Vorinostat (SAHA) in Uterine Sarcoma

• Sponsor: Medical University of Graz (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03509207
• Collaborator: (none)
• Enrollment: 3
• Location: 1
• Arm: 1
• Actual Duration (Months): 13.7
• Patients Per Site Per Month: 0.2

Study Details

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
• 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: Dec 14, 2017
• Actual Primary Completion Date: Feb 4, 2019
• Actual Study Completion Date: Feb 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 Names: Zolinza

Outcome Measures

Primary Outcome Measures

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

   This endpoint is evaluated by the amount of clinical adverse experiences.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	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)

• Study Protocol - Dec 22, 2016

More Information

Publications

None provided.

• Responsible Party: Medical University of Graz
• ClinicalTrials.gov Identifier: NCT03509207
• Other Study ID Numbers: SAHA
• First Posted: Apr 26, 2018
• Last Update Posted: Aug 4, 2020
• Last Verified: Jul 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• 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: Sarcoma; Leiomyosarcoma; Carcinosarcoma; Mixed Tumor, Mullerian; Endometrial Stromal Tumors; Vorinostat

Study Results

Participant Flow

Recruitment Details	3 patients were enrolled. The study was prematurely closed due to the sluggish patient recruitment and the difficult acquisition of the investigational product.
Pre-assignment Detail	There were no Screening failures in the Course of the study.

Arm/Group Title	Vorinostat, Zolinza Oral Capsules
Arm/Group Description	Vorinostat Oral Capsules 400mg daily 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.
Period Title: Overall Study
STARTED	3
COMPLETED	1
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	Vorinostat, Zolinza Oral Capsules
Arm/Group Description	Vorinostat Oral Capsules 400mg daily 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.
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	3 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	3 100%
Male	0 0%
Race and Ethnicity Not Collected (Count of Participants)
Region of Enrollment (participants) [Number]
Austria	3 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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)
Time Frame	9 months

Outcome Measure Data

Analysis Population Description

Only one Patient reached the first end Point. Statistical Evaluation was therefore not possible. For this reason no data are reported in the data table.

Arm/Group Title	Vorinostat, Zolinza Oral Capsules
Arm/Group Description	Vorinostat Oral Capsules 400mg daily 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.
Measure Participants	0

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Only one Patient reached the first end Point. Statistical Evaluation was therefore not possible. For this reason no data are reported in the data table.

Arm/Group Title	Vorinostat, Zolinza Oral Capsules
Arm/Group Description	Vorinostat Oral Capsules 400mg daily 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.
Measure Participants	0

Adverse Events

Time Frame	From enrolment to study completion per Patient, up to 41 weeks.
Arm/Group Title	Vorinostat, Zolinza Oral Capsules
Arm/Group Description	Vorinostat Oral Capsules 400mg daily 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.
All Cause Mortality
	Vorinostat, Zolinza Oral Capsules
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Serious Adverse Events
	Vorinostat, Zolinza Oral Capsules
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Reproductive system and breast disorders
Death of uterine carcinoma	2/3 (66.7%)	2
abscess of the vaginal vault	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
pleural effusion	2/3 (66.7%)	2
Other (Not Including Serious) Adverse Events
	Vorinostat, Zolinza Oral Capsules
	Affected / at Risk (%)	# Events
Total	0/3 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.