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A Phase I Trial of SAHA (NSC 701852) and Decitabine (IND 50733, NSC 127716) in Patients With Relapsed, Refractory or Poor Prognosis Leukemia


Phase 1
18 Years
N/A
Not Enrolling
Both
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), Chronic Myelomonocytic Leukemia, Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable, Philadelphia Chromosome Negative Chronic Myelogenous Leukemia, Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Lymphoblastic Leukemia, Recurrent Adult Acute Myeloid Leukemia, Relapsing Chronic Myelogenous Leukemia

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Trial Information

A Phase I Trial of SAHA (NSC 701852) and Decitabine (IND 50733, NSC 127716) in Patients With Relapsed, Refractory or Poor Prognosis Leukemia


PRIMARY OBJECTIVES:

I. To determine the maximal tolerated dose (MTD) and dose limiting toxicities (DLT) of
vorinostat in combination with Decitabine in patients with relapsed/refractory or poor
prognosis acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL),
myelodysplastic syndrome (MDS) or chronic myeloid leukemia in accelerated or blastic phase
(CML-BP).

1.2 To describe the clinical activity of the combination of Decitabine and vorinostat in
this patient population.

1.3 To determine the in vivo molecular effects of this combination. This will include
measuring the effects on DNA methylation, histone H3 and H4 acetylation and changes in gene
expression.

1.4 To determine the pharmacokinetic characteristics of the combination.

OUTLINE: This is a dose-escalation study.

Patients receive decitabine IV over 1 hour on days 1-5 and oral vorinostat (SAHA) three
times daily on days 6-19. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

Cohorts of 6 patients receive escalating doses of decitabine and SAHA until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2
of 6 patients experience dose-limiting toxicity. Once the MTD is determined, 10 additional
patients are treated at that dose.

After completion of study treatment, patients are followed for 4 weeks.


Inclusion Criteria:



- Patients must have histologically confirmed acute myelogenous leukemia (AML), acute
lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), myelodysplastic
syndrome (MDS) or myeloproliferative disease (MPD)

- Patients with refractory or relapsed acute myelogenous leukemia (AML), acute
lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), myelodysplastic
syndrome (MDS) IPSS intermediate 1 and above and myeloproliferative disease (MPD)
will be considered for the study; patients with CML are eligible if they have
documented hematologic resistance to imatinib mesylate, or lack of any cytogenetic
response to imatinib mesylate after 12 months of therapy; patients with Chronic
Myelomonocytic Leukemia (CMML) or Philadelphia negative CML are eligible if their
disease is not controlled by standard therapy (e.g. hydroxyurea) or if they show
signs of disease progression on standard therapy (blast count > 5%, platelet count <
100K); patients with Acute Promyelocytic Leukemia are eligible only if they have
progressed after standard chemotherapy, ATRA as well as Arsenic Trioxide therapy;
untreated patients older than 60 years of age with AML (except APL) or MDS IPSS
intermediate 1 and above, not eligible for standard therapy, are also eligible

- Patients must have been off chemotherapy for 2 weeks (six weeks for nitrosoureas or
mitomycin C) prior to entering this study and recovered from the toxic effects of
that therapy unless there is evidence of rapidly progressive disease; if there is
evidence or rapidly progressive disease, the use of hydroxyurea is allowed prior to
starting the clinical trial and during the first cycle of therapy; other histone
deacetylase inhibitors, including valproic acid, should be stopped 2 weeks prior to
entering this study

- Life expectancy of greater than 8 weeks

- ECOG performance status 0-2

- Total bilirubin =< 2 mg/dL

- AST(SGOT) or ALT(SGPT) =< 2.5 X institutional upper limit of normal

- Creatinine =< 2 mg/dL

- Cardiac ejection fraction >= 50%

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation; should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients may not be receiving any other investigational agents

- Patients with clinical evidence of CNS disease should be excluded from this clinical
trial because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to vorinostat or decitabine

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with vorinostat

- HIV-positive patients receiving combination antiretroviral therapy are ineligible

- Vorinostat should not be taken concomitantly with other HDAC inhibitors or compounds
with HDAC inhibitor like activity, such as valproic acid; patients who have received
such agents as anti-tumor therapy should not enroll in vorinostat oncology trials;
patients who have received such agents for other indications, e.g. epilepsy, may
enroll on vorinostat trials after a 30 day washout period

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum tolerated dose and dose-limiting toxicity of vorinostat and decitabine

Outcome Time Frame:

28 days

Safety Issue:

Yes

Principal Investigator

Jean-Pierre Issa

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center

Authority:

United States: Food and Drug Administration

Study ID:

NCI-2012-03088

NCT ID:

NCT00357708

Start Date:

June 2006

Completion Date:

Related Keywords:

  • 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)
  • Chronic Myelomonocytic Leukemia
  • Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable
  • Philadelphia Chromosome Negative Chronic Myelogenous Leukemia
  • Previously Treated Myelodysplastic Syndromes
  • Recurrent Adult Acute Lymphoblastic Leukemia
  • Recurrent Adult Acute Myeloid Leukemia
  • Relapsing Chronic Myelogenous Leukemia
  • Congenital Abnormalities
  • Neoplasms
  • Leukemia
  • Leukemia, Lymphoid
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Leukemia, Myelomonocytic, Chronic
  • Myelodysplastic Syndromes
  • Preleukemia
  • Leukemia, Myelomonocytic, Acute
  • Myeloproliferative Disorders
  • Philadelphia Chromosome
  • Myelodysplastic-Myeloproliferative Diseases

Name

Location

M D Anderson Cancer CenterHouston, Texas  77030