Selinexor With Combination Chemotherapy in Treating Patients With Acute Myeloid Leukemia

Phase I Investigator Sponsored Study to Assess the Tolerability and Efficacy of Selinexor in Combination With High Dose Cytarabine (HiDAC) and Mitoxantrone Chemotherapy for Remission Induction in Acute Myelogenous Leukemia (AML)

This phase I trial studies the side effects and the best dose of selinexor when give together with standard chemotherapy, high dose cytarabine and mitoxantrone hydrochloride, in treating patients with acute myeloid leukemia. Selinexor may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and mitoxantrone hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving selinexor together with standard chemotherapy may be a better treatment for patients with acute myeloid leukemia.

Study Overview

• Status: Completed
• Conditions: Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Selinexor; Drug: Cytarabine; Drug: Mitoxantrone Hydrochloride

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed, written informed consent in accordance with federal, local, and institutional guidelines
• Patients with newly diagnosed or relapsed/refractory AML, except acute promyelocytic leukemia (APL), requiring intensive induction chemotherapy
• Eastern Cooperative Oncology Group (ECOG) performance status of =< 2
• Creatinine clearance > 30 cc/min calculated using the Cockcroft and Gault (1976) formula or measured
• Total bilirubin =< 2 mg/dl unless high indirect bilirubin is due to a congenital disorder
• Transaminases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) =< 3.0 x upper limit of normal (ULN) unless due to leukemia infiltration
• Prothrombin time (PT) and partial thromboplastin time (PTT) =< 2 x ULN
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures
• It is important patients understand the need to use birth control while on this study; female patients of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening (< 3 days prior to first dose), male patients with partners of childbearing potential must agree to use effective contraception during the study period and a period of 3 months after the last dose of study drug; for both male and female patients, effective methods of contraception must be used throughout the study and for three months following the last dose

Exclusion Criteria:

• Treatment with any investigational agent within two weeks prior to first dose in this study; hydroxyurea is allowed to control the AML prior to treatment on the study
• AML central nervous system (CNS) involvement
• Major surgery within 2 weeks of first dose of study drug; patients must have recovered from the effects of any surgery performed greater than 2 weeks previously
• Patient has a concurrent advantage active malignancy under treatment

• Unstable cardiovascular function:

  • Symptomatic ischemia, or
  • Uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular [AV] block or asymptomatic left anterior fascicular block/right bundle branch block [left anterior fascicular block (LAFB)/right bundle branch block (RBBB)] will not be excluded), or
  • Congestive heart failure (CHF) New York Heart Association (NYHA) class >= 3, or
  • Myocardial infarction (MI) within 3 months
• 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
• 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
• Any medical condition which, in the investigator's opinion, could compromise the patient's safety
• Patients unable to swallow tablets or patients with malabsorption syndrome, or any other disease significantly affecting gastrointestinal function
• Seizure or cerebrovascular accident (CVA) in the last year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: selinexor, cytarabine, and mitoxantrone; INDUCTION CHEMOTHERAPY: Patients receive high-dose cytarabine and mitoxantrone hydrochloride per standard of care on days 1 and 5, and selinexor PO on days 2, 4, 9, and 11. CONSOLIDATION CHEMOTHERAPY: Patients receive high-dose cytarabine per standard of care on days 1, 3, and 5, and selinexor PO on days 2, 4, 9, and 11. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE CHEMOTHERAPY: Patients achieving at least stable disease after consolidation chemotherapy may receive selinexor PO on days 1, 8, 15, and 22 at the discretion of principal investigator.

Drug: Selinexor; Given PO; Other Names: KPT-330; Drug: Cytarabine; Given per standard of care; Other Names: Ara-C; Drug: Mitoxantrone Hydrochloride; Given per standard of care; Other Names: Mitroxone

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
MTD of selinexor based on the dose-limiting toxicity graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03	56 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Allo-SCT success rate		After completion of induction therapy (6 months to a year)
Incidence of adverse events graded according to NCI CTCAE version 4.03		Up to 30 days post-treatment
Incidence of non-relapse mortality		Up to 1 year
Overall survival (OS) rates	The median duration of OS will be estimated based on the 50th percentile of the Kaplan-Meier distribution; additional summary statistics will be presented, including the 25th and 75th percentiles, 95% CIs on the median and other percentiles, and proportion of censored data. Kaplan-Meier survival rates will also be calculated.	Date induction chemotherapy to the date of disease relapse or death, assessed up to 1 year
Progression-free survival (PFS) rates	PFS will be estimated based on the 50th percentile of the Kaplan-Meier distribution; additional summary statistics will be presented, including the 25th and 75th percentiles, 95% confidence intervals (CIs) on the median and other percentiles, and proportion of censored data. Kaplan-Meier survival rates will also be calculated.	Date induction chemotherapy to the date of disease relapse or death, assessed up to 1 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
MRD status as measured by WT1 transcript levels using quantitative real time-PCR	Cox models may be used to determine MRD status during the treatment course.	Up to 1 year

Collaborators and Investigators

• Sponsor: University of Chicago
• Collaborators: National Cancer Institute (NCI)

Publications and helpful links

General Publications

• Wang AY, Weiner H, Green M, Chang H, Fulton N, Larson RA, Odenike O, Artz AS, Bishop MR, Godley LA, Thirman MJ, Kosuri S, Churpek JE, Curran E, Pettit K, Stock W, Liu H. A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia. J Hematol Oncol. 2018 Jan 5;11(1):4. doi: 10.1186/s13045-017-0550-8.

Study record dates

Study Major Dates

• Study Start (Actual): October 7, 2015
• Primary Completion (Actual): January 1, 2018
• Study Completion (Actual): May 3, 2019

Study Registration Dates

• First Submitted: October 5, 2015
• First Submitted That Met QC Criteria: October 7, 2015
• First Posted (Estimate): October 9, 2015

Study Record Updates

• Last Update Posted (Actual): April 8, 2020
• Last Update Submitted That Met QC Criteria: April 6, 2020
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cytarabine; Mitoxantrone
• Other Study ID Numbers: IRB15-0412 (Other Identifier: University of Chicago Comprehensive Cancer Center); P30CA014599 (U.S. NIH Grant/Contract); NCI-2015-01647 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No