vorinostat (saha) in uterine sarcoma

Conditions: Leiomyosarcoma; Endometrial Stromal Tumors; Carcinosarcomas Uterine

Summary: uterine sarcomas are rare tumors with a poor prognosis. the main purpose of this phase ii proof-of-principle- pilot study is to test the efficacy of the hydroxamic acid-based histone deacetylase inhibitor (hdaci) vorinostat (saha) as monotherapy in patients with hdac-positive, progressive, metastatic uterine sarcomas and mixed epithelial and mesenchymal tumors after prior anti-proliferative therapy.

this is an open-label, single arm, proof of concept-study of the hdac-inhibitor vorinostat in patients with refractory uterine sarcoma that have been pre-tested for an high expression of hdac. patients will receive vorinostat, 400 mg (4 capsules á 100mg of zolinza) orally once daily for the first 14 days of a 21 day cycle. treatment will be continued for 4 cycles (treatment period 1). patients with a response or stable disease after 4 cycles as determined by computed tomography (ct) of target an non target-lesions will be continued on vorinostat therapy at the tolerated schedule and dosage until disease progression, unacceptable toxicity or patients' withdrawal of the consent. at the maximum, a total of 12 cycles will be administered over a 9 months period (treatment periods 2 and 3).

Eligibility criteria:
inclusion criteria: * histologically confirmed metastatic uterine sarcoma (endometrial stromal sarcoma, undifferentiated uterine sarcoma, leiomyosarcoma, adenosarcoma and carcinosarcoma * high hdac-positivity of the tumor determined by immunohistochemistry * patients must have received prior systemic antineoplastic therapy * patient is not amenable for curative therapy * age \>= 18 years * estimated life expectancy \> 3 months * measurable disease on ct/mri (at least one measurable lesion \>1cm) or chest x-ray (at least one measurable lesion \>2cm) * karnofsky performance status of 60-100 * adequate hematologic, renal and hepatic function * subject is able to swallow and retain oral medication and does not have uncontrolled emesis * no fertility preserved * written informed consent exclusion criteria: * lack of or low expression of hdac (see 4.1 "pre-screening") * significant cardiac disease * other invasive malignant tumor diagnosed within the last 5 years (e.g. metastases from breast cancer in the last 3 years) * significant bowel obstruction * severe uncontrolled infection * known hiv-positivity * symptomatic brain metastasis or leptomeningeal disease * pre-existing significant liver disease, severe hepatic impairment (bilirubin no greater than 1.5 times upper limit of normal (uln) and/or aspartate aminotransferase (ast)/ alanine aminotransferase (alt) greater than 2.5 times uln) * known history of allergic reaction to vorinostat or similar medications * systemic therapy or an investigational agent within 21 days prior to study inclusion * uncontrolled hypertension (sustained systolic blood pressure \> 150 mmhg or diastolic pressure \> 100 mmhg despite optimal medical management) * major surgery within 3 weeks of enrollment when diagnosed at an early stage * symptomatic congestive heart failure * unstable angina pectoris or cardiac arrhythmia * myocardial infarction within last 6 months * known active hepatitis b or hepatitis c * psychiatric illness/social situations that would limit compliance with study requirements- * prior history of thrombotic or thromboembolic events, unless adequately controlled by anticoagulant therapy

Keywords: uterine sarcoma histone deacetylases