5-Fluoro-2'-Deoxycytidine and Tetrahydrouridine in Treating Patients With Acute Myeloid Leukemia or Myelodysplastic Syndromes

Sponsor

City of Hope Medical Center (Other)

Overall Status

Completed

CT.gov ID

NCT01041443

Collaborator

(none)

Enrollment

Location

Arm

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial is studying the side effects and best dose of 5-Fluoro-2'-deoxycytidine (FdCyd) when given together with tetrahydrouridine (THU) in treating patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). FdCyd may inhibit cancer cell growth by increasing the production in cells of compounds that suppress growth or by otherwise killing cells. Although FdCyd is stable as a drug solution, it is rapidly inactivated by an enzyme present in people. THU is included in the treatment to inhibit the enzyme, prolonging the time FdCyd remains in the body

Condition or Disease	Intervention/Treatment	Phase
Adult Acute Myeloid Leukemia de Novo Myelodysplastic Syndromes Previously Treated Myelodysplastic Syndromes Recurrent Adult Acute Myeloid Leukemia Secondary Acute Myeloid Leukemia Secondary Myelodysplastic Syndromes Untreated Adult Acute Myeloid Leukemia	Drug: 5-fluoro-2-deoxycytidine Drug: tetrahydrouridine Other: laboratory biomarker analysis Genetic: reverse transcriptase-polymerase chain reaction Genetic: DNA methylation analysis	Phase 1

Detailed Description

OBJECTIVES: I. Determine the maximum tolerated dose (MTD) of FdCyd administered with a fixed dose of THU in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), once daily on days 1-10 of a 21-day treatment cycle. II. To describe the toxicities of FdCyd/THU in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). III. To document all clinical responses and hematologic improvement in patients treated with FdCyd/THU. IV. To obtain preliminary information regarding the effect of FdCyd/THU on deoxyribonucleic acid (DNA) methylation patterns in peripheral blood mononuclear cells and bone marrow aspirates, including malignant myeloid cells; the ratio of gamma- to beta-globin messenger ribonucleic acid (mRNA) in blood cells; and serum cytokines. OUTLINE: This is a dose-escalation study of FdCyd. Patients receive FdCyd intravenously (IV) over 3 hours and THU IV over 3 hours on days 1-10. Courses repeat every 21days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for 4 weeks.

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:

A Phase I Study of 5-Fluoro-2'-Deoxycytidine With Tetrahydrouridine (FdCyd + THU) in Myeloid Leukemia and MDS

Study Start Date :

Dec 1, 2009

Actual Primary Completion Date :

Oct 1, 2013

Actual Study Completion Date :

Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (enzyme inhibitor therapy) Patients receive FdCyd IV over 3 hours and THU IV over 3 hours on days 1-10. Courses repeat every 21days in the absence of disease progression or unacceptable toxicity.	Drug: 5-fluoro-2-deoxycytidine Given IV Other Names: FdCyd Drug: tetrahydrouridine Given IV Other Names: THU Other: laboratory biomarker analysis Correlative studies Genetic: reverse transcriptase-polymerase chain reaction Correlative studies Other Names: RT-PCR Genetic: DNA methylation analysis Correlative studies

Arm

Intervention/Treatment

Experimental: Treatment (enzyme inhibitor therapy)

Patients receive FdCyd IV over 3 hours and THU IV over 3 hours on days 1-10. Courses repeat every 21days in the absence of disease progression or unacceptable toxicity.

Drug: 5-fluoro-2-deoxycytidine

Given IV

Other Names:

FdCyd

Drug: tetrahydrouridine

Given IV

Other Names:

THU

Other: laboratory biomarker analysis

Correlative studies

Genetic: reverse transcriptase-polymerase chain reaction

Correlative studies

Other Names:

RT-PCR

Genetic: DNA methylation analysis

Correlative studies

Outcome Measures

Primary Outcome Measures

MTD and dose-limiting toxicity (DLT) of the new 10-day schedule of FdCyd/THU [10 days]
Toxicities will be summarized by Common Terminology Criteria for Adverse Events (CTCAE) grade and attribution using the version current at the initiation of the protocol.

Secondary Outcome Measures

Toxicities of the FdCyd/THU treatment [3 years]
Time to progression [3 years]
Overall survival [3 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients must have the following diagnosis:

Acute myeloid leukemia
Relapsed or refractory
Newly diagnosed in patients age 60 and above or of any age unable to receive standard induction regimen
Patients with MDS with an International Prognostic Scoring System (IPSS) score >= 0.5
Newly diagnosed
Relapsed or refractory
Any prior therapy must have been completed >= 2 weeks prior to enrollment and the participant must have recovered to eligibility levels from prior toxicity
No limit to number of prior regimens
Hydroxyurea is allowed prior to enrollment to keep white blood cell count (WBC) below 20 K
Valproic acid not being used for seizure control should be stopped 72 hours before starting therapy
Prior therapy with hypomethylating agent (decitabine or azacitidine) is allowed and must be completed >= 6 weeks prior to enrollment
Relapsed patients are eligible post allogeneic or matched unrelated donor (MUD) transplant after 100 days; there should be no active acute graft versus host disease of any grade and patient should not be receiving immunosuppression for acute graft versus host disease; the patient must not have Chronic Graft versus Host disease (cGvHD) other than mild skin, oral, or ocular cGvHD not requiring systemic immunosuppression
Relapsed patients are eligible post autologous transplant after 100 days post transplant, with recovery of their counts absolute neutrophil count (ANC) > 1000 and platelets greater than 75K at some point post transplant
Karnofsky performance status >= 60%
Total bilirubin < 1.5 x institutional upper limit of normal
Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
Creatinine < 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min for patients with creatinine levels above 1.5 x institutional upper limit of normal
Pregnant women will be excluded from this trial; nursing women are also excluded; women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) for the duration of study participation, and for 3 months after completion of study; 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
Patients should not be receiving any other investigational agents

Exclusion Criteria:

Patients with clinically significant illnesses which would compromise participation in the study, including, but not limited to: active or uncontrolled infection, immune deficiencies or confirmed diagnosis of human immunodeficiency virus (HIV) infection, active Hepatitis B, active Hepatitis C, or uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
Patients with additional (other than AML/MDS) currently active primary malignancy other than curatively treated carcinoma in situ (CIS) of the cervix, or basal or squamous cell carcinoma of the skin; patients are not considered to have a "currently active" malignancy if they have completed therapy for a prior malignancy and disease free from prior malignancies for > 2 years
Patients with active central nervous system (CNS) disease; these patients are 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
Active infections, including opportunistic following allo, MUD, or auto transplant (including but not limited to cytomegalovirus [CMV], fungal infection etc)