Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesPhase 1NCT02299518
Selinexor and Chemotherapy in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia
A Phase 1 study testing mitoxantrone hydrochloride, etoposide and cytarabine in people with Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities and Adult Acute Myeloid Leukemia With Del(5q), run by Alice Mims at 1 site in United States.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
- What is being tested?
- mitoxantrone hydrochloride, etoposide and cytarabine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 23 participants
- Where
- 1 siteUnited States
- Study dates
- 18 May 2015to 6 Mar 2018
- Phase
- Phase 1
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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
Who cannot join
- 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
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- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
The State Ohio University Comprehensive Cancer Center
Columbus, Ohio, 43210
About this study
Official title: 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.
Read the detailed description
PRIMARY OBJECTIVES:
- 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:
- 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:
- 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.
- 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)
- Being tested
- mitoxantrone hydrochloride, etoposide, cytarabine, selinexor, laboratory biomarker analysis
- Medical subject headings
- Congenital Abnormalities, Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
mitoxantrone hydrochlorideDrug
Also called CL 232315, DHAD, DHAQ
Given IV
etoposideDrug
Also called EPEG, VP-16, VP-16-213
Given IV and PO
cytarabineDrug
Also called ARA-C, arabinofuranosylcytosine, arabinosylcytosine, Cytosar-U
Given IV
selinexorDrug
Also called CRM1 nuclear export inhibitor KPT-330, KPT-330, selective inhibitor of nuclear export KPT-330, SINE KPT-330
Given PO
laboratory biomarker analysisOther
Correlative studies
Also called pharmacological studies
Correlative studies
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: etoposide; Drug: selinexor; Other: laboratory biomarker analysis; Other: pharmacological study |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 28 days
Secondary outcomes (3)
Degree of response
Summarized within each stratum and at each dose level.
Measured: Up to 30 days after completion of study treatment
Duration of response
Duration of response will be reported for patients who achieve complete remission.
Measured: 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.
Measured: Up to 30 days after completion of study treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Nov 2014 (estimated)
- Study start18 May 2015
- Primary completion6 Mar 2018
- Study completion6 Mar 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 23 participants (actual)
Sponsor and investigators
- Lead sponsor
- Alice Mims
- Sponsor type
- University, hospital or other
- Collaborators
- Karyopharm Therapeutics Inc
- Responsible party
- Sponsor-investigator, Alice Mims, Ohio State University Comprehensive Cancer Center
- Investigators
- Alice Mims, MD, Principal investigator, Ohio State University Comprehensive Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02299518
- Sponsor's protocol ID
- OSU 14089
- Other IDs
- NCI-2014-02229
- Status last verified
- Jun 2023
- First submitted
- 19 Nov 2014
- Last updated
- 15 Jun 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
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.
PubMed 37665178