Vorinostat and Decitabine in Treating Patients With Relapsed, Refractory, or Poor-Prognosis Hematologic Cancer or Other Diseases

Chronic Myelomonocytic Leukemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00357708
• Other study ID #: NCI-2012-03088
• Secondary ID: 2005-0723U01CA06
• Status: Completed
• Phase: Phase 1
• First received: July 26, 2006
• Last updated: January 4, 2013
• Start date: June 2006

Study information

• Verified date: January 2013
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This phase I trial is studying the side effects and best dose of vorinostat and decitabine in treating patients with relapsed, refractory, or poor-prognosis hematologic cancer or other diseases. Vorinostat 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 or by stopping them from dividing. Giving vorinostat together with decitabine may kill more cancer cells

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. primary completion date: October 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

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

Related Conditions & MeSH terms

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

Intervention

Drug:
• decitabine
Given IV
• vorinostat
Given orally

Other:
• laboratory biomarker analysis
Correlative studies
• pharmacological study
Correlative studies

Locations

Country	Name	City	State
United States	M D Anderson Cancer Center	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated dose and dose-limiting toxicity of vorinostat and decitabine		28 days	Yes