Clinical trial NCT03509207
Conditions: Leiomyosarcoma Endometrial Stromal Tumors Carcinosarcomas Uterine
Keywords: Uterine sarcoma Histone deacetylases
Sponsor: Medical University of Graz
Start date: 2017-12-14; Completion date: 2019-02-04
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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).

Arms: arm 1: Vorinostat Oral Capsules 400mg daily
Interventions: intervention 1: Vorinostat Oral Capsule
Intervention descriptions: intervention 1: 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.

Protocol documents:
Prot_000.pdf: 
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STUDY PROTOCOL 
in accordance with AMG 
 
 
 
 
A pilot study of peroral Vorinostat (SAHA) in 
patients with refractory histone deacetylase-positive 
uterine sarcoma 
 
SAHA-Pilot-2016 
 
 
Version: 3, 22.12.2016 
Authors: Martina Dieber-Rotheneder, Edgar Petru, Kurt Zatloukal 
Sponsor: Medical University of Graz 
Eudra-CT number: 2016-000782-22 
Running head: SAHA-Pilot-2016 
 
Principal Investigator:  Edgar Petru, MD, Medical University of Graz,     
Clinic of Obstetrics and Gynecology, 
Auenbruggerplatz 14, 8036 Graz, Austria 
 
 
The information contained in this study protocol is absolutely confidential. Its sole purpose is 
to inform the sponsor, the investigators, the study staff, the ethics committee, the official 
authorities, and patients. This study protocol may not be passed on to a third party without 
the consent of the sponsor or the principal investigator of the clinical trial. 
 


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Table of contents 
 
Responsibilities and addresses ............................................................................................. 4 
Synopsis................................................................................................................................ 6 
1 
Scientific Background / Introduction ............................................................................... 9 
1.1 
Study Diseases ....................................................................................................... 9 
1.1.1 
Leiomyosarcoma .............................................................................................. 9 
1.1.2 
Endometrial stromal tumors .............................................................................. 9 
1.1.3 
Mixed epithelial and mesenchymal tumors ......................................................11 
Genetic alterations in uterine sarcomas ............................................................................12 
1.2 
Therapeutic approaches for uterine sarcomas ........................................................13 
1.3 
Study medication ....................................................................................................16 
1.3.1 
Mechanism of Action .......................................................................................16 
1.3.2 
Nonclinical activity ...........................................................................................17 
1.3.3 
Pharmacocinetics/ pharmacodynamics/ toxicology ..........................................18 
1.3.4 
Clinical experience ..........................................................................................19 
1.3.5 
Benefits and risks to clinical trial participants ...................................................21 
2 
Aim of the trial ...............................................................................................................24 
3 
Recruitment and selection of patients ...........................................................................25 
3.1 
Inclusion Criteria ....................................................................................................25 
3.2 
Exclusion criteria. ...................................................................................................26 
4 
Study specific activities .................................................................................................27 
4.1 
Pre-screening (Visit I) .............................................................................................27 
4.2 
Screening (Visit II) ..................................................................................................31 
4.3 
Treatment ...............................................................................................................33 
4.3.1 
Vorinostat administration .................................................................................33 
4.3.2 
Dose modification and delays ..........................................................................33 
4.3.3 
Supportive Care ..............................................................................................33 
4.3.4 
Prior and concomitant therapy .........................................................................34 
4.4 
Measurement of effect ............................................................................................34 
4.5 
Follow up ................................................................................................................40 
5 
Safety monitoring and reporting ....................................................................................41 
5.1 
Adverse Events ......................................................................................................41 
5.2 
Serious Adverse Events .........................................................................................42 
5.3 
Reporting obligations (in accordance with the AMG) ..............................................42 
5.4 
Termination of the trial ............................................................................................44 
5.4.1 Premature termination of the trial for a proband (drop-out) ...................................44 
5.4.2 Premature termination of the entire trial ...............................................................44 
5.4.3 Termination of the entire trial ...............................................................................44 


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6 
Monitoring and Audit – Assurance of data quality .........................................................45 
7 
Biometry .......................................................................................................................45 
Data handling and record keeping ....................................................................................46 
8 
Ethical and legal matters...............................................................................................47 
9 
Modification of the study protocol ..................................................................................48 
10 Publication of study results ...........................................................................................48 
11 Financing ......................................................................................................................48 
12 References ...................................................................................................................49 
List of abbreviations .............................................................................................................57 
List of tables .........................................................................................................................59 
List of appendices ................................................................................................................59 
Confirmation of the final protocol ..........................................................................................60 
 
 
 


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Responsibilities and addresses 
 
Sponsor:  
Medical University of Graz 
Auenbruggerplatz 2 
A-8036 Graz, Austria 
 
Sponsor Contact Person / Principal investigator / Emergency  
Edgar Petru, MD 
Med Univ Graz 
Dept. of Obstetrics and Gynecology 
Auenbruggerplatz 14 
A-8036 Graz, Austria 
Phone: +43 385 81082 
Fax: +43 385 12546 
Mobile: +43 664 27 33 425 
E-mail: edgar.petru@medunigraz.at 
 
Protocol Contact Person/ Study Coordinator: 
Dr. Martina Dieber-Rotheneder 
Med Univ Graz 
Institute of Pathology 
Auenbruggerplatz 25 
A-8036 Graz, Austria 
Phone: +43 380 4402 
Fax: +43 384329 
Mobile: +43 664 3014576 
E-mail: martina.dieber@medunigraz.at 
 
Responsible Pathologist 
PD Dr. Bernadette Liegl-Atzwanger 
Med Univ Graz 
Institute of Pathology 
Auenbruggerplatz 25  
A-8036 Graz, Austria 
Phone: +43 385 80459 
Fax: +43 384329 
E-mail: bernadette.liegl-atzwanger@medunigraz.at 
 
Scientific Advisor 
Prof. Dr Kurt Zatloukal 
Med Univ Graz 
Institute of Pathology 
Auenbruggerplatz 25  
A-8036 Graz, Austria 
Phone: +43 380 4402 
Fax: +43 384329 
Mobile: +43 664 3014576 
E-mail: kurt.zatloukal@medunigraz.at 
 
 
 


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Study centre 
Med Univ Graz 
Dept. of Obstetrics and Gynecology 
Auenbruggerplatz 14 
A-8036 Graz, Austria 
Phone: +43 316 385 81082 
Fax: +43 316 385 12546 
 


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Synopsis 
 
Sponsor 
 
Medical University of Graz  
 
Name 
A pilot study of peroral Vorinostat (SAHA) in patients with refractory histone 
deacetylase-positive uterine sarcoma 
 
Running head 
SAHA-Pilot- 2016 
Target 
population
(or indication) 
 
Patients with refractory, histone deacetylase-positive, pre-treated uterine 
sarcomas (endometrial stromal sarcoma <ESS>, undifferentiated sarcoma 
<UUS, leiomyosarcoma <LMS>), adenosarcoma <AS> and carcinosarcoma 
<CS>) after hysterectomy 
Study 
design 
and 
phase 
Phase II pilot study  
Version of protocol
1 
Aims of the clinical 
trial 
 
Primary aim of the trial 
The main purpose of this single-arm phase II proof-of-principle- pilot study is 
to test the efficacy of the hydroxamic acid-based HDAC inhibitor Vorinostat 
(SAHA) as monotherapy in patients with histone deacetylase-positive, 
progressive, metastatic uterine sarcomas (ESS, UUS, LMS) and  mixed 
epithelial and mesenchymal tumors (CS, AS) after prior anti-proliferative 
therapy.  
 
Secondary aims of the trial 
Safety/toxicity 
Outcome 
measures 
(endpoints) 
of 
the 
clinical 
trial 
 
 
Primary outcome measure 
Progression-free survival (PFS) at 3, 6 and 9  months  
 
Secondary outcome measures 
Safety/toxicity 
 
Number of patients
 8
Total duration of the 
trial 
 4 years including follow-up, recruitment period of 3 years 
Time schedule 
With reference to the trial 
 
Recruitment 
period: 
2016-2018
 
Planned 
start 
(FPFV): 
06.2016
 
Planned end (LPLV): 07.2019 
With reference to patients  
 
Duration of treatment: 3 to 9 months depending on clinical benefit 


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Main inclusion 
criteria 
• 
Histologically confirmed metastatic uterine sarcoma (endometrial 
stromal sarcoma <ESS>, undifferentiated uterine sarcoma <UUS, 
leiomyosarcoma <LMS>; adenosarcoma <AS> and carcinosarcoma 
<CS>)  
• 
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 
 
Main 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 
AST/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 


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• 
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 medications 
 
Active substance: Vorinostat (superoylanilide hydroxamic acid, SAHA) 
Commercial name: Zolinza 
Manufacturer: Merck Sharp and Dohme (MSD) 
 
Treatment plan 
 
Vorinostat, 400 mg (4 capsules á 100mg of Zolinza) orally once daily with 
food 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 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). 
 
 
 


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1 
Scientific Background / Introduction 
 
1.1 Study Diseases  
 
Uterine sarcomas are rare tumors and comprise <5% of all primary uterine malignancies. 
(D'Angelo and Prat 2010, Kobayashi et al. 2013). The common variants of these 
mesenchymal tumors are leiomyosarcoma, endometrial stromal and related tumors as well 
as mixed epithelial and mesenchymal malignancies. 
1.1.1 Leiomyosarcoma 
 
Clinical features: Leiomyosarcoma (LMS) is the most common subtype of uterine sarcoma, 
since carcinosarcoma are currently classified as metaplastic carcinomas (see below). It 
accounts for 63% of all cases. LMS usually occur in women over 40 years of age and usually 
presents with abnormal vaginal bleeding, palpable pelvic mass and pelvic pain (D'Angelo and 
Prat 2010).  
Pathological features of LMS are severe nuclear atypia and high mitotic rate exceeding 15 
mitotic figures per 10 high-power fields (>15 MF per 10 HPF).  
Immunohistochemistry and molecular pathology: Most tumors are positive for desmin, 
smooth muscle actin, h-caldesmon und HDAC8. They are often immunoreactive for CD10 
and cytokeratins. Conventional LMS express estrogen- (ER), progesterone- (PR) and 
androgen receptors in about 30-40% of the cases.(De Fusco et al. 1989, Oliva et al. 2002, 
Kurman et al. 2014).  
Prognosis: LMS are very aggressive tumors with poor prognosis even if confined to the 
uterus and even if diagnosed at an early stage (Abeler et al. 2009, D'Angelo and Prat 2010). 
The recurrence rate is around 71% (Major et al. 1993). Overall 5 year survival rates range 
from 15 to 25% (Pelmus et al. 2009).  
1.1.2 Endometrial stromal tumors  
 
Clinical features: Endometrial stromal tumors belong to the rarest uterine neoplasms 
accounting for less than 1% thereof (Puliyath and Nair 2012). Patients typically present with 
abnormal uterine bleeding and pelvic pain. The uterus may be enlarged or there may be a 
pelvic mass (Kurihara et al. 2008, Kurman et al. 2014). The pathogenesis of ESS is 
unknown, but exposure to tamoxifen, unopposed estrogens, and conditions such as 
polycystic disease of ovary are implicated (Cohen 2004, Puliyath and Nair 2012). 


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Pathological features: The histopathologic classification of endometrial stromal tumors from 
2003 was revised by the WHO in 2014. According to this 2014 WHO classification (Kurman 
et al. 2014, Ali and Rouzbahman 2015) endometrial stromal tumors are divided into:  
1) non-invasive endometrial stromal nodule (ESN), a well-circumscribed benign 
mesenchymal tumor consisting of uniform cells closely resembling the uterine stromal cells of 
normal proliferative-phase endometrium;  
2) low-grade endometrial stromal sarcoma (LG-ESS), an infiltrative tumor with stromal cells 
cytologically almost identical to those observed in the ESN but associated  with low 
aggressive malignant behaviour,  
3) high–grade endometrial stromal sarcoma (HG-ESS), malignant tumors of endometrial 
stromal derivation  with round cell morphology sometimes associated with a low- grade 
spindle cell component and  
4) undifferentiated endometrial <uterine> sarcomas (UES, UUS). The heterogeneous group 
of UES often lacks specific differentiation and usually bears no morphological resemblance 
to endometrial sarcoma. (Kurman et al. 2014). They can be subdivided into groups with 
either uniform or pleomorphic nuclei. (Jakate et al. 2013).  
Immunohistochemistry and molecular pathology: Typically but not always, LG-ESS are 
diffusely and strongly positive for CD10, often positive for smooth-muscle actin and 
occasionally for desmin, but they are negative for h-caldesmon and HDAC8. ESS frequently 
contain ER and PR (Reich and Regauer 2007). HG-ESS: the high-grade round cell areas are 
CD10, ER and PR negative but show strong diffuse cyclinD1 positivity whereas the low-
grade spindle cell component is typically strongly and diffusely CD10, ER and PR positive 
and shows variable, heterogeneous cyclin D1 expression (>50%) (Lee et al. 2012). UES are 
variably CD10 positive and ER and PR negative or weakly positive. Cyclin D1 can be 
diffusely positive (Kurihara et al. 2008). 
HG-ESS are usually necrotic and express a high mitotic activity (typically >10MF per 10 
HPF). The overall 5-year survival rate of patients with low-grade ESS ranges from 68% to 
100% whereas that of UES patients is markedly lower - patients usually die within two years 
(Kurihara et al. 2008, Tanner et al. 2012).  
Prognosis: In comparison to LG-ESS, patients with HG-ESS have earlier and more frequent 
recurrences (often>1 year), (Kurman et al. 2014). 
 


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1.1.3 Mixed epithelial and mesenchymal tumors 
 
Clinical features: Adenosarcoma (AS) and carcinosarcoma (CS) of the uterus (also 
referred to as malignant mixed mullerian tumor, MMMT) are biphasic neoplasm composed of 
epithelial and mesenchymal elements. Most women present with vaginal bleeding and 
uterine enlargement. In AS there may also be a mass pertruding into the vagina (Kurman et 
al. 2014). 
In AS the epithelial component is benign or atypical and the stromal component is low-grade 
malignant. AS with a high-grade sarcomatous component >25%, are classified as “AS with 
sarcomatous overgrowth”. Around two third of AS occur in postmenopausal women, 30% are 
found in pre-menopausal patients (Kurman et al. 2014).  
Carcinosarcomas typically also occur in post-menopausal women and account for almost 
one half of all uterine sarcomas. On the basis of the clonal origin of both tumor components, 
CS are currently thought to be metablastic carcinomas rather than uterine sarcoma 
(D'Angelo and Prat 2011). They are customarily separated into two types harboring either 
heterologous or homologous mesenchymal elements. The homologous components of CSs 
are usually spindle cell sarcoma without obvious differentiation many resemble pleomorphic 
sarcomas. The most common heterologous elements are malignant skeletal muscle or 
cartilage resembling either rhabdomyosarcoma (D'Angelo and Prat 2011).  
Immunohistochemistry and molecular pathology:  In most AS without sarcomatous 
overgrowth, the immunophenotype of the stromal component resembles that of an ESS. 
Cases with sarcomatous overgrowth show immunoreaction for Ki67 and p53 and loss of 
CD10, ER and PR expression (Gallardo and Prat 2009, D'Angelo and Prat 2011). 
Carcinosarcomas show only a low expression or absence of steroid receptors (ER, PR) and 
CD10. ER and PR are only expressed in the carcinomatous component, CD10 only in the 
sarcomatous elements (Kobayashi et al. 2013). 
Prognosis: Carcinosarcomas are highly aggressive tumors. Its 5 year overall survival rate is 
less than 35% (Ferguson et al. 2007). These tumors are associated with a particularly poor 
outcome and have a pattern of spread similar to that of high-grade endometrial carcinoma 
(Ferguson et al. 2007). The prognosis of AS is far more favorable than that of CS except 
when associated with myometrial invasion or sarcomatous overgrowth. 
 
 


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Genetic alterations in uterine sarcomas  
 
Chromosomal and cytogenetic studies have shown some heterogeneous genetic aberrations 
in endometrial stromal tumors. One of the most frequent genetic aberrations found is the 
t(7;17)(p15;q21) chromosomal translocation (Hennig et al. 1997), mainly present in LG-ESS 
(Dal Cin et al. 1992, Pauwels et al. 1996). At the sites of the 7p15 and 17q21 breakpoints 
fusion of two zinc-finger proteins, the so-called JAZF1/JJAZ1 gene fusion was found, quite 
distinctive for ESS (Koontz et al. 2001, Hrzenjak et al. 2005, Jakate et al. 2013). High-grade 
ESS typically harbour the YWHAE-FAM22 genetic fusion as a result of t(10;17) (q22;p13) 
translocation (Lee et al. 2012, Lee et al. 2012) These tumors are associated with high-grade 
morphology and aggressive clinical behaviour which is important for prognostic and 
therapeutic purposes (Lee et al. 2012, Ried and Gaiser 2012). Undifferentiated uterine 
sarcoma have complex chromosomal changes, including gains of 2q, 4q, 6q, 7p, 9q, 20q 
and losses of 3q, 10p, 14q (Halbwedl et al. 2005). Although detection of these genetic 
alterations is undoubtedly an improvement in diagnostics for differentiation between LG-ESS, 
HG-ESS and UES, clinical utility and potential benefit for therapy needs to be established.  
Uterine leiomyosarcomas have both complex numerical and structural chromosomal 
aberrations and it is suggested that genomic instability is a hallmark of malignancy in uterine 
smooth muscle cell tumors (Fletcher et al. 1990, Sandberg 2005, Kurman et al. 2014). In 
particular, frequent losses of 13q, 10q, 16Q, 12p, and  2p as well as occasional gain of 17p, 
Xp, and 1q were observed (Hu et al. 2001). 
In general, in carcinosarcoma, gains (85%) are observed more frequently, than losses 
(30%). Chromosomal amplification is not random and is closely associated with 
chromosomes 8q and 20q (42 and 70%), (Schipf et al. 2008). The two chromosomes contain 
oncogenes, c-myc and ZNF 217, which are relevant to various types of tumor. Amplification 
of c-myc correlates with distant metastases and is a factor of poor prognosis (Kobayashi et 
al. 2013). The genetic and epigenetic aberrations of As remain largely unknown (Kobayashi 
et al. 2013). 
Up-regulation of nuclear p53 expression which occurs as an early event of tumorigenesis, 
was associated with carcinosarcoma (73%), LMS (38%) and ESS (27%) (Nordal et al. 1998). 
  
 
 


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1.2 Therapeutic approaches for uterine sarcomas 
 
For all types of uterine sarcoma, patients with operable tumors undergo primary surgery 
including abdominal hysterectomy ± bilateral salpingo-oophorectomy. In CS usually pelvic 
lymph node dissection is performed also (Kobayashi et al. 2013). Radiotherapy is 
uncommonly used as an increased pelvic control rate. In ESS, radiotherapy may be useful in 
controlling local recurrncies (Reed 2008). In the adjuvant treatment setting, chemotherapy is 
not established. Its use is mainly palliative (Kobayashi et al. 2013, Serrano and George 
2013).   
 
The most frequently used chemotherapeutic options for uterine sarcoma are summarized in 
Table 1. 
 
Table1: Possible systemic regimens in uterine sarcoma 
 
 
Monotherapy 
Combination therapy 
LMS 
Trabectedin, Pazopanib 
Gemcitabine 
+ 
Docetaxel 
Doxorubicin + Ifosfamide  
LG-ESS
Progestin/aromatase inhibitors,  
Doxorubicin 
 
HG-ESS,UES
Ifosfamide, Doxorubicin 
Doxorubicin+Ifosfamide 
CS, AS 
Cisplatin, Ifosfamide, Doxorubicin, 
Paclitaxel, Carboplatin 
Ifosfamide + Cisplatin, Ifosfamide 
+ Paclitaxel 
 
(Hensley et al. 2002, Hensley et al. 2008, Hensley et al. 2008, Powell et al. 2010), (Imesch et 
al. 2014, Imesch et al. 2014), (Amant et al. 2015) (Sutton et al. 1996) (Thanopoulou et al. 
2015) (Reed 2013, Serrano and George 2013) 
 
Because of tumor rarity, one can hardly expect that novel molecularly targeted therapies will 
be specifically developed against uterine sarcoma. Therefore, therapies used for other solid 
tumors, have been investigated with regard to their efficacy for treatment of uterine sarcomas 
based on research focussed on molecular pathophysiology of these malignancies. 
 
Chemotherapy regimens for LMS often include gemcitabine + docetaxel (Hensley et al. 
2008) as well as doxorubicin + ifosfamide (Amant et al. 2015). Trabectedin (ET-743), a 
synthesized molecule, is a marine-derived antineoplastic agent that disrupts the cell cycle 
and was efficient in phase ll trials for LMS (Demetri et al. 2009, Kobayashi et al. 2013, Amant 
et al. 2015). Molecular targeted therapies have been conducted to assess the efficacy of 
pazopanib, mTOR, COX-2 and angiogenesis inhibitors. However, clinical trials with imatinib 


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and sunitinib failed to show improved outcomes as second or third line LMS treatment 
(Hensley et al. 2009, Kobayashi et al. 2013). A randomized, double-blinded, placebo-
controlled phase III trial with the angiogenesis inhibitor pazopanib showed a consistent 
prolongation of progression-free survival of 4.6 vs 1.6 months (van der Graaf et al. 2012). 
Almost all patients with unresectable metastatic LMS are considered incurable; hence, in 
almost all cases, the treatment intension for systemic disease is palliative, with the goal of 
decreasing tumor bulk, diminishing symptoms, improving quality of life, and prolonging 
survival (Serrano and George 2013). 
 
Therapeutic options for ESS/UES have been summarized in-depth in various reviews (Amant 
et al. 2009, Ioffe et al. 2009, Thanopoulou and Judson 2012) Current primary therapy for 
endometrial stromal sarcoma is surgery, mainly abdominal hysterectomy. The role of bilateral 
salpingo-oophorectomy and ovary preservation remain controversial (Amant et al. 2007, 
Reich and Regauer 2007, Chan et al. 2008, Feng et al. 2013). Lymphadenectomy does not 
have an effect on survival (Chan et al. 2008).  
The expression of molecular targets for tyrosine kinase inhibitors (TKI) in ESS and UES 
was reported (Geller et al. 2004, Moinfar et al. 2005, Park et al. 2013). However, only a few 
cases of responses to imatinib in patients with uterine sarcomas expressing at least one 
target of TKI have been described. A single case of UES with EGFR expression temporarily 
responded to imatinib (Mitsuhashi et al. 2007). Furthermore, a complete metabolic response 
to imatinib mesylate in a patient with a  low-grade ESS has been reported (Kalender et al. 
2009). In contrast, a retrospective immunohistochemical and molecular analysis of potential 
targets of TKI in 52 ESS and 13 UES highly question the use of TKI in endometrial stromal 
tumors (Sardinha et al. 2013, Hrzenjak et al. 2014). 
 
 In some studies, a therapeutic use of progestins and aromatase inhibitors in the treatment 
of low-grade ESS has been shown. Aromatase inhibitors such as letrozole block the 
enzyme aromatase, which turns androgen into estrogen, thus reducing estrogen production 
in postmenopausal women. As a consequence, the amount of body estrogen for stimulation 
of estrogen-receptor positive tumor cells is decreased. Progestins bind to progesterone 
receptors and downregulate gene transcription. This is especially true for estrogen receptors, 
leading to the reduction of circulating estrogens and decrease in endometrial gland and 
stromal proliferation. (Puliyath and Nair 2012) In their review, Thanopolou et al. summarized, 
among other results, data of 18 patients with recurrent/metastatic ESS treated with 
aromatase inhibitors. Five complete responses and eleven partial responses were seen. In 
addition, a negative impact of hormonal replacement therapy in ESS was demonstrated 
(Thanopoulou and Judson 2012). A high percentage of ESS cases express hormone 


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receptors, especially estrogen (40-100%) and progesterone (60-100%) receptors (Chu et al. 
2003, Pink et al. 2006, Thanopoulou and Judson 2012). On the other hand, contradictory 
data were published regarding the expression of androgen receptors in uterine sarcomas 
(Moinfar et al. 2004, Koivisto-Korander et al. 2011). Hormonal therapies seem to have 
differential efficacy in ESS and UES. ESS tumors frequently express estrogen and 
progesterone receptors and usually show better response to hormonal therapies. Although 
hormonal therapy has been shown to be able to stabilize disease or to induce a remission, it 
must be stressed that this effect depends on the receptor status (Amant et al. 2009). On the 
other side, UES tumors usually do not express hormone receptors and, therefore, are not 
susceptible to hormonal therapy. When the hormonal armentarium is exhausted, in the 
absence of hormone receptors or when progression into a high-grade malignancy occurs 
combination of doxorubicin and ifosfamide seem to be active cytotoxic drugs (Sutton et al. 
1996, Amant et al. 2009). 
 
Patients with higher stage of CSs may be considered for ifosfamide plus pacitraxel 
combination chemotherapy (Homesley et al. 2007, Powell et al. 2010). Adjunctive 
ifosfamide and cisplatin chemotherapy may also improve progression-free survival. 
Nevertheless, the incidence of tumor recurrence is high and the added toxicity may not justify 
the use of the combination (Sutton et al. 2000, Kobayashi et al. 2013). Compared to other 
uterine sarcoma, CSs exhibit a higher response rate to monotherapies (Imesch et al. 2014). 
There is no adjuvant or palliative chemotherapy-regimen existing for AS treatment. 
Recurrences are usually treated in the same way as CS (Petru et al. 2014, 4th Edition). 
 
In general, it can be summarized that responses to various chemotherapeutic agents have 
been poor. There exist only limited treatment options for uterine sarcomas (D'Angelo and 
Prat 2010, Kobayashi et al. 2013, Serrano and George 2013). 
 
 


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1.3 Study medication 
 
Vorinostat (superoylanilide hydroxamic acid, SAHA), Zolinza 
Manufacturer: Merck Sharp and Dohme (MSD) 
Histonedeacatylase inhibitor, new approach of targeted therapy 
 
Vorinostat (superoylanilide hydroxamic acid, SAHA), Zolinza manufactured by Merck Sharp 
and Dohme (MSD), a subsidiary of Merck Co, Inc is a potent, orally active, competitive 
inhibitor of histone deacetylases (HDAC), prescribing information, see appendix 2. Zolinza 
was approved by the FDA in 2006 for the treatment of patients with advanced cutaneous T-
cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following  
two systemic therapies (Mann et al. 2007). In addition to activity in hematologic 
malignancies, vorinostat has demonstrated promising efficacy in clinical trials with wide 
range of solid malignancies as breast cancer, lung cancer and prostate cancer. These 
studies, with vorinostat in monotherapy, have been summarized by us in a review (Hrzenjak 
et al. 2014) and are shown in table 2 (chapter 1.3.4 “Clinical experience”). 
 
Storage and handling: Zolinza can be stored at 20-25°C, excursions permitted between 15-
30°C (see prescribing information, Appendix 2). The capsules should not be opened or 
crushed. Direct contact of the powder in Zolinza capsules with the skin or mucous 
membranes should be avoided. If such contact occurs it should be thoroughly washed. 
 
1.3.1 Mechanism of Action 
 
Histone deacetylases exert their action during post-translational acetylation of core 
nucleosomal histones, which affects chromatin structure and thus regulates gene expression. 
Many cancer types, including uterine sarcoma, are characterized by epigenetic alterations 
(Boumber and Issa 2011, Ho et al. 2013). Acetylation and deacetylation of histone proteins 
are chemical modifications controlled by two groups of enzymes – histone acetylases (HATs) 
and histone deacetylases (HDACs). These enzymes regulate the acetylation level of histone 
proteins, thereby influencing the chromatin condensation and chromatin susceptibility for 
different transcription factors. Moreover, not only histone proteins, but also many other 
cellular proteins, are prone to those epigenetic modifications. Thus, the potential influence of 
de/acetylation on different cellular events goes far beyond our present knowledge. So far, 18 
different isoforms of HDACs are known. The majority of them are zinc-dependent 
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dependent, but NAD+-dependent enzymes (Verdin et al. 2003, Bieliauskas and Pflum 2008). 
Because of their localisation both in cell nucleus and in cytoplasm, class II HDACs (HDAC 4, 
5, 6, 7, 9 and 10) have a very broad range of substrates making their inhibition of special 
interest. 
 
Histone deacetylases might be of particular relevance for ESS and UES since HDAC2 and 3 
were found to be expressed in all ESS samples with strong immunohistological positivity 
indicating overexpression in approximately 80% of samples (Hrzenjak et al. 2014). Despite 
>80% homology on the protein level between HDAC1 and HDAC2, which are both 
constitutively expressed class I HDACs, HDAC1 was not overexpressed in analysed tumor 
samples when compared to non-neoplastic endometrial tissue (Hrzenjak et al. 2006).  
 
Further clues on the role of HDAC in ESS and UES-related cell lines have been obtained in 
studies using vorinostat which is a potent inhibitor of both class I and II HDACs (Marks et al. 
2004, Marks et al. 2004, Marks 2007). Vorinostat binds directly to the active centre of histone 
deacetylases, thereby acting as chelator for zinc ion and blocking the catalytic site of those 
enzymes (Finnin et al. 1999). In cell culture, vorinostat efficiently inhibits cell growth of 
various tumor cell types in a micromolar range. These inhibitory effects are mainly based on 
the activation of apoptosis, inhibition of cell growth or the activation of autophagic 
mechanisms and seem to be, at least to some degree, cell-type specific (Hrzenjak et al. 
2014). 
 
1.3.2 Nonclinical activity 
 
Inhibition of HDAC2 expression by the HDAC-inhibitor sodium valproate resulted in 
increased inhibition of cell-growth which has been accompanied by G1 arrest and by 
reduction of the number of cells in the S-phase of the cell cycle, as determined by 
fluorescence activated cell sorting (FACS). Interestingly, in the endometrial stromal sarcoma 
cell line ESS-1 (Gunawan et al. 1998), increased growth inhibition was primarily based on 
arrested cell proliferation and not on apoptosis. The effects of valproate on ESS-1 cells were 
attributed to the inhibition of HDAC2 which has been verified by comparative studies using 
cells transfected with HDAC2-specific siRNA. 
 
Experiments of our group and others showed that vorinostat efficiently inhibited growth of 
endometrial stromal sarcoma (ESS-1) and uterine sarcoma cell lines (MES-SA), (Harker et 
al. 1983) by influencing different HDAC members (HDAC 2, 3 and 7) (Hrzenjak et al. 2008, 
Hrzenjak et al. 2010). In MES-SA cells the growth inhibition was based on increased 


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activation of apoptosis. The cell lines differed in expression of CD10, Cyclin D1, P53 and 
PTEN-mutation. In contrast to MES-SA cells, ESS-1 cells are positive for CD10, cyclinD1and 
PTEN mutation but negative for P53. Other in vitro studies in ESS-1 with vorinostat showed 
similar results, indicating inhibition of G1/S transition based on down-regulation of HDAC7 
expression. These inhibitory effects were not apoptosis-based, but relied on vorinostat-based 
activation of autophagy (Hrzenjak et al. 2008). In nude mice xenografts of MES-SA cells 50 
mg/kg/day vorinostat administered over three weeks resulted in a more than 50% reduction 
of tumor size, as compared to a control group (Hrzenjak et al. 2010). This reduction of tumor 
size was rather based on vorinostat-based activation of apoptosis than on diminished tumor-
cell proliferation. Based on these results, the main mechanism of cell growth inhibition by 
vorinostat seems to depend on the cell-type. On the other hand, these differences might also 
be dependent on duration of vorinostat treatment and/or the time-interval between treatment 
and final cell proliferation analysis (Hrzenjak et al. 2014).  
 
1.3.3 Pharmacocinetics/ pharmacodynamics/ toxicology   
 
A 
pharmacological-toxicological 
expert 
report 
as 
well 
as 
pharmacokinetics 
and 
pharmacodynamics are summarized in the “EMA Withdrawal assessment report” for 
vorinostat from 2008/2009 (Appendix 1) in the “Full prescribing information of Zolinza” by 
Merck USA (Appendix 2) and by Iwamoto in 2013 (Iwamoto et al. 2013) 
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessme
nt_report/2010/01/WC500063049.pdf.) 
https://www.merck.com/product/usa/pi_circulars/z/zolinza/zolinza_pi.pdf 
The main reason for the withdrawal of the application for marketing authorisation in the 
European Union was based on the provisional view of the CHMP (Committee for Medicinal 
Products for Human Use) that the available data were not sufficient to permit a treatment 
licence. The main points of criticism were the absence of comparative data and concerns 
about thromboembolic events. 
 
Since that time much effort has been put into many clinical trials with vorinostat in mono- or 
combination- therapy of various hematologic malignancies and solid tumors (see next 
chapter). 
 
 


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1.3.4 Clinical experience  
 
Both clinical trials and post-trial clinical experience have confirmed the efficacy and 
tolerability of vorinostat.  
 
Searching for “Vorinostat AND solid tumors” currently 5 open clinical trials recruiting patients 
can be found on http://www.clinicaltrials.gov (see Table 2) 
 
Table 2: Open clinical trials with vorinostat in solid tumors 
 
Title 
Phase 
Clinical 
Trials.gov 
identifier 
Hydroxychloroquine + Vorinostat in Advanced Solid Tumors 
1 
NCT01023737 
Vorinostat in Combination With Paclitaxel and Carboplatin in 
Treating Patients With Metastatic or Recurrent Solid Tumors 
and HIV Infection 
1 
NCT01249443 
Clinical Study of Vorinostat in Combination With Etoposide in 
Pediatric Patients < 21 Years at Diagnosis With Refractory 
Solid Tumors 
1,2 
NCT01294670 
Vorinostat in Children 
1,2 
NCT01422499 
MLN9708 and Vorinostat in Patients With Advanced p53 
Mutant Malignancies
1 
NCT02042989 
 
 
Duvic et al describe the long-term tolerability of vorinostat administered to heavily pretreated 
patients with CTCL (Duvic et al. 2009). Fifteen of the initial 74 patients entered the extension 
phase after 6 months of basic treatment. Six of these patients continued on vorinostat 
therapy for more than two years. One patient continued to respond over 1445 days (4 years).  
 
A survey of completed clinical trials with HDAC inhibitor monotherapies in solid tumors was 
reviewed by out group last year (Table 3) 
 


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Table 3: A survey of completed clinical trials with HDAC inhibitor monotherapies in solid tumors
 (Hrzenjak et al. 2014) 
 
Drug/ Tumor type 
Trial 
phase 
Number of 
patients 
Response 
First author, year 
A) vorinostat
gastrointestinal cancer 
 I 
16 
7 SD (>8 weeks) 
Doi et al., 2013 
advanced solid tumors  
I 
57 
12 SD, 1 PR 
Ramalingam et al., 2010 
advanced prostate cancer 
II 
27 
2 SD (84 and 135d) 
Bradley et al., 2009  
solid tumors 
I 
18 
9 SD, 9 PD 
Fujiwara et al., 2009 
glioblastoma multiforme GBM 
II 
66 
PFS 6 m 9/52.. 
Galanis et al., 2009 
advanced cancer 
I 
25 
No prolongation of QTs 
Munster et al., 2009 
relapsed NSCLC 
II 
16 
8 SD (TTP: median 2.3 m) 
Traynor et al., 2009 
thyroid cancer 
II 
19 
9SD (TTP: median 24w) 
Woyach et al., 2009 
recurrent/metastatic head and neck cancer 
II 
12 
3SD, 1PR (unconfirmed) 
Blumenschein et al., 2008 
metastatic breast cancer 
II 
12 
4 SD (4-14m) 
Luu et al., 2008 
epithial ovarian or peritoneal carcinoma 
II 
27 
1PR, 9 SD (2 PFS >6m)  
Modesitt et al., 2008 
relapsed or refractory breast, colorectal or NSCLC 
II 
16 
8 SD (TTP: median 33.5d) 
Vansteenkiste et al., 2008 
mesothelioma 
I 
13 
2 PR, 4SD 
Krug et al., 2006 
advanced cancer 
I 
23 
PR, 1/14, SD 2/14 
Rubin et al., 2006 
advanced cancer(solid/hematological: 50/23) 
I 
73 
1 CR, 5 PR (2 unconfirmed) 16 SD Kelly et al., 2005 
B) romidepsin
 
thyroid carcinoma 
II 
20 
13 SD 
Sherman et al., 2013 
head and neck cancer 
II 
14 
2SD 
Haigentz et al., 2012 
recurrent glioma 
I/II 
8/35 
PFS median 8w, 1 PFS of 6m  
Iwamoto et al. 2011 
prostate cancer 
II 
25 
2 PR >or=6m 
Molife et al., 2010 
SCLC 
II 
16 
3SD, PFS median 1.8m 
Otterson et al., 2010 
colorectal cancer 
II 
25 
4SD 
Whitehead et al., 2009 
lung cancer 
II 
18 
9SD 
Schrump et al., 2008 
renal cell cancer 
II 
25 
1 CR 
Stadler  et al., 2006 
 
 
 
 
C) belinostat
 
 
 
 
unresectable hepatocellular carcinoma 
I/II 
54 
PFS (median: 2.64m), SD:45.2% 
Yeo et al.,2012 
recurrent or refractory thymic epithelial tumors 
II 
41 
PFS at 6m: 46% 
Giaccone et al., 2011 
epithelial ovariancancer  
II 
32 
PFS (median: 2.3), SD 9/15 
Mackay et al., 2010 
/micropapillary ovarian tumors 
 
 
PFS (median: 13.4m), SD 2/12 
 
advanced malignant pleural mesothelioma 
II 
13 
2SD, PFS (median: 1m) 
Ramalingam et al., 2009 
advanced refarctory solid tumors 
I 
46 
18SD 
Steele et al., 2008 
 
 
 
 
D) panabinostat
 
 
 
 
refractory metastatic renal cell carcinoma 
II 
20 
none 
Hainsworth et al., 2011 
 
 
 
 
E) entinostat
 
 
 
 
pretreated metastatic melanoma 
II 
28 
7SD(4/3), (TTP median: 55/51d) 
Hauschield et al., 2008 
Abbreviations: 
FL: follicular lymphoma; MZL: marginal zone lymphoma; MCL: mantle cell lymphoma; NSCLC:  non-small cell lung cancer 
CR, complete response; PR, partial response; SD, stable disease; ORR, overall response rate;PFS, progression free survival;  
TTP, time to progression; d,days; m, months 
 
 


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Furthermore, Lee and McGuire present a case study of woman with LMS who had 
progressed through multiple chemotherapeutic agents who achieved a partial response to 
vorinostat treatment (Lee and McGuire 2012). Stable disease was observed after 6 weeks 
and shrinkage in both her liver and lung metastases at 3 months. This patient remained on 
vorinostat for 18 months when she developed progressive disease.  Before, she had 
exhausted all treatment options for effective chemotherapy including first and second line 
combination chemotherapies. The best and longest duration of response, overall stable 
disease (OSD) for over 1.5 years, was achieved with vorinostat (400mg/day), with only initial 
mild nausea which resolved, and with metastases shrinkage.  
 
1.3.5 Benefits and risks to clinical trial participants 
All patients enrolled in this study will receive an oral vorinostat treatment as second line 
therapy after operation and after a prior hormone- or chemotherapy. One advantage of 
vorinostat is the ease of administration since oral application does not require outpatient 
treatment. Tumors of all patients included in this study must reveal a high expression of 
HDAC in IHC (see section 4.1) to have the potential for clinical benefit. 
Preclinical data demonstrate that vorinostat is active not only in hematologic malignancies 
but also in a variety of solid tumors (see last section) and data from early-phase clinical 
studies (completed or preliminary) are consistent with these observations. This study 
proposes to establish improved clinical outcomes for patients with advanced uterine sarcoma  
Treatment with vorinostat is expected to be well tolerated and it is hypothesized that it will 
result in delayed disease progression by 3 or more months. 
The safety of multiple daily doses of Zolinza was evaluated in hematologic patients as well 
as patients with non-CTCL cancers.  
Due to the significant role of metabolism in elimination of vorinostat, the impact of hepatic 
dysfunction was studied in patients with varying degrees of hepatic impairment (Ramalingam 
et al. 2010). The highest dose studied in mild, moderate and severe hepatic impairment was 
400, 300 and 200 mg daily respectively. The incidence of Grade 3 or 4 adverse reactions 
was similar among the hepatic function groups. The most common grade 3 or 4 adverse 
reaction in this study was thrombocytopenia. 
Patients in our study will be carefully monitored for key toxicities that have been observed 
with vorinostat (see Tables 4 and 5) as described in chapter 4. 
 


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Table 4: Summary of safety outcomes of patients with non-CTCL malignancies 
Source: 
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessme
nt_report/2010/01/WC500063049.pdf  
Risk will be further minimized by adherence to inclusion/exclusion selection criteria (see 
section 3), close safety monitoring (see section 5), dose adjustment guidelines (see section 
4.2) and Zolinza prescribing information (Appendix 2). Safety, efficacy and trial data will be 
reviewed by an independent monitor as outlined in the protocol. Patients will be further 
monitored for the first signs of deep vein thrombosis and pulmonary embolism at each study 
visit. 
The most common drug-related adverse experiences in patients with solid tumors treated 
with vorinostat 400 mg once daily were: gastrointestinal (diarrhea, nausea, anorexia, weight 
decrease, vomiting, constipation, appetite decrease); constitutional symptoms (fatigue, 
chills); hematologic abnormalities (thrombocytopenia, anemia) and taste disorders 
(dysgeusia, dry mouth), (Tables 4 and 5). Hyperglycemia and creatinine increase were the 
most common laboratory adverse experiences.  
To assess potential of cardiac rhythm and electrocardiogram alterations and the propensity 
of vorinostat to prolong QTc interval, a QT assessment study of vorinostat was conducted in 
advanced-stage cancer patients (Munster et al. 2009). Single supratherapeutic doses of 800 
mg vorinostat were generally well tolerated and not associated with prolongation of the QTc 
interval.  
At clinically relevant concentrations, vorinostat is neither an inhibitor nor an inducer of CYP 
enzymes and is not eliminated via CYP pathways (package insert, see Appendix 2)


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Table 5:  Vorinostat monotherapy. Summary of specific clinical or laboratory adverse 
experiences by preferred term (incidence ≥10% in1 or more dose levels) 
 
 Source: 
http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessme
nt_report/2010/01/WC500063049.pdf 
 
 
 


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2 
Aim of the trial 
Uterine sarcoma is a rare but usually deadly orphan disease. The prognosis of patients has 
not changed in the last 20 years with an overall five-year survival between 17 und 54% 
(Trope et al. 2012). Uterine sarcoma patients with extra-uterine disease have a particularly 
poor prognosis and are candidates for new clinical trials (Trope et al. 2012, Reed 2013, 
Ledermann and Ray-Coquard 2014).  
Surgical excision of the primary tumor is the treatment of choice. Due to the heterogeneity of 
uterine sarcomas and the limited efficacy of currently available treatment options in general, 
there exists no uniform treatment pattern for these rare malignancies (Dizon and Birrer 
2014). There is currently no standard therapy for patients with recurrent metastatic disease 
(Puliyath and Nair 2012, Serrano and George 2013). 
Histone acetylation plays a central role in the control of gene expression, influencing 
transcriptional control of many genes, including tumor suppressor genes. Mechanisms that 
involve hypoacetylation of core nucleosome histone proteins and DNA methylation have 
been reported to lead to the tight coiling of chromatin, thereby silencing the expression of a 
variety of genes, including those implicated in the regulation of cell survival, proliferation, 
differentiation, and apoptosis.  
Histone deacetylase inhibitors belong to a novel, powerful class of drugs which are 
promising for treatment of different hematologic and solid malignancies (Qiu et al. 2013). 
They have been shown to restore expression of silenced genes by remodeling the tightly 
coiled chromatin, which leads to the induction of differentiation, and subsequent apoptosis. 
So far, three different HDAC inhibitors have been approved by the US Food and Drug 
Administration (FDA): Vorinostat (SAHA, Zolinza) (Marks and Breslow 2007), romidepsin 
(FK-228, Istodax), (Grant et al. 2010) and panobinostat (LBH589, Farydak), (Richardson et 
al. 2015).  
The HDAC-inhibitor vorinostat (Zolinza) is already approved in the United States, Canada, 
Australia and Japan for treatment of a specific type of lymphoma. Zolinza is not yet approved 
for its use in Europe but has been used worldwide in numerous clinical trials (see previous 
section) in mono- and combination therapy of hematologic malignancies and various solid 
tumors. Safety and long-term tolerability (>2years) of Zolinza is already evaluated (Duvic et 
al. 2009) 
As we could show, HDAC overexpression is a characteristic feature of uterine sarcoma 
(Hrzenjak et al. 2006, Hrzenjak et al. 2008, Hrzenjak et al. 2010, Hrzenjak et al. 2014) and 
uterine sarcoma cell lines (Quan et al. 2014). Therefore, a high HDAC - positivity was elected 


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as an inclusion criterion in this clinical trial. The selective reduction of tumor cell growth in 
pre-clinical in vitro studies and tumor xenografts by HDAC-inhibitors confirm the rationale for 
their therapeutic use in uterine sarcoma (Hrzenjak et al. 2010).  
Since HDAC inhibitors including vorinostat represent a potential targeted therapy for the 
treatment of uterine sarcoma, the current pilot study investigates the use of vorinostat in pre-
treated uterine sarcomas. 
 
3 
Recruitment and selection of patients  
 
Number of patients:  8   
Duration of the trial: 2016-2019 
3.1 Inclusion Criteria 
 
• 
Histologically confirmed diagnosis of metastatic uterine sarcoma (endometrial stromal 
sarcoma 
<ESS>, 
undifferentiated 
sarcomas 
<UUS, 
leiomyosarcoma 
<LMS>; 
adenosarcoma <AS> and carcinosarcoma <CS>)  
• 
HDAC-positivity of the tumor determined by immunohistochemistry 
• 
Prior systemic antineoplastic therapy  
• 
Patient is not amenable for acurative therapy  
• 
Women, age ≥ 18 years 
• 
Life expectancy > 3 months  
• 
Measurable (> 1cm) or non-measurable (but radiologically evaluable) disease per 
RECIST version 1.1 on computed tomography (CT) scan or MRT scan 
• 
Karnofsky performance status of 60-100 
• 
No fertility preserved 
• 
Subject is able to swallow and retain oral medication and does not have uncontrolled 
emesis. 
• 
Adequate hematologic, renal and hepatic function as follows (within 28 days of 
enrollment):  
• 
Bone Marrow: Absolute neutrophil count (ANC) ≥ 1500/mm3 (1.5 × 109/L); 
Platelets ≥ 100,000/mm3 (100 × 109/L); Hemoglobin ≥ 9.5 g/dL; 
• 
Renal Function: Serum creatinine ≤ 1.5 × upper limit of normal (ULN) range 
OR creatinine clearance ≥ 50 mL/min/1.73 m2 (according to local 


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assessment method) for subjects with creatinine levels above institutional 
normal; 
• 
Hepatic function: Aspartate aminotransferase (AST) ≤ 2.5 × upper limit of 
normal; alanine transaminase (ALT) ≤ 2.5 × upper limit of normal; bilirubin ≤ 
1.5 × the ULN range. For subjects with liver metastases, AST < 5 × ULN 
range; ALT < 5 × ULN range. Subjects with Gilbert's Syndrome may have a 
bilirubin ≥ 1.5 × the ULN range although no evidence of biliary obstruction 
exists; in this case the AST/ALT values have to be normal. 
• 
Written informed consent 
 
3.2 Exclusion criteria.  
 
 
• 
Lack of or low expression of HDAC (tumor material tested by immunohistochemistry, see 
“pre-screening” in the next section) 
• 
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 active infection 
• 
Known HIV-positivity 
• 
Symptomatic brain metastasis or leptomeningeal disease 
• 
Pre-existing liver disease, severe hepatic impairment  (Bilirubin no greater than 1.5 times 
upper limit of normal (ULN)and or AST/ALT greater than 2.5 times ULN 
• 
Known history of allergic reaction to vorinostat or similar medications  
• 
Received 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. 
• 
Prior history of thrombotic or thromboembolic events, unless adequately controlled by 
anticoagulant therapy 
• 
Clinically significant uncontrolled condition(s): 
o Symptomatic congestive heart failure; 
o Unstable angina pectoris or cardiac arrhythmia; 
o Myocardial infarction within last 6 months; 
o Known active hepatitis B or hepatitis C  


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o Psychiatric illness/social situations that would limit compliance with 
study requirements 
4 
Study specific activities 
 
Table 6 lists all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments will be supported in the patient’s 
source documentation (CRFs). The study procedures outlined in table 6 are described in 
detail in this section. 
 
4.1 Pre-screening (Visit I) 
 
Signed and dated Informed Consent will be obtained prior to the initiation of any screening 
or study-specific procedures. Subjects will be considered screen failures if the informed 
consent has been signed but the subject does not meet eligibility criteria (e.g. if there is no 
high expression of HDAC). The reason for screen failure will be documented in the source 
document and will be captured in the CRF. 
 
Pre-Screening: All patients considered to be treated in this study will be pre-screened for 
HDAC-expression. The archived tumor material of each patient (all patients underwent 
surgery before entering the clinical trial) will be examined for the expression of HDAC1, 
HDAC2 and 3. Only patients with a high HDAC expression fulfilling all other inclusion 
parameters will enter in the clinical trial. A “high expression” means that at least 1 out of 3 
HDACs react highly positive in immunohistochemistry. Tumor specimens will be considered 
“highly positive” for HDAC if more than 50% of tumor cells reveal an intense staining, 
determined by two independent observers.  
 
Medical history: The following information will be collected during the Pre-Screening visit: 
 
Complete medical history, including documentation of any clinical significant medical 
condition, presence and severity of any symptoms and toxicity associated with metastatic 
malignancy and/or previous treatment. 
 
In addition a detailed oncologic history will be recorded: 
○ Date of primary diagnosis of malignancy 
○ Pathology of primary tumor 
○ Surgical history 
○ Anticancer and radiation treatment administered (including dates and type of modality); 
 


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At each visit, the subject's medical history will be reviewed and clinically significant changes 
from baseline will be recorded in the source documents and in the adverse event section of 
the CRF. 
 
Table 6a: Flow chart of study activities (treatment period 1: cycles 1-4) 
 
Period
Screening period
Treatment period  1 (TP1) 
Final visit or
Start of TP2 
Visit (V) 
I 
II 
III 
IV 
V 
VI 
VII 
Cycle 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
 
Study week 
-8 until -4 
- 4 until  0 
1 
4 
7 
10 
13 
Activity
Pre-
Screening 
 
Screening 
Start 
of 
treatment 
 
 
 
Decision 
for 
Prolongation 
Informed Consent 
X
Medical history 
X
HDAC of tumor 
X
Physical examination 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
Body height 
X
Body weight 
X
X
X
X
X
X
Karnofsky p.status 
X
X
X
X
X
X
QLQ C30 questionnaire 
X
X
X
X
X
X
12- lead- ECG 
X
X1
X1
X1
Tumor-assessment: CT 
Chest, abdomen, pelvis 
X 
X4 
Hematology 
X
X  X2 X2
X  X3
X  X3
X  X3
X
Chemistry 
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Blood 
coagulation 
parameters 
X 
 
 
 
 
 
Adverse events  
(AE/SAE) assessment 
X 
X 
X 
X 
X 
X 
Drug dispense/ 
X
X
X
X
X
Drug accountability 
X
X
X
Concomitant medication 
X
X
X
X
X
 
1 Can be done by the patients’ practicioner or internist in the previous week 
2 Should be done at the study center or by the patients’ practicioner or internist in each of the following two weeks 
3 Should be done at the study center or by the patients’ practicioner or internist in one of the following two weeks  
4 Should be done in the clinic in the previous 2 weeks 
 


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Table 6b: Flow chart of study activities (treatment period 2: cycles 5-8) 
 
Period 
Treatment period  2(TP2) 
Final visit or
Start of TP3 
Visit (V) 
VII
VIII
IX
X
XI
Cycle  
Cycle 5
Cycle 6
Cycle 7
Cycle 8
Study week 
13
16
19
22
25
Activity 
 
 
 
Decision for 
Prolongation 
Physical examination 
X
X
X
X
X
Vital signs 
X
X
X
X
X
Body weight 
X
X
X
X
X
Karnofsky p.status 
X
X
X
X
X
QLQ C30 questionnaire 
X
X
X
X
X
12- lead- ECG 
X1
X1
X1
Tumor-assessment: 
CT 
Chest , abdomen, pelvis 
X3 
X3 
Hematology 
X
X  X2
X  X2
X  X2
X
Chemistry 
X
X
X
X
X
Urinalysis 
X
X
X
X
X
Adverse events  
(AE incl SAE) assessment 
X 
X 
X 
X 
X 
Drug dispense/ 
X
X
X
X
X
Drug accountability 
X
X
X
Concomitant medication 
X
X
X
X
X
 
1 Can be done by the patients’ practicioner or internist in the previous week 
2 Should be done at the study center or by the patients’ practicioner or internist in one of the following two weeks  
3 Should be done at the clinic in the previous 2 .weeks 


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Table 6c: Flow chart of study activities (treatment period 3: cycles 9-12)  
 
Period 
Treatment period  3 (TP3) 
Final visit 
30±7d Day
Follow-up  
visit 
Visit (V)
XI
XII
XIII
XIV
XV
XVI
Cycle  
Cycle 9 
Cycle 10 
Cycle 11 
Cycle 12 
Study week
25
28
31
34
37
41
Activity
 
 
 
Physical examination 
X
X
X
X
X
X
Vital signs 
X
X
X
X
X
X
Body weight 
X
X
X
X
X
X
Karnofsky p.status 
X
X
X
X
X
X
QLQ C30 questionnaire 
X
X 
X 
X 
X 
X 
12- lead- ECG 
X1
X1
X1
X1
Tumor-assessment: CT 
Chest , abdomen, pelvis 
X3 
X3 
X3 
Hematology 
X
X  X2
X  X2
X  X2
X
X
Chemistry 
X
X
X
X
X
X
Urinalysis 
X
X
X
X
X
X
Adverse events  
(AE 
incl 
SAE) 
assessment 
X 
X 
X 
X 
X 
X 
Drug dispense/ 
X
X
X
X
Drug accountability 
X 
X
X
X
X
Concomitant medication 
X 
X 
X 
X 
X 
X 
 
 
1 Can be done by the patients’ practicioner or internist in the previous week 
2 Should be done at the study center or by the patients’ practicioner or internist in one of the following two weeks  
3 Should be done at the clinic in the previous 2 weeks 
 
 


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4.2 Screening (Visit II) 
 
A complete physical examination will be performed at the screening visit and before each 
cycle. Vital signs (heart rate, sitting blood pressure, and body temperature) will be recorded 
in addition. Height will be recorded at screening visit only. Since all patients underwent 
hysterectomy prior to the study, no pregnancy test is needed.  
Physical exams will be done during all study visits to rule out disease progression. If 
progression is suspected, subsequent confirmation by CT will follow (see chapter 4.3).  
 
A resting 12-lead electrocardiography (ECG) will be performed at the screening visit, once 
during cycles 1 and 2 and before every second study visit by the patients’ 
practitioner/internist or at the study site. In case of clinical significant abnormalities, the 
clinical evaluation will be performed by a cardiologist who will determine whether any 
pathologic or clinically significant signs have occurred.  
Table 7: Karnofsky performance status 
 
Able to carry on normal activity and to work; no 
special care needed. 
100 Normal no complaints; no evidence of 
disease. 
90 Able to carry on normal activity; minor 
signs or symptoms of disease. 
80 Normal activity with effort; some signs 
or symptoms of disease.  
Unable to work; able to live at home and care for 
most 
personal 
needs; 
varying 
amount 
of 
assistance needed. 
70 Cares for self; unable to carry on 
normal activity or to do active work. 
60
Requires occasional assistance, but is 
able to care for most of his personal 
needs. 
50 Requires considerable assistance and 
frequent medical care.  
Unable to care for self; requires equivalent of 
institutional or hospital care; disease may be 
progressing rapidly. 
40 Disabled; requires special care and 
assistance. 
30 Severely disabled; hospital admission is 
indicated although death not imminent. 
20
Very 
sick; 
hospital 
admission 
necessary; active supportive treatment 
necessary. 
10 Moribund; fatal processes progressing 
rapidly. 
0 Dead 
 
 
 


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Patient reported outcomes: A determination of the Karnofsky status (Table 7 and Appendix 
3) (Karnofsky and Buchenal 1949) and of the quality of life will be determined at the 
screening visit and the starting visit of each cycle via QLQ C30 questionnaire (Appendix 4). If 
the investigator feels that the quality of life of an individual patient is impaired, a dose 
reduction may be performed at the discretion of the investigator. The dose reduction has to 
be stated in the CRF. 
 
Clinical Laboratory Tests 
Hematology, laboratory chemistry and urinalysis will be collected at the screening visit and all 
visits before each subsequent cycle and at the final and follow-up visit. All subjects will 
undergo the laboratory assessments as outlined in Table 8. Blood coagulation will be only 
determined at the screening visit, afterwards only on the decision of the principal investigator. 
In the context of this routine blood testing, additional 10ml of blood (5ml of plasma) will be 
obtained for future biomarker studies. 
 
Table 8: Clinical Laboratory Tests  
 
Hematology
Clinical Chemistry
Urinalysis
Hemoglobin 
Mean corpuscular volume 
Mean corpuscular hemoglobin 
concentration 
Hematocrit 
Red Blood Cell (RBC) count 
White Blood Cell (WBC) count 
Neutrophils 
Granulocytes 
Lymphocytes    
Monocytes 
Basophils  
Eosinophils  
Platelet count  
(Blood coagulation) 
Sodium 
Potassium 
Chloride 
Blood Urea Nitrogen (BUN) 
Serum creatinine 
Glucose 
Calcium 
Magnesium 
Total protein 
Albumin 
Total bilirubin 
Serum glutamic-pyruvic 
transaminase (SGPT/ALT) 
Serum glutamic-oxaloacetic 
transaminase (SGOT/AST) 
Alkaline phosphatase 
Uric acid 
Lactate dehydrogenase (LDH) 
Serum or urine β-HCG* 
Glomerular filtration rate 
C-reactive protein (CRP) 
Ketones 
pH 
Protein 
Blood 
Glucose 
Urobilinogen 
Nitrate 
 
 
 
 


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4.3 Treatment 
 
4.3.1 Vorinostat administration  
Dispense of the study drug vorinostat will start at visit III. Patients will receive 64 capsules of 
Zolinza at the starting visit of each cycle. Vorinostat, 400 mg (4 capsules á 100mg of Zolinza) 
will be administered orally once daily with food for the first 14 days of a 21 day cycle on an 
outpatient basis. Patients will be instructed to drink at least 2 L/day of fluid to prevent 
dehydration and should promptly report excessive vomiting or diarrhea and any evidence of 
deep vein thrombosis to their physician.  
 
Duration of therapy: Patients with a response or stable disease on therapy will be continued 
on vorinostat therapy at the same schedule and dosage until disease progression, 
unacceptable toxicity or withdrawal of the consent for up to 9 months (12 cycles at the 
maximum). A follow- up- visit will be after 30 +/- 5 days after the last day of the last cycle. 
 
4.3.2 Dose modification and delays 
If a patient is intolerant to therapy (significant fatigue etc.), the dose will be reduced to 300 
mg orally once daily. Any changes from screening assessments, observed prior to dosing, 
will be recorded in the subject's CRF.  
It will be acceptable for individual chemotherapy doses to be delivered within a “24h” 
window, for example: ”Day 7 chemotherapy“ may be delivered on Day 6, Day 7, or Day 8, 
respectively. 
4.3.3 Supportive Care  
Antiemetics, antibiotics, blood-transfusions, nutritional support, non-radiation palliative 
treatment for pain will be used according to institutional policy. Patients will receive 5-HT3-
antagonists, according to the investigator’s discretion. Bisphosphonate or denosumab 
therapy will be used in the case of bone metastases  
Erythrocyte-stimulation (e.g.erythropoietin, darbepoetin alpha) and colony stimulating factors 
(e.g. G-CSF) may be administered as supportive care or to maintain dose intensity or to 
avoid dose delays according to standard practice, institutional or clinical practice guidelines. 
 


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4.3.4 Prior and concomitant therapy  
 
Due to potential interactions of vorinostat with other drugs coadministered, the case report 
form will capture the concurrent use of all other drugs, over-the-counter medications, or 
alternative therapies. Prior therapy with biologic agents including vaccines and 
immunostimulants are allowed. Concomitant agents are not allowed. 
 
Radiation: Prior treatment with radiation is allowed as long as it was performed no later than 
28 days prior to vorinostat treatment.  
 
4.4 Measurement of effect   
 
The measurement of effect for tumor response will be performed at the end of each 
treatment period (weeks 12, 24, 36) and in the week before the follow-up visit.  
 
RECIST (Version 1.1) for Tumor Response 
Response criteria will be assessed using RECIST version 1.1 (Eisenhauer et al. 2009). 
Changes in the target and non-target lesions over the course of therapy must be evaluated 
using the criteria listed below. 
 
Eligibility 
Subjects with measurable or non-measurable (but radiologically evaluable) disease with at 
least one lesion outside previously irradiated areas at baseline can have objective tumor 
response evaluated by RECIST (version 1.1). Measurable disease is defined by the 
presence of at least one measurable lesion in at least one site which has not received prior 
radiotherapy. Lesions that have been previously irradiated will be considered non-target 
lesions. If the measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology, if possible.  
 
Measurability 
Measurable Lesions: Lesions accurately measured in at least one dimension with a minimum 
size of: Longest diameter ≥ 10 mm (CT scan slice thickness no greater than 5 mm) 10-mm 
caliper measurement by clinical exam 
Non-Measurable Lesions All other lesions, including small lesions (longest diameter < 10 
mm) as well as truly non-measurable lesions. Lesions considered truly non-measurable 
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disease, lymphangitis cutis/pulmonis, and abdominal masses that are not confirmed and 
followed by imaging techniques. 
Measurable Malignant Lymph Nodes: To be considered pathologically enlarged and 
measurable, a lymph node must be ≥ 15 mm in short axis when assessed by CT scan (CT 
scan slice thickness recommended to be no greater than 5 mm). At Baseline and in follow-
up, only the short axis will be measured and followed. 
Non-Measurable Malignant Lymph Nodes: Pathological lymph nodes with ≥ 10 to < 15 mm 
short axis. 
Special Considerations Regarding Lesion Measurability  
Bone lesions - Bone lesions are considered non-target lesions. 
Cystic lesions -Lesions that meet the criteria for radiographically defined simple cysts should 
not be considered as malignant lesions (neither measurable nor non-measurable) since they 
are, by definition, simple cysts. 
 "Cystic lesions" thought to represent cystic metastases can be considered measurable 
lesions if they meet the definition of measurability described above. However, if noncystic 
lesions are present in the same patient, these are preferred for selection as target lesions. 
Lesions with prior local treatment 
 
Tumor lesions situated in a previously irradiated area will be considered non-target lesions. 
All baseline evaluations should be performed as closely as possible to the beginning of 
treatment. The same method of assessment and the same technique should be used to 
characterize each identified and reported lesion at baseline and during follow-up.  
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes) and ≥ 10 mm diameter as assessed using calipers. In 
the case of skin lesions, documentation by color photography including a ruler to estimate 
the size of the lesion is recommended. All measurements should be taken using calipers and 
recorded in metric notation, if clinically assessed. When lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken, since it is more 
objective and may also be reviewed at the end of the study. 
Methods of Measurement  
Conventional CT should be performed with contiguous axial cuts of 5 mm or less in slice 
thickness for tumors of the chest, abdomen and pelvis. A scale should be incorporated into 


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all radiographic measurements. MRI can be performed if required by local law, but must have 
sponsor/central imaging center approval. Non-axial slices may be of value in the 
interpretation of paraspinal lesions findings and other lesions that are better appreciated in 
non-axial planes. Lesions followed on non-axial imaging should be assessed qualitatively 
(i.e., as CR, Non-CR/Non-PD, unequivocal PD, unequivocal new, NE). Lesions only visible 
on non-axial imaging are not considered suitable as target lesions. 
For accurate objective response evaluation, ultrasound or bone scan should not be used to 
measure tumor lesions. 
The utilization of endoscopy and laparoscopy for objective tumor evaluation is not advised. 
However, such techniques can be useful in confirming complete pathological response when 
biopsies are obtained. 
Cytology and histology can be used to differentiate between benign and malignant fluid 
collections in cases of new and/or enlarging pleural effusion and/or ascites in which the 
response will be based on other target or non-target lesions. New effusions or ascites should 
be considered unknown until cytology confirms whether they are benign or malignant. If 
cytology is available and suggesting malignancy, the data must be entered into the CRF and 
will be considered in the determination of progression. While fluid collections are present, the 
response determination cannot be considered CR. 
Baseline Documentation of "Target" and "Non-Target" Lesions 
All measurable lesions, up to a maximum of 2 lesions per organ and 5 lesions in total 
representative of all involved organs should be identified as target lesions and recorded and 
measured at Baseline. Tumor lesions situated in a previously irradiated area or in an area 
subjected to other loco-regional therapy are considered non-target lesions.  
Lymph nodes merit special mention, since they are normal anatomical structures, which may 
be visible by imaging, even if not involved by tumor. Pathological nodes, which are defined 
as measurable and may be identified as target lesions (no more than 2 may be selected), 
must meet the criterion of a short axis of ≥ 15 mm by CT scan. Only the short axis of these 
nodes will contribute to the baseline sum. The short axis of the node is the diameter normally 
used by radiologists to judge whether a node is involved by solid tumor. Nodal size is 
normally reported as 2 dimensions in the plane in which the image is obtained (for CT scan 
this is almost always the axial plane). The smaller of these measures is the short axis. For 
example, an abdominal node, which is reported as being 20 mm × 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
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mm but < 15 mm) should be considered non-target lesions. Nodes that have a short axis < 
10 mm are considered non-pathological and should not be recorded or followed. 
A sum of the diameters (SOD) for all target lesions will be calculated and reported as the 
baseline sum SOD. If lymph nodes are to be included in the sum, then, as noted above, only 
the short axis is added into the sum. The baseline SOD will be used as reference by which to 
characterize the objective tumor response. 
All other lesions (or sites of disease), including pathological lymph nodes, CNS metastases 
and skin lesions, should be identified as non-target lesions and should also be recorded at 
Baseline. Measurements of these lesions are not required, but the presence (stable, 
increasing, or decreasing) or absence of each should be noted throughout follow-up. 
Evaluation of Target Lesions 
Complete Response (CR) 
The disappearance of all target lesions. Any pathological lymph nodes (whether target or 
non-target) must have reduction in short axis to < 10 mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters. 
Progressive Disease (PD) 
At least a 20% increase in the sum of diameters of target lesions, taking as reference the 
smallest SOD recorded since the treatment started (baseline or after) or the appearance of 
one or more new lesions. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.  
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking 
as reference the smallest SOD since the treatment started (baseline or after). 
Assessment of Target Lesions 
Lymph nodes identified as target lesions should always have the actual short axis 
measurement recorded (measured in the same anatomical plane as the baseline 
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lymph nodes are included as target lesions, the "sum" of lesions may not be zero, even if 
complete response criteria are met, since a normal lymph node is defined as having a short 
axis of < 10 mm. For PR, SD, and PD, the actual short axis measurement of the nodes is to 
be included in the sum of target lesions. All lesions (nodal and non-nodal) recorded at 
Baseline should have their actual measurements recorded at each subsequent evaluation, 
even when very small (< 5 mm). However, sometimes target lesions or lymph nodes become 
too small to measure. If it is in the opinion of the radiologist that the lesion has likely 
disappeared, the measurement should be recorded as 0 mm. If the radiologist believes that 
the lesion is present, but too small to measure, a default value of 5 mm should be assigned 
(as derived from the 5-mm CT slice thickness). The measurement of these lesions is 
potentially non -reproducible; therefore, providing this default value will prevent false 
responses or progression based upon measurement error.  
If interventions occur during the study that affect disease burden, such as surgery, the 
lesion(s) affected will typically be considered non-evaluable (NE) from that point forward and 
subsequent time points will be either NE or PD (if evidence of progression is available). 
 
Evaluation of Non-Target Lesions 
Complete Response (CR) 
The disappearance of all non-target lesions. All lymph nodes must be non-pathological in 
size (< 10 mm short axis). 
Non-CR/Non-PD 
Persistence of one or more non-target lesion(s). 
Progressive Disease (PD) 
Unequivocal progression of existing non-target lesions. 
In this setting, to achieve "unequivocal progression" on the basis of non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in the 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently 
to merit discontinuation of therapy. A modest "increase" in the size of one or more non-target 
lesions is usually not sufficient to qualify for unequivocal progression status. The designation 
of overall progression solely on the basis of change in non –target disease in the face of SD 
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New Lesions 
The appearance of new malignant lesions denotes disease progression. While there are no 
specific criteria for the identification of new radiographic lesions, the findings of a new lesion 
should be unequivocal, i.e., not attributable to differences in scanning technique, timing of 
scanning, phase of contrast administration, change in imaging modality, or possibly 
representing something other than tumor (e.g., some "new" bone lesions may be simply 
healing or flare of pre-existing lesions). A lesion identified on a follow-up study in an 
anatomical location that was not scanned at Baseline is considered a new lesion and will 
indicate disease progression. 
If a new lesion is equivocal (e.g., too small to measure), continued therapy and follow-up 
evaluation will clarify whether it truly represents new disease. If repeat scans confirm there is 
a new lesion, then progression should be declared using the date of the initial scan 
Calculating Final Response:  
Final response will be calculated according to Table 9 and 10 respectively. 
Table 9: Response of combined lesion type 
 
Table 10: Calculating final response for non-measurable disease 


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Definition of Disease Progression 
 
Disease progression will be defined as progression of disease by RECIST (version 1.1). 
Clinical data that support progression will be collected and submitted for central review.  
If the subject experiences symptomatic deterioration and clinical progression is determined 
by the investigator, every effort will be made to document radiographic or clinical evidence of 
progression for analysis of the primary endpoint, even after discontinuation of treatment.  
 
Antitumor efficacy 
 
Patients with a response or stable disease after every 4th cycle 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 within a 9 months period. If the principal investigator decided that 
a subject should discontinue the study, a Final Visit will be conducted.  
 
 
4.5 Follow up 
 
All subjects will have one Follow-up Visit approximately 30 days after the last dose of study 
drug.  
 
Post treatment information   
will be collected on an individual basis with special emphasis given to overall survival. 
 


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5 Safety monitoring and reporting  
 
5.1 Adverse Events  
 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product and which does not 
necessarily have a causal relationship with this treatment. An adverse event can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, whether 
or not the event is considered causally related to the use of the product. Such an event can 
result from use of the drug as stipulated in the protocol or labeling, as well as from accidental 
or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a pre-existing 
condition or illness is considered an adverse event. 
Laboratory abnormalities and changes in vital signs are considered to be adverse events 
only if they result in discontinuation from the study, necessitate therapeutic medical 
intervention and/or if the Investigator considers them to be adverse events.  
 
The investigator will monitor each subject for clinical and laboratory evidence of 
adverse events on a routine basis throughout the study. The investigator will assess and 
record any adverse event in detail including the date of onset, event diagnosis (if known) or 
sign/symptom, severity, time course (end date, ongoing, intermittent), relationship of the 
adverse event to study drug, and any action(s) taken. For serious adverse events considered 
as having "no reasonable possibility" of being associated with study drug, the investigator will 
provide another cause of the event. For adverse events to be considered intermittent, the 
events must be of similar nature and severity. Adverse events, whether in response to a 
query, observed by site personnel, or reported spontaneously by the subject will be recorded. 
All adverse events will be followed to a satisfactory conclusion. 
 
 
 


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5.2 Serious Adverse Events  
 
A serious adverse event (SAE) is an adverse event that is fatal or life-threatening 
(independent of the dose), necessitates in-hospital treatment or its prolongation, leads to 
permanent or serious disability or incapacity or a congenital abnormality or birth defect. 
 
A suspected unexpected serious adverse reaction (SUSAR) is designated as such according 
to Guideline 2001/20/EG. A serious adverse reaction is deemed unexpected when it is not 
listed in the corresponding basic document (summary of product characteristics, prescribing 
information, see Appendix 2).  
 
Note: All deaths on study require both routine and expedited reporting regardless of 
causality. Attribution to treatment or other cause must be provided. 
 
5.3 Reporting obligations (in accordance with the AMG) 
 
Principal investigator: AE, SAE and SUSAR to the sponsor 
Reports about adverse events 
AMG (Austrian Act on Pharmaceutical Products) § 41d. (1) The principal 
investigator must inform the sponsor immediately about any serious adverse events, 
except for those events that, according to the study protocol or the investigator's 
brochure, need not be reported immediately. The immediate report must be followed 
by detailed written reports. In immediate reports and subsequent reports, the study 
participants must be designated by code numbers. 
(2) Undesirable events and abnormal laboratory values that are specified as critical 
circumstances for safety evaluations in the study protocol must be reported to the 
sponsor in accordance with the reporting requirements within the time limits 
mentioned in the study protocol. 
(3) In the event of the death of a study participant, the investigator must provide the 
sponsor with all required additional information. 
(4) The sponsor must document in detail and in writing all adverse events passed on 
to him by the investigators. These documents must be presented, upon request, to 
the appropriate authorities of all contracting parties of the European Economic Area 
in whose territories the clinical trial is being conducted. 
 
 


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Sponsor: 
AMG §41e (Austrian Act on Pharmaceutical Products §41e). (1) The sponsor 
must ensure that all important information about suspected serious adverse events 
that occur in the same clinical trial within the country or abroad and were either life-
threatening or led to death are recorded and sent to the Federal Agency for Safety in 
Healthcare as well as the appropriate authorities of all contracting parties of the 
European Economic Area in whose territories the clinical trial is performed, and are 
communicated to the competent ethics committees as early as possible, but in any 
case within seven days after the sponsor received notice of the concerned case and 
that, subsequently, appropriate information about further measures is passed on 
within a renewed time period of eight days. 
(2) All other suspected serious adverse events that occur in the same clinical trial 
within the country or abroad must be communicated to the authorities mentioned in 
paragraph 1 as well as the competent ethics committees as early as possible, but 
definitely within 15 days from the time the sponsor was first notified of the event(s). 
(3) The sponsor must also inform all other investigators of the same clinical trial in 
accordance with paragraphs 1 and 2. For the entire duration of the clinical trial, once 
every year, the sponsor must send a list of all suspected severe adverse events that 
occurred during the entire period of the trial to the authorities named in paragraph 1 
and the competent ethics committee, as well as a report about the safety of the study 
participants. 
 
Since the information about adverse reactions in the prescribing information for the treatment 
of CTCL with Zolinza is logically restricted primarily to those obtained from clinical trials of 
CTCL/ hematologic malignancies, the information given in the EMA withdrawal assessment 
report about the results obtained in clinical trials with solid tumors is used in this protocol 
(http://www.ema.europa.eu/docs/en_GB/document_library/Application_withdrawal_assessm
ent_report/2010/01/WC500063049.pdf) (Appendix1). 


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5.4  Termination of the trial 
 
5.4.1 Premature termination of the trial for a proband (drop-out) 
One or several of the following circumstances will lead to the premature termination of the 
trial for a single proband (this proband shall be regarded as a drop-out): 
 
 
• 
The proband's withdrawal of her consent 
• 
Intolerable adverse effects 
• 
Occurrence of an exclusion criterion 
• 
Other circumstances that would endanger the health of the proband if she were to 
continue her participation in the trial 
• 
Non-compliance of the patient 
 
5.4.2 Premature termination of the entire trial 
Premature termination of the clinical trial will be considered when the risk-benefit ratio 
changes markedly for the patient, the use of the study medication is no longer justifiable, the 
sponsor believes it is necessary to terminate the clinical trial for safety reasons, or when the 
clinical trial proves to be impracticable. 
 
For the benefit of, and in the interest of the probands, the principal investigator / sponsor may 
terminate the trial at any time prematurely due to relevant medical or ethical concerns, lack of 
feasibility or if serious adverse effects or other unforeseen circumstances occur. 
 
 In case of premature termination of the trial, the responsible ethics committee and the 
authorities (BASG) must be informed within 15 days; the reasons for termination must be 
clearly stated herein. 
 
5.4.3 Termination of the entire trial 
The principal investigator / sponsor is responsible for providing all documents required for the 
notification of the regular or premature termination of the trial to the competent authority 
(BASG) and the Ethics Committee. 
 
 


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6 Monitoring and Audit – Assurance of data quality 
 
Monitoring and audits will be performed during the clinical trial for the purpose of quality 
assurance. 
The investigator consents to data evaluation being performed by the person in charge of 
monitoring in order to ensure satisfactory data collection and adherence to the study 
protocol.  
Furthermore, the investigator states that he/she is willing to cooperate with this person and 
will provide this person with all required information whenever necessary. This includes 
access to all documents associated with the trial, including study-relevant medical files of 
patients in original form. The tasks of the investigator include maintenance of these patients' 
medical files as comprehensively as possible; this includes information concerning medical 
history, accompanying diseases, inclusion in the trial, data about visits, results of 
investigations, dispensing medication, and adverse events. The monitor will also be 
permitted to perform data evaluation and draw comparisons with the relevant medical files in 
accordance with the SOPs and ICH-GCP guidelines at pre-determined intervals, in order to 
ensure adherence to the study protocol and continuous registration of data. All original 
medical reports required as sources for the information given in the CRF or the database will 
be inspected. The study participants will have given their consent to such inspection by 
signing the consent form. 
The person in charge of monitoring is obliged to treat all information as confidential, and to 
preserve the basic claims of the study participants in respect of integrity and protection of 
their privacy. 
 
 
7 Biometry 
 
This clinical trial will be conducted in a limited number of highly selected and pre-treated 
patients suffering from recurrent uterine sarcomas which are very rare tumors within a pilot 
study. It is based on a high expression of HDAC in the tumor irrespective of the particular 
type of the uterine sarcoma. 
 
In a simulation based on 15 cases, a 3 months PFS rate of about 0.2 (20%) and a 6 months 
PFS rate of about 0.1 (10%), the standard error for the estimation is ~ 0.13 or 0.16 
respectively (Kaplan-Meier estimation, standard error: Greenwood), yielding a confidence 
interval of ~ ±0.25. 


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Because of the rarity of these tumors, we will only be able to treat 4-8 patients (see below) in 
a pilot study in a proper time. It might be expected that in case of success vorinostat would 
possibly qualify for an orphan drug status for uterine sarcomas. Testing of this novel targeted 
therapy in a pilot study might act as a door–opener for further multi-centre and/or multi-
national clinical trials to improve the therapy of these very rare gynecologic malignancies. 
This pilot study should provide the scientific basis for a further industry-sponsored clinical 
trial. 
 
To evaluate 4 patients treated per protocol for at least 6 months a total of 8 patients will be 
included in this study. Reasons for a premature end of treatment will be tumor progression, 
withdrawal of consent, or toxicity and/or death because of the severity of the underlying 
disease. 
 
The objective of this pilot study is to assess if the study drug is active with respect to tumor 
response. This will be evaluated after 3, 6 and 9 months of treatment (at the end of each 
treatment period) and 1 month after the end of the treatment at the follow-up visit. The 
statistical evaluation will be descriptive. 
 
Subjects will be considered screen failures if the informed consent has been signed but the 
subject does not meet eligibility criteria (e.g., immunohistochemical HDAC analysis). The 
reason for screen failure will be documented in the source document and will be captured in 
the CRF. 
 
 
Data handling and record keeping  
 
Case report forms (CRFs) will be provided on plain paper. Records and CRFs will be kept for 
a minimum of 15 years. 
 
 
 


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8 Ethical and legal matters 
 
During the implementation of the trial, the (current versions of) following guidelines and laws 
must be followed in addition to the Declaration of Helsinki (such as): 
• Current version of AMG (Austrian Act on Pharmaceutical Products) 
• ICH-GCP guideline 
• EU directives 2001/20/EC and 2005/28/EC 
 
Vote of the ethics committee / Informed Consent  
 
In accordance with § 40 AMG (Austrian Act on Pharmaceutical Products), the clinical trial will 
be started only after the competent ethics committee has issued its statement of approval 
and the appropriate authorities (BASG) have provided their non-prohibition/approval. 
 
Signed informed consent will be obtained from the subject in order to participate in this study. 
The informed consent, approved by the local Ethics Committee must be signed and dated by 
each subject prior to undergoing any study procedures or before any prohibited medications 
are withheld from the subject in order for the subject to participate in this study. 
 
Insurance 
During the clinical trial, a no-fault insurance (personal injury protection insurance in 
accordance with § 47 of the Austrian Act on Medicinal Products and § 32 of the Austrian Act 
on Pharmaceutical Products) shall be concluded for the patient on behalf of the sponsor. 
Exact contact data of the insurance company and the policy number must be mentioned in 
the patient informed consent. 
 
Principal investigator 
 
By signing the study protocol the principal investigator confirms that he has read and 
understood the study protocol, and will work in accordance with the protocol. The principal 
investigator guarantees the confidentiality of all information. 
 
Storage and data protection 
 
The registration, transfer, storage and evaluation of personal data in this clinical trial will be 
subject to legal regulations (AMG - Austrian Act on Pharmaceutical Products - and data 
protection law). A prerequisite for this purpose is the participant's voluntary consent in the 
consent form, given prior to her participation in the clinical trial. The participants will be 
informed of the following as part of the information about this clinical trial: 


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1. 
Data obtained in the course of this clinical trial will be recorded on paper forms or 
electronic data storage devices, treated as strictly confidential, and passed on exclusively to 
the following persons without mentioning names (pseudonymised): 
 
− 
the sponsor of the trial for scientific evaluation and assessment of adverse events. 
 
2. 
If required for the inspection of the clinical trial, persons authorised by the sponsor 
and committed to secrecy (monitoring, auditing), authorised persons in national and foreign 
health authorities, and authorised persons of the competent ethics committee may inspect 
personal data at the study centre. 
 
3. 
The participant will be informed that she may terminate her participation in the clinical 
trial at any time without stating reasons and with no subsequent disadvantages. However, 
due to the legal obligation of documentation (AMG; Austrian Act on Pharmaceutical 
Products), authorised persons committed to secrecy may be permitted to inspect personal 
data for test purposes, for a period of time specified by law.  
 
9 Modification of the study protocol 
 
The vote of the ethics committee applies solely to the information contained in the 
application; it does not include extensions or modifications of the research project 
undertaken at a later point in time. In case of any modification, an amendment of the study 
protocol signed by the principal investigator is required. Any modification of the study 
protocol must be attached as an amendment to all study protocols in circulation. The ethics 
committee must be informed of all modifications in the study protocol.  
Substantial amendments must also be reported to the authorities (BASG).  
10 Publication of study results 
 
The clinical trial results will be published by the principal investigator and the scientists 
involved whether or not the results are favorable in a renowned magazine.  
 
11 Financing 
 
This study is funded by the generous donation of a private person (Udo Saldow). Mr. Saldow 
has no commercial interest in the results and publication of the study. 
 


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List of abbreviations   
AE 
Adverse Event 
AMG 
Austrian Act on Pharmaceutical Products 
CD10 
Cluster of Differentiation 10 
COX-2 
Cyclooxygenase 2 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computed Tomography 
CTCL 
Cutaneous T-cell lymphoma 
CYP 
Cytochrome P450 Enzymes 
d 
Days 
ECG 
Electrocardiogram 
EGFR 
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
EORTC QLQ-30 
European Organization for Research and Treatment of 
Cancer’s core quality of life questionnaire 
ER 
Estrogen Receptor 
ESS 
Endometrial stromal sarcomas 
ESS-1 
Endometrial sarcoma cell line 
FACS 
Fluorescence activated cell sorting  
FDA 
US Food and Drug Administration 
FL 
Follicular lymphoma 
FPFV 
First patient, first visit 
GCP 
Good Clinical Practice 
HAT 
Histone acetylase 
HDAC 
Histone deacetylase Inhibitor 
HG-ESS 
High-grade endometrial stromal sarcoma 
HIV 
Human Immunodeficiency Virus 
IC 
Informed Consent 
ICH 
International Conference on Harmonization 
IHC 
Immunohistochemistry 
JAZF1/JJAZ1  
Genrearrangement bei LG-ESS 
Ki67 
Nuclear protein associated with cell proliferation 
LG-ESS 
Low-grade endometrial stromal sarcoma 
LMS 
Leiomyosarcoma 


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LPLV 
Last patient, last visit 
m 
Months 
MCL 
Mantle cell lymphoma 
MES-SA 
Uterine sarcoma cell line  
MF/HPF 
mitotic figures per high power field 
CS 
Malignant mixed Muellerian tumors, carcinosarcomas 
MRI 
Magnetic Resonance Imaging 
mTOR 
Mechanistic Target of Rapamycin 
MZL 
Marginal zone lymphoma 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OSD 
Overall stable disease 
p53 
Tumorprotein p53 
PE 
Physical examination 
PFS 
Progression-free Survival 
PR 
Progesterone Receptor 
PR 
Partial Response 
PTCL 
Peripheral T-cell lymphoma  
PTEN 
Phosphatase and Tensin homolog 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious Adverse Event 
SAHA 
Suberoylanilide hydroxamic acid  
SD 
Stable disease 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TKI 
Tyrosine kinase inhibitors 
TTP 
Time to progression 
UES 
Undifferentiated endometrial sarcoma 
UUS 
Undifferentiated uterine sarcomas 
WHO 
World Health Organisation 
YWHAE-FAM22  
Genrearrangement bei HG-ESS 
 


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List of tables 
 
List of tables  
 
 
 
 
 
 
 
 
       Page 
Table 1 
Possible systemic regimens in uterine sarcoma 
 
 
 
13 
Table 2 
A survey of completed clinical trials with HDAC inhibitor  
 
 
monotherapies in solid tumors 
 
 
 
 
 
19 
 
Table 3 
Open clinical trials with vorinostat in solid tumors  
 
 
20 
Table 4 
Summary of safety outcomes  
of patients with non-CTCL malignancies 
 
 
 
 
22 
 
 
 
Table 5 
Vorinostat monotherapy. Summary of specific  
clinical or laboratory adverse experiences  
 
 
 
23 
 
Table 6 
Flow chart of study activities  
 
 
 
 
 
28 
Table 7 
Karnofsky performance status 
 
 
 
 
 
31 
Table 8 
Clinical Laboratory Tests 
 
 
 
 
 
 
32 
Table 9 
Response of combined lesion type  
 
 
 
 
39 
Table10 
Calculating final response for non-measurable disease 
 
 
39 
 
List of appendices 
   
Appendix 1 
EMA Withdrawal assessment report  
Appendix 2: 
Prescribing information of Zolinza 
Appendix 3  
Karnofsky-/ ECOG- Index 
Appendix 4  
EORTC QLQ-C30 questionnaire (version 3.0) 
 
 
 
 


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Confirmation of the final protocol   
The signatories declare that they agree to fulfill their responsibilities within this study in 
accordance with local law, the Declaration of Helsinki, ICH-GCP and the study protocol as 
presented.  
 
 
Principal Investigator /Sponsor representative 
 
Prof. Dr Edgar Petru  
 
____________________     ______________________
 
 
 
 
 
 
 
 
 
Date 
 
 
   Signature 
 
Responsible Pathologist 
 
PD. Dr. Bernadette Liegl-Atzwanger   ___________________     ______________________
 
   
 
 
 
 
 
 
 
Date 
 
 
    Signature