Clinical trial NCT03509207: Vorinostat (SAHA) in Uterine Sarcoma
Official title: A Pilot Study of Peroral Vorinostat (SAHA) in Patients With Refractory Histone Deacetylase-positive Uterine Sarcoma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leiomyosarcoma
Endometrial Stromal Tumors
Carcinosarcomas Uterine
Keywords: Uterine sarcoma
Histone deacetylases
Lead sponsor: Medical University of Graz
Sponsor class: OTHER
First posted: 2018-04-26
Enrollment: 3
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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

Primary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: 9 months
Secondary outcomes:
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
timeFrame: 9 months
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Medical University of Graz, Clinic of Obstetrics and Gynecology
Study officials:
affiliation: Department of OB/GYN of the Medical University of Graz
name: Edgar Petru, MD
role: PRINCIPAL_INVESTIGATOR
References: