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

Phase 1 Study of Selinexor in Combination With Topoisomerase-II Inhibition in Acute Myeloid Leukemia

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Adult Acute Myeloid Leukemia; 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(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Secondary Acute Myeloid Leukemia; Adult Acute Myeloid Leukemia With t(15;17)(q22;q12)
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: cytarabine; Drug: mitoxantrone hydrochloride; Drug: etoposide; Drug: selinexor

Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the safety and tolerability of selinexor in combination with mitoxantrone hydrochloride, etoposide, cytarabine (MEC) or oral etoposide (respective cohorts are independent of each other) in patients with relapsed or refractory acute myeloid leukemia (AML).

II. To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting toxicities (DLT) of these combinations.

III. To determine the recommended phase 2 dose (RP2D) of these combinations.

SECONDARY OBJECTIVES:

I. To determine the rate and duration of complete remission (CR) ± hematologic recovery of selinexor plus MEC therapy in AML.

II. To determine the overall response rate (ORR). III. To define the rate of complete remission (CR + CR with incomplete blood count recovery [CRi]) rate by the end of induction therapy.

IV. Determine the disease-free survival for patients who reached CR/CRi within 1 year.

TERTIARY OBJECTIVES:

I. To conduct pharmacodynamic studies by measuring the effect of these chemotherapy combinations on the inhibition of exportin 1 (XPO1).

II. To conduct pharmacokinetic sampling of selinexor and etoposide at limited time points to assess drug metabolism, peak plasma levels and area under curve (AUC).

OUTLINE: This is a dose-escalation study of selinexor. Patients are assigned to 1 of 2 cohorts.

COHORT A (PATIENTS FIT FOR INTENSIVE THERAPY, AGE < 60): Patients receive mitoxantrone hydrochloride intravenously (IV), etoposide IV, and cytarabine IV once daily (QD) on days 1-6 and selinexor orally (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.

COHORT B (PATIENTS UNFIT FOR INTENSIVE THERAPY, AGE ≥ 60): 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.

After completion of study treatment, patients are followed up for at least 30 days.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • The State Ohio University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A (mitoxantrone, etoposide, cytarabine, selinexor); 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: cytarabine; Given IV; Other Names: Cytosar-U; cytosine arabinoside; ARA-C; arabinofuranosylcytosine; arabinosylcytosine; Drug: mitoxantrone hydrochloride; Given IV; Other Names: CL 232315; DHAD; DHAQ; Drug: etoposide; Given IV and PO; Other Names: EPEG; VP-16; VP-16-213; Drug: selinexor; Given PO; Other Names: KPT-330; SINE KPT-330; CRM1 nuclear export inhibitor KPT-330; selective inhibitor of nuclear export KPT-330
Experimental: Cohort B (etoposide, selinexor); 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.	Other: laboratory biomarker analysis; Correlative studies; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies; Drug: etoposide; Given IV and PO; Other Names: EPEG; VP-16; VP-16-213; Drug: selinexor; Given PO; Other Names: KPT-330; SINE KPT-330; CRM1 nuclear export inhibitor KPT-330; selective inhibitor of nuclear export KPT-330

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Degree of response	Summarized within each stratum and at each dose level.	Up to 30 days after completion of study treatment
Duration of response	Duration of response will be reported for patients who achieve complete remission.	Up to 30 days after completion of study treatment
ORR	Will be presented for those patients treated at the MTD with an exact 95% confidence interval.	Up to 30 days after completion of study treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in expression of XPO1 and surrogates or direct targets of XPO1	The impact of selinexor on the inhibition of XPO1 expression and various genes/microribonucleic acids that serve as surrogates or direct targets of XPO1 will be characterized. Expression prior to administration of selinexor and following treatment with selinexor will be described graphically using boxplots or summary measures (e.g. mean and standard errors). Trends of dose response will be explored within each stratum, as well as whether targets are being "hit" between the strata. Due to data limitations in early clinical trials, analyses will be descriptive in nature.	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.	Intracellular PK of selinexor will be evaluated primarily by determining total intracellular concentrations of parent drugs on day 1 and day 8. The primary hypothesis is that selinexor intracellular exposure (area under the concentration-time curve, AUCIC), normalized to plasma exposure (AUCP), will be greater on Day 1 vs. Day 8 due to reduced intracellular selinexor-glutathione conjugation in the presence of etoposide. The AUCIC and AUCIC/AUCP ratio will be evaluated for correlations with selinexor activity."	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.	Intracellular PK of etoposide will be evaluated primarily by determining total intracellular concentrations of parent drugs on day 1 and day 8. The primary hypothesis is that selinexor intracellular exposure (area under the concentration-time curve, AUCIC), normalized to plasma exposure (AUCP), will be greater on Day 1 vs. Day 8 due to reduced intracellular selinexor-glutathione conjugation in the presence of etoposide. The AUCIC and AUCIC/AUCP ratio will be evaluated for correlations with selinexor activity."	1, 2, 4 and 24 hours post-dose days 1 and 15 of course 1; pre-dose days 3 and 17 of course 1

Collaborators and Investigators

• Sponsor: Alice Mims
• Collaborators: Karyopharm Therapeutics Inc
• Investigators: Principal Investigator: Alice Mims, MD, Ohio State University Comprehensive Cancer Center

Publications and helpful links

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): May 18, 2015
• Primary Completion (Actual): March 6, 2018
• Study Completion (Actual): March 6, 2018

Study Registration Dates

• First Submitted: November 19, 2014
• First Submitted That Met QC Criteria: November 20, 2014
• First Posted (Estimated): November 24, 2014

Study Record Updates

• Last Update Posted (Actual): June 15, 2023
• Last Update Submitted That Met QC Criteria: June 12, 2023
• Last Verified: June 1, 2023

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; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Etoposide; Etoposide phosphate; Cytarabine; Mitoxantrone
• Other Study ID Numbers: OSU 14089; NCI-2014-02229 (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