Study on Efficacy and Tolerability of Vorinostat in Patients With Advanced, Metastatic Soft Tissue Sarcoma (STS)

A Phase II Study to Investigate the Efficacy and Tolerability of Vorinostat in Patients Suffering From Advanced, Metastatic Soft Tissue Sarcoma

Primary objective of the study is to investigate the efficacy of vorinostat in patients suffering from selected histological types of soft tissue sarcoma. Further evaluations relate to the safety and tolerability of vorinostat, its pharmacokinetics (course of plasma concentration over time) and pharmacodynamics (mode of action). Only subjects with advanced, metastatic disease will be included in this trail.

The treatment with vorinostat will be administered daily over 28 days. This period will be referred to as a therapy cycle. Two consecutive therapy cycles will be separated by a 7-days therapy break. In case of a good response and no relevant side effects, the treatment with vorinostat can be continued for up to 1 year after begin of the treatment. If any relevant side effects or intolerability occur, the dose and/or schedule of administration will be modified according to the pre-defined criteria.

Inclusion Criteria:

1. Patients with verified, metastatic soft tissue sarcoma of the following histologies:

   • undifferentiated highgrade pleomorphic sarcoma/pleomorphic malignant fibrous histiocytoma,
   • undifferentiated pleomorphic sarcoma with grand cells/grand cell fibrotic histiocytoma,
   • undifferentiated pleomorphic sarcoma with prominent inflammation/inflamed MFH,
   • myxofibrosarcoma,
   • liposarcoma,
   • synovial sarcoma,
   • rhabdomyosarcoma (pleomorph, alveolar und embryonal),
   • leiomyosarcoma,
   • adult fibrosarcoma,
   • angiosarcoma,
   • malignant hemangiopericytoma/ malignant solitaire fibrous tumor,
   • malignant peripheral neurilemma tumor,
   • extraskeletal mesenchymal chondrosarcoma,
   • extraskeletal myxoid chondrosarcoma,
   • undifferentiated sarcoma of non other specified (NOS) type.

2. Verified relapse or disease progression at study inclusion, i.e. therapeutic failure of the first line therapy with anthracyclines,

3. Measurable disease according to the RECIST criteria,

4. Previous systemic therapy of advanced and/or metastatic disease,

5. An interval of at least 4 weeks since the last surgery, chemotherapy or radiation,

6. Age over 18,

7. Following laboratory findings:

   • ANC ≥ 1.0 x 10³/mm³,
   • platelets ≥ 100.000/mm³,
   • hemoglobin ≥ 9 g/dl,
   • creatinin < 1.5 x ULN (upper limit of normal),
   • AST and ALT < 2.5 x ULN,
   • total bilirubin < 1.5 x ULN,

8. Life expectancy of at least 12 weeks,

9. Negative pregnancy test,

10. Consent for an effective contraception during and up to 6 month after the study completion.

11. Written informed consent,

12. Ability to understand the goal and the consequences of this trial.

Exclusion Criteria:

1. Proof of the following histologies:

   • gastrointestinal stromal tumor (GIST),
   • malignant mesothelioma,
   • neuroblastoma,
   • osteosarcoma,
   • Ewing's sarcoma/PNET,

2. Concurrent radio- or chemotherapy,

3. Participation in another interventional trial within 4 weeks prior to the inclusion,

4. Previous therapy with another HDAC-inhibitor (e.g. depsipeptide, MS-275, LAQ-824, PXD-101 und valproic acid). Patients, who underwent a therapy with valproic acid for treatment of seizures, can be included after a wash-out period of at least 30 days,

5. Symptomatic brain metastases, that have not been treated by radiotherapy. The interval between the last radiation and the study inclusion must not be shorter than 30 days,

6. Previous malignant disease (except for a non-melanoma of the skin and a carcinoma in situ of uterus), unless in complete remission and after the last therapy for at least 5 years,

7. Ejection fraction < 40 %,

8. Nursing,

9. Known allergy against the IMP or drugs with similar chemical structure or additives,

10. Active hepatitis B and/or C and HIV-infection