Belinostat (PXD101) to Treat Tumors of the Thymus at an Advanced Stage

Background:

Cisplatin-containing chemotherapy is the standard of care for advanced unresectable thymoma
and thymic carcinoma. New options for treatment are necessary in patients with advanced
thymoma and thymic carcinoma that have progressed on cisplatin-containing therapy. Histone
deacetylase inhibitors have shown promising clinical activity in many malignancies.
Belinostat, a potent histone deacetylase inhibitor, is a promising agent, which may have
activity in patients with thymic malignancies.

Objectives:

- To assess objective response rate according to the Response Evaluation Criteria in
Solid Tumors (RECIST) criteria for belinostat monotherapy.

- To assess safety of belinostat.

- To evaluate time to response, duration of response, progression-free survival and
overall survival.

- To identify chromosomal gains or losses and gene methylation status by comparative
genomic hybridization and methylation microarrays in thymoma / thymic carcinomas in
relation to clinical outcome.

- To assess expression levels of particular proteins on the pretreatment tumor sample, by
immunohistochemistry (IHC) and correlate them with clinical outcome.

- To identify and measure changes in p21 and protein hyperacetylation in peripheral blood
mononuclear cells (PBMC), and vascular endothelial growth factor (VEGF) and basic
fibroblast growth factor (bFGF) in plasma and correlate them with clinical outcome.

- To measure changes in modulation of T-cell function in peripheral blood lymphocytes.

Eligibility:

- Patients with histologically confirmed thymic carcinoma or thymoma who have previously
been treated on at least one platinum containing chemotherapy regimen.

- Measurable disease by RECIST criteria.

- Adequate renal, hepatic and hematopoietic function.

- QT Interval must be less than 500 msec at baseline by electrocardiogram (EKG)
(Fridericia's formula used for correction).

- No major surgery, radiotherapy, or chemotherapy within 28 days of belinostat therapy.

Design:

- Patients will receive belinostat as a 30-minute intravenous (IV) infusion of 1000
mg/m^2/day during days 1-5 every 3 weeks. After 12 cycles of treatment, cycles will be
given every 4 weeks.

- Treatment with belinostat alone will continue until disease progression.

- Toxicity will be assessed every cycle by the Common Terminology Criteria for Adverse
Events (CTCAE) Version 3.0 until December 31, 2010, and by CTCAE Version 4.0 beginning
January 1, 2011.

- Tumor response assessments by RECIST criteria will be performed every 2 cycles. After
12 cycles, response assessment will be every 3 cycles.

- Correlative studies including comparative genomic hybridization, methylation microarray
analysis, and tissue immunohistochemistry studies will be done on existing tumor
blocks.

- Blood samples for circulating plasma biomarkers of response including VEGF will be
drawn the first day of cycle 1 and 2 as well as cycle 1, day 3.

- Blood samples for protein hyperacetylation and T cell modulation analyses will be drawn
the first day of cycle 1 and 2.

- INCLUSION CRITERIA:

Histologically confirmed invasive recurrent or metastatic thymoma or thymic carcinoma by
the pathology department / Center for Cancer Research (CCR) / National Cancer Institute
(NCI).

Patients must have had at least one prior platin-containing chemotherapy regimen. There is
no limit to the number of prior chemotherapy regimens received. Progressive disease should
have been documented before entry into the study.

Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded) as greater
than 20 mm with conventional techniques or as greater than 10 mm with spiral computed
tomography (CT) scan.

Patients must have recovered from toxicity related to prior therapy to at least to grade 1
(defined by the Common Terminology Criteria for Adverse Events (CTCAE) 3.0 until December
31, 2010, and by CTCAE 4.0 beginning January 1, 2011) and must not have had prior
chemotherapy within 4 weeks. Patients must be at least 28 days since any prior radiation
or major surgery.

- Target lesions cannot be selected within previously irradiated areas, if not newly
arising or clearly progressing after irradiation as proven by repeat scanning.

- Concurrent corticosteroids for myasthenia gravis, or other paraneoplastic syndromes,
or other chronic conditions are allowed.

Age greater than 18 years.

Life expectancy of greater than 3 months.

Performance status (Eastern Cooperative Oncology Group (ECOG)) less than or equal to 2.

Patients must have adequate organ and marrow function (as defined below). Patients must
have returned to base line or grade one from any acute toxicity related to prior therapy.

Laboratory Test/Required Value:

Absolute neutrophil count greater than 1,500/microl.

Platelets greater than 100,000/microl.

International normalized ratio (INR) less than or equal to 1.5 times upper limit of normal
(ULN) or

Partial thromboplastin time (PTT) abnormality can be explained by the presences of lupus
anticoagulant or in the therapeutic range if on anticoagulation.

Total bilirubin less than or equal to 1.5 times institutional upper limits of normal.

Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase(SGOT) and alanine
aminotransferase (ALT)/serum glutamic pyruvic transaminase(SGPT) less than or equal to 3
times institutional upper limit of normal.

Creatinine less than or equal to 1.5 times institutional upper limits of normal or
Calculated Creatinine greater than 45 mL/min/1.73 m^2 for patients with creatinine.

Clearance levels above institutional normal.

The effects of belinostat on the developing human fetus at the recommended therapeutic
dose are unknown. For this reason and because histone deacetylase (HDAC) inhibitors are
known to be teratogenic, 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 and continue for at least 2 months
after completion. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately. Because
there is an unknown but potential risk for adverse events in nursing infants secondary to
treatment of the mother with belinostat, breastfeeding should be discontinued if the
mother is treated with belinostat.

Ability to comply with intravenous administration schedule, and the ability to understand
and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

Patients with symptomatic brain metastases 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.
However, patients who have had treatment for their brain metastases and whose brain
metastatic disease status has remained stable for at least 3 months without steroids may
be enrolled at the discretion of the principal investigator.

Uncontrolled medical illness including, but not limited to, ongoing or uncontrolled,
symptomatic congestive heart failure (American Heart Association (AHA) Class II or worse),
uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, or psychiatric
illness/social situations that would limit compliance with study requirements.

Marked baseline prolongation of Q wave, T wave (QT)/corrected QT(QTc) interval, e.g.,
repeated demonstration of a QTc interval greater than 500 msec (Fridericia's formula used
for correction); Long QT Syndrome. Any concomitant medication that may cause QTc
prolongation, induce Torsades de Pointes.

Human immunodeficiency virus (HIV)-positive patients receiving combination anti-retroviral
therapy are excluded from the study because of possible pharmacokinetic interactions with
belinostat.(HIV) positive patients not receiving antiretroviral therapy are excluded due
to the possibility that belinostat may worsen their condition and the likelihood that the
underlying condition may obscure the attribution of adverse events with respect to
belinostat.

Patients may not be receiving any other investigational agents.

History of another invasive malignancy in the last five years. Adequately treated
non-invasive, non-melanoma skin cancers as well as in situ carcinoma of the cervix will be
allowed.

Prior treatment with drugs of the HDAC inhibitor class.

Patients with tumor amenable to potentially curative therapy as assessed by the
investigator.

Subjects with resectable tumors would not be eligible for the study.