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

A Multicenter Phase II Study of Belinostat (PXD-101) in Previously Chemotherapy Treated Thymoma and Thymic Carcinoma

Background:

• Cisplatin-containing chemotherapy is the standard treatment for advanced tumors of the thymus that cannot be removed surgically.
• New treatment options are needed for patients with advanced tumors of the thymus that do not improve with cisplatin-containing therapy.
• Belinostat is a drug that inhibits enzymes called histone deacetylase. Histone deacetylase inhibitors have shown promising activity in many cancers and may be useful in treating patients with thymic tumors.

Objectives:

-To assess the safety and effectiveness of belinostat for treatment of malignant thymic tumors in patients who failed after standard treatment.

Eligibility:

-Patients 18 years of age or older with an advanced thymic tumor that has progressed after treatment with platinum-containing chemotherapy.

Design:

• Patients receive belinostat treatment in 21-day cycles. The drug is given as an infusion through a vein during days 1 through 5 of each cycle. Treatment cycles continue as long as the medicine is tolerated and the cancer does not worsen.
• Patients have a physical examination and several blood tests during every cycle.
• Patients have an electrocardiogram every cycle before starting the belinostat infusion and again on the last day of the infusion.
• Patients undergo computed tomography (CT) or other imaging test, such as ultrasound or MRI, every two cycles to evaluate the response of the tumor to treatment.
• Tumor tissue obtained from a previous biopsy is used for research purposes.

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.