiting or diarrhea adequately controlled with antiemetics/antidiarrheals; Infection or febrile neutropenia adequately controlled with antibiotics; Liver function abnormalities (without clinical symptoms) that recover to baseline or grade 0-1 within 7 days; Grade 3-4 electrolyte or metabolic laboratory abnormalities that are not considered clinically significant by the treating investigator/physician and that recover to baseline or grade 0-1 within 7 days; Alopecia. Hematologic - Grade 3-4 neutropenia and/or thrombocytopenia (thought to be due to marrow hypoplasia and NOT leukemic burden) that does not recover to grade ≤2 by day 56.

A CR designation requires that the patient achieve the morphologic leukemia-free state and have an absolute neutrophil count of more than 1,000/μL and platelets of 100,000/μL. A CRi designation requires that the patient achieve the morphologic leukemia-free state with incomplete recovery of neutrophils (\<1,000/μL) or platelets (\<100,000/μL).

Disease free survival is measured from the time measurement criteria are met for CR/CRi until the first date that relapse is objectively documented.

Time to progression is a secondary endpoint that will be measured as the time from when the patient started treatment to the time the patient is first recorded as having relapsed, or the date of death if the patient dies due to causes other than disease progression.

Overall survival is a secondary endpoint that will be measured as time from the start of treatment until death from any cause, or the last date the patient was known to be alive.

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