Decitabine and Selinexor in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia

NCT02093403 | Completed Phase 1 DMC

• 2 other identifiers: OSU-13182NCI-2014-00559
• Study Type: interventional
• Target: 25
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of Selinexor when given together with decitabine in treating patients with acute myeloid leukemia that has returned after treatment (relapsed) or does not respond to treatment (refractory). Drugs used in chemotherapy, such as decitabine and Selinexor, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing.

Conditions

Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Untreated Adult Acute Myeloid Leukemia

Keywords

AML; Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia with T(8;21)(Q22;Q22); adult Acute Myeloid Leukemia with 11q23 (MLL) abnormalities; adult Acute Myeloid Leukemia with del(5q); adult Acute Myeloid Leukemia with inv(16)(p13;q22)

Outcome Measures

Primary Outcomes (4)

• MTD defined as the dose where at most one patient experiences DLT with the next higher dose having at least 2 patients who experience DLT graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03

  31 days

• Incidence of severe (grade 3+) adverse events or toxicities assessed by NCI CTCAE version 4.03

  The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

  Up to 3 years

• Tolerability of the regimen defined by the number of patients who required dose modifications and/or dose delays

  Up to 3 years

• Proportion of patients who go off treatment due to adverse reactions

  Up to 3 years

Secondary Outcomes (6)

• Overall response rate

  Up to 3 years

• Complete response rate

  Up to 3 years

• Change in expression of XPO1

  Baseline to up to day 31 of course 1

• Change in expression of genes associated with XPO1

  Baseline to up to day 31 of course 1

• Change in expression of miRs associated with XPO1

  Baseline to up to day 31 of course 1

Study Arms (1)

Treatment (decitabine and selinexor)

EXPERIMENTAL

INDUCTION: Patients receive decitabine IV over 1 hour on days 1-10 and selinexor PO on days 11, 13, 18, 20, 25 and 27. Treatment repeats every 31 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive decitabine IV over 1 hour on days 1-5 and selinexor PO on days 6, 8, 13, 15, 20 and 22. Courses repeat every 31 days in the absence of disease progression or unacceptable toxicity.

Drug: decitabine; Drug: selinexor; Other: pharmacological study; Other: laboratory biomarker analysis

Interventions

decitabine DRUG

Given IV

Also known as: 5-aza-dCyd, 5AZA, DAC

Treatment (decitabine and selinexor)

selinexor DRUG

Given PO

Also known as: CRM1 nuclear export inhibitor KPT-330, KPT-330, selective inhibitor of nuclear export KPT-330, SINE KPT-330

Treatment (decitabine and selinexor)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Treatment (decitabine and selinexor)

laboratory biomarker analysis OTHER

Correlative studies

Treatment (decitabine and selinexor)

Eligibility Criteria

• Age: 19 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with relapsed or refractory AML
• Newly diagnosed elderly AML patients (\> 60 years) unfit for intensive chemotherapy with cytarabine and anthracyclines are also eligible to this trial given that no clinically beneficial therapy exists for these patients
• Patients with secondary AML or therapy related disease (t-AML) are eligible; patients who received decitabine or 5-azacytidine as prior treatment for myelodysplastic syndrome (MDS) or AML remain eligible; however, none of these agents is permitted within 6 months of study entry
• If the patient has co-morbid medical illness, life expectancy attributed to this must be greater than 6 months
• Eastern Cooperative Oncology Group (ECOG) performance status \< 2
• Total bilirubin \< 2.0 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) \< 2.5 X institutional upper limit of normal
• Creatinine \< 2.0 mg/d
• Glomerular filtration rate (GFR) \> 50 mL/min
• New York Heart Association (NYHA) congestive heart failure (CHF) class II or better
• 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 the written informed consent document
• Human immunodeficiency virus (HIV) infection without history of acquired immune deficiency syndrome (AIDS) and sufficiently high cluster of differentiation (CD)4 cells (\> 400/mm\^3) and low HIV viral loads (\< 30,000 copies/ml plasma) not requiring anti-HIV therapy are eligible
• Patients must have recovered from the toxicity of prior therapy to less than grade 2

You may not qualify if:

• Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• Patients receiving any other investigational agents or patients that have received other investigational agents within 14 days of enrollment
• Patients with active central nervous system (CNS) malignancy; asymptomatic small lesions are not considered active; treated lesions may be considered inactive if they are stable for at least 3 months; patients with malignant cells in their cerebrospinal fluid (CSF) without CNS symptoms may be included
• Patients with history of allergic reactions attributed to compounds of similar chemical or biologic composition to decitabine that are not easily managed
• Major surgery within 2 weeks before day 1
• Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose
• Known active hepatitis A, B, or C infection; or known to be positive for hepatitis C virus (HCV) ribonucleic acid (RNA) or HBsAg (hepatitis B virus \[HBV\] surface antigen)
• Patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea
• History of seizures, movement disorders or cerebrovascular accident within the past 3 years prior to cycle 1 day 1
• Patients with macular degeneration, uncontrolled glaucoma, or markedly decreased visual acuity
• Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure (New York Heart Association \[NYHA\] class III or IV), unstable angina pectoris, myocardial infarction within 6 months prior to enrollment, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities; prior to study entry, any electrocardiogram (ECG) abnormality at screening has to be documented by the investigator as not medically relevant
• Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study
• Pregnant women or women who are breastfeeding are excluded from this study; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening; pregnancy testing is not required for post-menopausal or surgically sterilized women
• Patients with advanced malignant solid tumors are excluded
• Patients with renal failure (GFR \< 50 mL/min) are excluded

Sponsors & Collaborators

• Bhavana Bhatnagar: lead
• Karyopharm Therapeutics Inc: collaborator

Study Sites (1)

Arthur G. James Cancer Hospital and Solove Research Institute at Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

Related Publications (1)

• Bhatnagar B, Zhao Q, Mims AS, Vasu S, Behbehani GK, Larkin K, Blachly JS, Blum W, Klisovic RB, Ruppert AS, Orwick S, Oakes C, Ranganathan P, Byrd JC, Walker AR, Garzon R. Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study. Leuk Lymphoma. 2020 Feb;61(2):387-396. doi: 10.1080/10428194.2019.1665664. Epub 2019 Sep 23.

  PMID: 31545113 DERIVED

Related Links

• The Jamesline

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Congenital Abnormalities

Interventions

Decitabine; selinexor

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Study Officials

• Bhavana Bhatnagar, DO

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: March 19, 2014
• First Posted: March 21, 2014
• Study Start: March 1, 2014
• Primary Completion: November 26, 2016
• Study Completion: November 26, 2016
• Last Updated: December 8, 2017

Record last verified: 2017-12

Locations

US (1)