Carcinosarcomas Uterine, Endometrial Stromal Tumors, Leiomyosarcoma
Conditions
Keywords
Uterine sarcoma, Histone deacetylases
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).
Interventions
DRUGVorinostat 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.
Sponsors
Medical University of Graz
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 9 months | This endpoint is evaluated by the amount of clinical adverse experiences. |
Countries
Austria
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 details
There were no Screening failures in the Course of the study.
Participants by arm
| Arm | Count |
|---|---|
| Vorinostat, Zolinza Oral Capsules 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. | 3 |
| Total | 3 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 2 |
Baseline characteristics
| Characteristic | Vorinostat, Zolinza Oral Capsules | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 3 Participants | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment Austria | 3 participants | — |
| Sex: Female, Male Female | 3 Participants | — |
| Sex: Female, Male Male | 0 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 3 |
| other Total, other adverse events | 0 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
Primary
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)
Time frame: 9 months
Population: 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.
Secondary
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
This endpoint is evaluated by the amount of clinical adverse experiences.
Time frame: 9 months
Population: 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.