PXD101 in Treating Patients With Acute Myeloid Leukemia

Phase 2

Completed

Conditions: 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 Inv(16)(p13;q22)
Adult Acute Myeloid Leukemia With t(8;21)(q22;q22)
Recurrent Adult Acute Myeloid Leukemia
Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities
Adult Acute Myeloid Leukemia With Del(5q)
Untreated Adult Acute Myeloid Leukemia

Interventions: Drug: belinostat
Other: laboratory biomarker analysis

Registration Number: NCT00357032

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying how well PXD101 works in treating patients with relapsed or refractory acute myeloid leukemia or older patients with newly diagnosed acute myeloid leukemia. PXD101 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer.

Detailed Description: PRIMARY OBJECTIVES:

I. Evaluate the response rate (complete response and partial response) in patients with acute myeloid leukemia treated with PXD101.

SECONDARY OBJECTIVES:

I. Evaluate the overall survival of these patients. II. Evaluate the duration of response in these patients. III. Evaluate the toxicity of this drug in these patients.

TERTIARY OBJECTIVES:

I. Evaluate molecular response to PXD101.

OUTLINE:

Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity.

Blood and bone marrow samples are obtained before and after study treatment for laboratory studies.

After completion of study treatment, patients are followed periodically for 1 year.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Patients must have histologically or cytologically confirmed acute myelogenous leukemia
The diagnosis must be made by bone marrow aspirate and biopsy; patients must have routine cytochemical evaluation along with immunophenotyping done by flow cytometry; cytogenetic analysis must also be performed
For patients age 18-59 years, at least one prior regimen of induction chemotherapy is required; patients who have been treated with bone marrow or stem cell transplantation are eligible; there is no prior therapy requirement for patients age > 60
- Patients for whom potentially curative treatment is available must be offered this treatment and decline
Life expectancy of greater than 3 months
ECOG performance status =< 2 (Karnofsky >= 60%)
Serum total bilirubin =< 2.0 mg/dl
AST and ALT =< 2.5 times upper limit of normal (ULN)
Creatinine clearance >= 60 mL/min OR creatinine < 1.5 times ULN
Eligibility of patients receiving any medications or substances known to affect or with the potential to affect the activity or pharmacokinetics of PXD101 will be determined following review of their case by the principal investigator
- Efforts should be made to switch patients with gliomas or brain metastases who are taking enzyme inducing anticonvulsant agents to other medications
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
Patients taking hydroxyurea for the purpose of cytoreduction should discontinue this medication at least 24 hours prior to the initiation of therapy with PXD101

Exclusion Criteria

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
Patients may not be receiving any other investigational agents
Patients with known central nervous system (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 PXD101
Patients may not have had prior treatment with another HDAC inhibitor within 1 week of initiation of therapy with PXD101; patients receiving valproic acid should stop this medication at least 1 week prior to therapy with PXD101
Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness that could compromise compliance with study requirements
Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with PXD101
HIV-positive patients are ineligible
Patients with a marked baseline prolongation of QT/QTc interval (e.g. repeated demonstration of a QTc interval 500 msec), Long QT Syndrome, or the required use of concomitant medication on PXD101 infusion days that may cause Torsade de Pointes (including disopyramide, dofetilide, ibutilide, procainamide, quinidine, sotalol, bepridil, amiodarone, arsenic trioxide, cisapride, lidoflazine, clarithromycin, erythromycin, halofantrine, pentamidine, sparfloxacin, domperidone, droperidol, chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide, and methadone)
Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, congestive heart failure related to primary cardiac disease, a condition requiring anti-arrhythmic therapy, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to trial entry

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (belinostat)	laboratory biomarker analysis	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity.
Treatment (belinostat)	belinostat	Patients receive PXD101 IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 6-12 months in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Complete Response Rate	Up to 1 year	Clinical responses were measured according to International Working Group criteria. Bone marrow studies were repeated at a minimum of every three cycles. Per International Working Group criteria: Complete Response (CR): Repeat bone marrow show \<5% myeloblasts, and peripheral blood evaluations lasting \>=2 months of hemoglobin(\>110 g/L), neutrophils(\>=1.5x10\^9/L), platelets(\>=100x10\^9/L), blasts (0%) and no dysplasia

Secondary Outcome Measures

Name	Time	Method
Toxicity Summary	Up to 1 year	Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 and above toxicities possibly, probably or definitely related to treatment.
Duration of Response	Up to 1 year	From time of documented treatment response (CR or PR) until progression of death. Complete Response (CR): Repeat bone marrow show \<5% myeloblasts, and peripheral blood evaluations lasting \>=2 months of hemoglobin(\>110 g/L), neutrophils(\>=1.5x10\^9/L), platelets(\>=100x10\^9/L), blasts (0%) and no dysplasia. Partial Resonse (PR): requires the same hematologic values for a CR but with a decrease of at least 50% in the percentage of blasts to a post-treatment value of 5% to 25% in the bone marrow aspirate. (If the pre-treatment blast percentage was 50-100%, this must decrease to a value between 5-25%. If the pre-treatment blast percentage was 20-49%, this must decrease by at least half to a value greater than 5%.) A value ≤ 5% is also considered a PR if Auer rods are present.
Overall Survival	Up to 1 year	Survival endpoints will be summarized by the method of Kaplan-Meier