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

NCT02299518 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: OSU 14089NCI-2014-02229
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

This phase I trial studies the side effects and best dose of selinexor when given together with etoposide with or without mitoxantrone hydrochloride and cytarabine in treating patients with acute myeloid leukemia that has returned (relapsed) or has not responded to treatment (refractory). Selinexor may help stop the growth of tumor cells by blocking an enzyme needed for cancer cell growth. Drugs used in chemotherapy, such as etoposide, mitoxantrone hydrochloride, and cytarabine, 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 chemotherapy together with selinexor work better in treating relapsed or refractory acute myeloid leukemia.

Conditions

Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Del(5q); Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• MTD of selinexor, defined as the highest safely tolerated dose where, at most, one patient experiences DLT in 6 evaluable patients, with the next higher dose having at least 2 patients who experience DLT

  The National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 will be used to characterize toxicities.

  28 days

Secondary Outcomes (3)

• Degree of response

  Up to 30 days after completion of study treatment

• Duration of response

  Up to 30 days after completion of study treatment

• ORR

  Up to 30 days after completion of study treatment

Other Outcomes (3)

• Change in expression of XPO1 and surrogates or direct targets of XPO1

  Baseline to up to day 35 (Cohort A) or day 29 of last course of treatment (Cohort B)

• Plasma pharmacokinetic (PK) parameters of selinexor will be assessed for oral and IV using non-compartmental and compartmental methods.

  1, 2, 4 and 24 hours post-dose days 1 and 15 of course 1; pre-dose days 3 and 17 of course 1

• Plasma pharmacokinetic (PK) parameters of etoposide and will be assessed for oral and IV using non-compartmental and compartmental methods.

  1, 2, 4 and 24 hours post-dose days 1 and 15 of course 1; pre-dose days 3 and 17 of course 1

Study Arms (2)

Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)

EXPERIMENTAL

Patients receive mitoxantrone hydrochloride IV, etoposide IV, and cytarabine IV QD on days 1-6 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment continues for 1 course (28 days). Further treatment is based on disease response. Patients achieving CR/CRi are evaluated for stem cell transplant; patients who do not proceed to transplant may receive selinexor as monotherapy in the absence of disease progression or unacceptable toxicity.

Drug: mitoxantrone hydrochloride; Drug: etoposide; Drug: cytarabine; Drug: selinexor; Other: laboratory biomarker analysis; Other: pharmacological study

Cohort B (etoposide, selinexor)

EXPERIMENTAL

Patients receive etoposide PO QD on days 1-5 and selinexor PO on days 1, 3, 8, 10, 15, and 17. Treatment may repeat every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients not achieving response after 4 courses discontinue treatment; patients achieving response may receive up to 4 courses of maintenance therapy every 8 weeks. Patients may then continue selinexor as monotherapy at the discretion of the principal investigator.

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

Interventions

mitoxantrone hydrochloride DRUG

Given IV

Also known as: CL 232315, DHAD, DHAQ

Cohort A (mitoxantrone, etoposide, cytarabine, selinexor)

etoposide DRUG

Given IV and PO

Also known as: EPEG, VP-16, VP-16-213

Cohort A (mitoxantrone, etoposide, cytarabine, selinexor); Cohort B (etoposide, selinexor)

cytarabine DRUG

Given IV

Also known as: ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U, cytosine arabinoside

Cohort A (mitoxantrone, etoposide, cytarabine, 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

Cohort A (mitoxantrone, etoposide, cytarabine, selinexor); Cohort B (etoposide, selinexor)

laboratory biomarker analysis OTHER

Correlative studies

Cohort A (mitoxantrone, etoposide, cytarabine, selinexor); Cohort B (etoposide, selinexor)

pharmacological study OTHER

Correlative studies

Also known as: pharmacological studies

Cohort A (mitoxantrone, etoposide, cytarabine, selinexor); Cohort B (etoposide, selinexor)

Eligibility Criteria

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

You may qualify if:

• Patients with relapsed or refractory AML; Cohort A patients must be \< 60 years of age and have failed at least one prior induction regimen for AML; Cohort B patients must be ≥ 60 years of age, unfit for intensive therapy (physician opinion), and have failed an induction regimen for AML. The maximum number of prior lines of induction for both cohorts is 3
• Patients with secondary AML or therapy related disease (t-AML) are eligible
• 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, except when patient is known to have Gilbert's Syndrome, the total bilirubin can be ≤3.0 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 (Cr) clearance \> 50 mL/min by Modification of Diet in Renal Disease (MDRD) calculation
• New York Heart Association (NYHA) congestive heart failure (CHF) class II or better
• Cardiac ejection fraction \>= 50%
• 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

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
• Major surgery within 2 weeks before day 1
• Uncontrolled active infection; patients with infection requiring parenteral antibiotics are eligible if the infection is controlled
• 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 (β)-human chorionic gonadotropin (β-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
• Patients whom, in the opinion of the investigators, are significantly below their ideal body weight
• Patients who are not able to swallow capsules or tablets

Sponsors & Collaborators

• Alice Mims: lead
• Karyopharm Therapeutics Inc: collaborator

Study Sites (1)

The State Ohio University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Publications (1)

• Bhatnagar B, Zhao Q, Mims AS, Vasu S, Behbehani GK, Larkin K, Blachly JS, Badawi MA, Hill KL, Dzwigalski KR, Phelps MA, Blum W, Klisovic RB, Ruppert AS, Ranganathan P, Walker AR, Garzon R. Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia. Leuk Lymphoma. 2023 Dec;64(13):2091-2100. doi: 10.1080/10428194.2023.2253480. Epub 2023 Sep 4.

  PMID: 37665178 DERIVED

Related Links

• The Jamesline

MeSH Terms

Conditions

Congenital Abnormalities; Leukemia, Myeloid, Acute

Interventions

Mitoxantrone; Etoposide; Cytarabine; selinexor

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Anthraquinones; Anthrones; Anthracenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Quinones; Polycyclic Compounds; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Glucosides; Glycosides; Carbohydrates; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Study Officials

• Alice Mims, MD

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

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

Study Record Dates

• First Submitted: November 19, 2014
• First Posted: November 24, 2014
• Study Start: May 18, 2015
• Primary Completion: March 6, 2018
• Study Completion: March 6, 2018
• Last Updated: June 15, 2023

Record last verified: 2023-06

Locations

US (1)