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

Sponsor

Bhavana Bhatnagar (Other)

Overall Status

Completed

CT.gov ID

NCT02093403

Collaborator

Karyopharm Therapeutics Inc (Industry)

Enrollment

Location

Arm

32.9

Actual Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Untreated Adult Acute Myeloid Leukemia	Drug: decitabine Drug: selinexor Other: pharmacological study Other: laboratory biomarker analysis	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To evaluate the safety and tolerability of Selinexor (KPT-330) in combination with decitabine in patients with acute myeloid leukemia (AML).
To define the specific toxicities, maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of this combination.
To determine the Recommended Phase 2 Dose (RP2D) of this combination.

SECONDARY OBJECTIVES:

To determine the overall response rate (ORR). II. To determine the rate and duration of complete remission (CR) +/- hematological recovery of KPT-330 plus decitabine in AML.
To conduct pharmacodynamic studies by measuring the effect of this chemotherapy combination on the kinome, micronome and epigenome.

OUTLINE: This is a dose-escalation study of selinexor.

INDUCTION: Patients receive decitabine intravenously (IV) over 1 hour on days 1-10 and Selinexor orally (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.

After completion of study treatment, patients are followed up periodically.

Study Design

Study Type:

Interventional

Actual Enrollment :

25 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of Decitabine (Dacogen) and Selinexor (KPT-330) in Acute Myeloid Leukemia

Actual Study Start Date :

Mar 1, 2014

Actual Primary Completion Date :

Nov 26, 2016

Actual Study Completion Date :

Nov 26, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (decitabine and selinexor) 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 Given IV Other Names: 5-aza-dCyd 5AZA DAC Drug: selinexor Given PO Other Names: CRM1 nuclear export inhibitor KPT-330 KPT-330 selective inhibitor of nuclear export KPT-330 SINE KPT-330 Other: pharmacological study Correlative studies Other Names: pharmacological studies Other: laboratory biomarker analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (decitabine and selinexor)

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

Given IV

Other Names:

5-aza-dCyd

5AZA

DAC

Drug: selinexor

Given PO

Other Names:

CRM1 nuclear export inhibitor KPT-330

KPT-330

selective inhibitor of nuclear export KPT-330

SINE KPT-330

Other: pharmacological study

Correlative studies

Other Names:

pharmacological studies

Other: laboratory biomarker analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

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 [Up to 3 years]
The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
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 Outcome Measures

Overall response rate [Up to 3 years]
Responses will be summarized by simple descriptive summary statistics across all dose levels. Overall response rate will estimated at the MTD and defined as the number of patients who achieve any level of clinical response (e.g. CR, incomplete blood count recovery, morphologic CR) divided by the total number of evaluable patients (i.e. any patient who received at least one dose of study treatment).
Complete response rate [Up to 3 years]
Responses will be summarized by simple descriptive summary statistics across all dose levels. Complete response rate will be estimated in those patients treated at the MTD.
Change in expression of XPO1 [Baseline to up to day 31 of course 1]
Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side-by-side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, micro-ribonucleic acids (miRs), and methylated signatures will be evaluated using scatterplots and the Spearman-rank correlation coefficient.
Change in expression of genes associated with XPO1 [Baseline to up to day 31 of course 1]
Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side-by-side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, miRs, and methylated signatures will be evaluated using scatterplots and the Spearman-rank correlation coefficient.
Change in expression of miRs associated with XPO1 [Baseline to up to day 31 of course 1]
Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side-by-side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, miRs, and methylated signatures will be evaluated using scatterplots and the Spearman-rank correlation coefficient.
Change in expression of methylated signatures [Baseline to up to day 31 of course 1]
Changes in expression of these markers across time will be explored by dose level graphically. Relationships between baseline expression levels and changes in expression levels with response and certain toxicities will also be explored graphically (e.g. side-by-side boxplots) and with quantitative summaries. Confidence intervals will be presented as the primary method of analysis. Correlations among expression of the genes, miRs, and methylated signatures will be evaluated using scatterplots and the Spearman-rank correlation coefficient.

Eligibility Criteria

Criteria

Ages Eligible for Study:

19 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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

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
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
Patients that in the opinion of the investigators are significantly below their ideal body weight