Bortezomib, Sorafenib Tosylate, and Decitabine in Treating Patients With Acute Myeloid Leukemia

Sponsor

National Cancer Institute (NCI) (NIH)

Overall Status

Active, not recruiting

CT.gov ID

NCT01861314

Collaborator

(none)

Enrollment

Location

Arm

Study Details

Study Description

Brief Summary

This phase I trial studies the side effects and the best dose of bortezomib and sorafenib tosylate when given together with decitabine in treating patients with acute myeloid leukemia. Bortezomib and sorafenib tosylate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as decitabine, 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 bortezomib and sorafenib tosylate together with decitabine may work better in treating acute myeloid leukemia.

Condition or Disease	Intervention/Treatment	Phase
Acute Myeloid Leukemia Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Therapy-Related Acute Myeloid Leukemia	Drug: Bortezomib Drug: Decitabine Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Sorafenib Tosylate	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To identify the biologically effective and tolerable dose (BETD) of the bortezomib/sorafenib (sorafenib tosylate) combination in acute myeloid leukemia (AML) with biological activity defined as the dose(s) that induce a 100% increase (i.e. a doubling) in the level of microRNA-29b (miR-29b) in bone marrow (BM) after bortezomib/sorafenib treatment from pretreatment levels in at least 5 out of 6 patients at a given dose levels.
To recommend a dose level for a Phase II study using this agent combination in patients with AML.
To define the specific toxicities and the dose limiting toxicity (DLT) of bortezomib in combination with sorafenib and decitabine.

SECONDARY OBJECTIVES:

To determine the overall response rate (ORR) of this combination. II. To determine the rate of complete remission (CR) of this combination. III. To conduct pharmacodynamic studies by measuring the effect of this chemotherapy combination on the micronome, kinome and epigenome.

OUTLINE: This is a dose-escalation study of bortezomib and sorafenib tosylate.

STEP A: Patients receive bortezomib subcutaneously (SC) on days 1 and 4, sorafenib tosylate orally (PO) twice daily (BID) on days 1-14, and decitabine intravenously (IV) over 1 hour on days 5-14.

STEP B: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 9-18 or 12-21.

STEP C: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14.

Treatment repeats every 28 days for up to 4 courses in the absence of unacceptable toxicity. Patients achieving complete response (CR) or incomplete CR (CRi) receive maintenance therapy comprising decitabine IV on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

15 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase I Study of The Combination of Bortezomib and Sorafenib Followed by Decitabine in Patients With Acute Myeloid Leukemia

Actual Study Start Date :

Jul 3, 2013

Actual Primary Completion Date :

Nov 6, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (bortezomib, sorafenib tosylate, decitabine) STEP A: Patients receive bortezomib SC on days 1 and 4, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. STEP B: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 9-18 or 12-21. STEP C: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. Treatment repeats every 28 days for up to 4 courses in the absence of unacceptable toxicity. Patients achieving CR or CRi receive maintenance therapy comprising decitabine IV on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: Bortezomib Given SC Other Names: [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid LDP 341 MLN341 PS-341 PS341 Velcade Drug: Decitabine Given IV Other Names: 5-Aza-2'-deoxycytidine Dacogen Decitabine for Injection Deoxyazacytidine Dezocitidine Other: Laboratory Biomarker Analysis Correlative studies Other: Pharmacological Study Correlative studies Drug: Sorafenib Tosylate Given PO Other Names: BAY 43-9006 Tosylate BAY 54-9085 Nexavar sorafenib

Arm

Intervention/Treatment

Experimental: Treatment (bortezomib, sorafenib tosylate, decitabine)

STEP A: Patients receive bortezomib SC on days 1 and 4, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. STEP B: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 9-18 or 12-21. STEP C: Patients receive bortezomib SC on days 1, 4, and 8 or 1, 4, 8 and 11, sorafenib tosylate PO BID on days 1-14, and decitabine IV over 1 hour on days 5-14. Treatment repeats every 28 days for up to 4 courses in the absence of unacceptable toxicity. Patients achieving CR or CRi receive maintenance therapy comprising decitabine IV on days 1-5. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Drug: Bortezomib

Given SC

Other Names:

[(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid

LDP 341

MLN341

PS-341

PS341

Velcade

Drug: Decitabine

Given IV

Other Names:

5-Aza-2'-deoxycytidine

Dacogen

Decitabine for Injection

Deoxyazacytidine

Dezocitidine

Other: Laboratory Biomarker Analysis

Correlative studies

Other: Pharmacological Study

Correlative studies

Drug: Sorafenib Tosylate

Given PO

Other Names:

BAY 43-9006 Tosylate

BAY 54-9085

Nexavar

sorafenib

Outcome Measures

Primary Outcome Measures

BETD of bortezomib, sorafenib tosylate, and decitabine using National Cancer Institute Common Terminology Criteria for Adverse Events version 4 [28 days]
Analysis will include summarization of the toxicity and tolerability by dose level. Frequency and severity of adverse events and tolerability of the regimen in each of the dose levels will be collected and summarized using descriptive statistics.

Secondary Outcome Measures

CR rate [Up to 30 days]
Will be correlated with miR29b levels at baseline and day 5 (or days 9 and 12). Assessment of clinical response will be made according to International Working Group criteria.
Change in miR-29b expression in blood and bone marrow [Baseline to up to day 12 of course 1]
miR-29b expression as a continuous measure will be summarized quantitatively and graphically by dose level in addition to the assessment of the ability to achieve a two-fold change in this expression from baseline at each of the dose levels.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have histologically or cytologically confirmed acute myeloid leukemia (AML) by World Health Organization (WHO) criteria in the blood and/or marrow AND age

= 60 and not candidates/refuse standard induction treatment OR who have one of the following: poor risk cytogenetics, AML following antecedent hematologic disorder, or therapy-related AML

Patients with relapsed or refractory AML age >= 18 years are also eligible for treatment; patients may have been treated for antecedent hematologic disorder with myeloid growth factors, recombinant erythropoietin, thalidomide, lenalidomide, 5-azacitidine or the 5 day schedule of decitabine; patients who have received the 10 day schedule of decitabine for treatment an antecedent hematologic disorder or AML are not 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
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transferase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transferase [SGPT]) < 2.5 X institutional upper limit of normal
Creatinine < 2.0 mg/dL or creatinine clearance (CrCl) >= 60 mL/min
Prothrombin time (PT)/international normalized ratio (INR) monitoring, < 1.5 x institutional upper limits of normal
Both women and men must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; if the patient does not agree, the patient is not eligible
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; hydroxyurea may be administered for count control both pre-treatment and during cycle 1 only
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 disease or with granulocytic sarcoma as sole site of disease
Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to sorafenib, bortezomib or decitabine that are not easily managed
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements; as infection is a common feature of AML, patients with active infection are permitted to enroll provided that the infection is under control; myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) class III or IV heart failure, uncontrolled angina, uncontrolled hypertension, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study
Patients with pre-existing grade 2 or higher neuropathy or other serious neurologic toxicity that would significantly increase risk of complications from bortezomib therapy are excluded
Patients with a known confirmed diagnosis of human immunodeficiency virus (HIV) infection who are taking chronic anti-retroviral therapy (HAART) are ineligible if there is a potential for drug-drug interactions with the chemotherapeutic agents; patients with a known confirmed diagnosis of HIV infection who meet standard eligibility criteria and are not taking HAART with a potential for drug-drug interactions are eligible
Patients with advanced malignant solid tumors are excluded
Patients with known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of sorafenib
Patients who are taking concomitant medications that in the investigator's opinion are strong inducers of the cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) enzymes and therefore likely to interact with the study agents, will not be eligible