PXD101 in Treating Patients With Acute Myeloid Leukemia

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase 2 Study of PXD101 in Patients With Relapsed or Refractory Acute Myelogenous Leukemia or Patients Over 60 With Newly-Diagnosed Acute Myelogenous Leukemia

Conditions
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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), Recurrent Adult Acute Myeloid Leukemia, Untreated Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: belinostat
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (belinostat)<br>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. | Drug: belinostat<br>* Given IV<br>* Other names: PXD101;Other: laboratory biomarker analysis<br>* Correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response Rate | 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 | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Survival endpoints will be summarized by the method of Kaplan-Meier | Up to 1 year | 
| Duration of Response | 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. | Up to 1 year | 
| Toxicity Summary | Assessed using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Grade 3 and above toxicities possibly, probably or definitely related to treatment. | Up to 1 year |