Vorinostat (SAHA) in Uterine Sarcoma

A Pilot Study of Peroral Vorinostat (SAHA) in Patients With Refractory Histone Deacetylase-positive Uterine Sarcoma

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.

Study Overview

• Status: Terminated
• Conditions: Leiomyosarcoma; Endometrial Stromal Tumors; Carcinosarcomas Uterine
• Intervention / Treatment: Drug: Vorinostat Oral Capsule

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).

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Medical University of Graz, Clinic of Obstetrics and Gynecology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Vorinostat, Zolinza Oral Capsules; Vorinostat Oral Capsules 400mg daily

Drug: Vorinostat Oral Capsule; Vorinostat, 400 mg orally once daily for the first 14 days of a 21 day cycle Treatment will be continued for 4 cycles. Patients with a response or stable disease after 4 cycles 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 period of 9 months.; Other Names: Zolinza

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival (PFS)	Change from Baseline Tumor Size to last available observation with respect to progress as defined by RECIST 1.1 (CT-Scan every 12 weeks up to 9 months)	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	This endpoint is evaluated by the amount of clinical adverse experiences.	9 months

Collaborators and Investigators

• Sponsor: Medical University of Graz
• Investigators: Principal Investigator: Edgar Petru, MD, Department of OB/GYN of the Medical University of Graz

Study record dates

Study Major Dates

• Study Start (Actual): December 14, 2017
• Primary Completion (Actual): February 4, 2019
• Study Completion (Actual): February 4, 2019

Study Registration Dates

• First Submitted: March 27, 2018
• First Submitted That Met QC Criteria: April 16, 2018
• First Posted (Actual): April 26, 2018

Study Record Updates

• Last Update Posted (Actual): August 4, 2020
• Last Update Submitted That Met QC Criteria: July 27, 2020
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Uterine sarcoma; Histone deacetylases
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Neoplasms, Complex and Mixed; Neoplasms, Connective Tissue; Endometrial Neoplasms; Neoplasms, Muscle Tissue; Sarcoma; Carcinosarcoma; Mixed Tumor, Mullerian; Leiomyosarcoma; Endometrial Stromal Tumors; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Histone Deacetylase Inhibitors; Vorinostat
• Other Study ID Numbers: SAHA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes