Belinostat (PXD101) to Treat Tumors of the Thymus at an Advanced Stage
Condition: Thymoma; Thymic Carcinoma
MeSH terms: Carcinoma; Thymoma; Thymus Neoplasms
Intervention: Belinostat (PDX101)
Intervention description: 1000 mg/m^2/day as a 30 minute intravenous (IV) infusion daily for 5 days every 3 weeks (day 1-5 of the 3 week treatment cycle). After 12 cycles of treatment, cycles will be given for 5 days every 4 weeks.
Intervention MeSH terms: Belinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 41.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Histone deacetylase (HDAC) Inhibitors; Mediastinal Neoplasm; Thymic Carcinoma; Thymoma

Summary:

      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.
    

Eligibility criteria:

        -  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.