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


Phase 1
60 Years
N/A
Not Enrolling
Both
Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome, 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), Secondary Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

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Trial Information

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


PRIMARY OBJECTIVES:

I. 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.

II. To recommend a dose level for a Phase II study using this agent combination in older
patients with AML.

III. To define the specific toxicities and the dose limiting toxicity (DLT) of bortezomib in
combination with sorafenib and decitabine.

SECONDARY OBJECTIVES:

I. 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.


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

- No prior therapy for AML is permitted except emergency leukopheresis or hydroxyurea
for leukocytosis; 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 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

- The effects of decitabine, bortezomib and sorafenib on the developing human fetus at
the recommended therapeutic dose are unknown; for this reason, 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 (due
to concern for increased toxicity with the regimen in combination with HAART);
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 CYP3A4 enzymes and therefore likely to interact with the
study agents, will not be eligible

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

BETD of bortezomib, sorafenib tosylate, and decitabine using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v. 4

Outcome Description:

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.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Alison Walker

Investigator Role:

Principal Investigator

Investigator Affiliation:

Ohio State University

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2013-00999

NCT ID:

NCT01861314

Start Date:

May 2013

Completion Date:

Related Keywords:

  • Acute Myeloid Leukemia With Multilineage Dysplasia Following Myelodysplastic Syndrome
  • 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)
  • Secondary Acute Myeloid Leukemia
  • Untreated Adult Acute Myeloid Leukemia
  • Congenital Abnormalities
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Myelodysplastic Syndromes
  • Preleukemia

Name

Location

Ohio State University Medical CenterColumbus, Ohio  43210