Vorinostat (SAHA) in Uterine Sarcoma

• ClinicalTrials.gov Identifier: NCT03509207
• Recruitment Status: Terminated
• First Posted: April 26, 2018
• Results First Posted: July 27, 2020
• Last Update Posted: August 4, 2020
• Sponsor: Medical University of Graz
• Information provided by (Responsible Party): Medical University of Graz

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Leiomyosarcoma; Endometrial Stromal Tumors; Carcinosarcomas Uterine	Drug: Vorinostat Oral Capsule	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Pilot Study of Peroral Vorinostat (SAHA) in Patients With Refractory Histone Deacetylase-positive Uterine Sarcoma
• Actual Study Start Date: December 14, 2017
• Actual Primary Completion Date: February 4, 2019
• Actual Study Completion Date: February 4, 2019

Arms and Interventions

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 Name: Zolinza

Outcome Measures

Primary Outcome Measures :

1. Progression-free Survival (PFS) [ Time Frame: 9 months ]
   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)

Secondary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) [ Time Frame: 9 months ]
   This endpoint is evaluated by the amount of clinical adverse experiences.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: Female
• Gender Based Eligibility: Yes
• Gender Eligibility Description: The investigated condition occurs exclusively in women
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

Austria

Medical University of Graz, Clinic of Obstetrics and Gynecology

Graz, Austria, 8036

Sponsors and Collaborators

Medical University of Graz

Investigators

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

  Study Documents (Full-Text)

Documents provided by Medical University of Graz:

Study Protocol  [PDF] December 22, 2016

No Statistical Analysis Plan (SAP) exists for this study.

More Information

• Responsible Party: Medical University of Graz
• ClinicalTrials.gov Identifier: NCT03509207
• Other Study ID Numbers: SAHA
• First Posted: April 26, 2018
• Results First Posted: July 27, 2020
• Last Update Posted: August 4, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Medical University of Graz:

Uterine sarcoma; Histone deacetylases

Additional relevant MeSH terms:

Vorinostat; Sarcoma; Leiomyosarcoma; Carcinosarcoma; Mixed Tumor, Mullerian; Endometrial Stromal Tumors; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Muscle Tissue; Neoplasms, Complex and Mixed; Neoplasms, Connective Tissue; Endometrial Neoplasms; Uterine Neoplasms; Uterine Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Antineoplastic Agents; Histone Deacetylase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action