Phase 1b/2 Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma

Phase 1b

- To determine the dose of vorinostat that can be safely combined with gemcitabine and
docetaxel in patients with advanced sarcomas.

- To characterize the Pharmacokinetics (PK) and Pharmacodynamics (PD) of vorinostat when
combined with gemcitabine and docetaxel in patients with advanced sarcomas.

Phase 2

- To determine the safety and efficacy of gemcitabine and docetaxel in combination with
vorinostat in patients with advanced sarcomas. The hypothesis is that gemcitabine and
docetaxel + vorinostat will be safe and will improve the 6-months progression-free rates
(PFR) of the combination by 20% (from 20% to 40%).

- To determine the objective response rate, progression-free, and overall survival of
patients with advanced sarcomas treated with gemcitabine and docetaxel + vorinostat;

- To develop a predictive molecular signature of response to treatment in advanced
sarcomas.

Inclusion Criteria:

- Patients must have histologically confirmed soft tissue sarcoma with evidence of
metastatic or unresectable disease.

- Patients must have measurable disease by RECIST 1.1.

- Up to 32 prior cytotoxic chemotherapy regimens in the metastatic setting are allowed.
Adjuvant chemotherapy or targeted therapy will not be considered a prior line of
treatment.

- Age ≥18 years.

- ECOG performance status ≤2 (Karnofsky ≥60%).

- Life expectancy of greater than 12 weeks.

- Patients must have normal organ and marrow function as defined below:

- leukocytes ≥3,000/µL

- absolute neutrophil count ≥1,500/µL

- platelets ≥100,000/µL

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) ≤1.5 X institutional upper limit of normal (ULN)

- creatinine ≤1.5 X institutional upper limit of normal (ULN)

- Peripheral neuropathy, if present, should be ≤grade 1.

- Women of Child bearing potential MUST use contraceptives.

- Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

- The following specific histologic subtypes of soft tissue sarcomas will be excluded:
GIST, Kaposi's sarcoma, mesothelioma, dermatofibrosarcoma, chordoma, alveolar
soft-part sarcoma. Also, all bone sarcomas are excluded including Ewing's sarcoma,
osteosarcoma, GIST, low grade chondrosarcoma, and chordoma.

- Patients who have had treatment with chemotherapy or radiotherapy within 4 weeks (6
weeks for nitrosoureas or mitomycin C) prior to starting study treatment or those who
have not recovered from adverse events due to agents administered more than 4 weeks
earlier.

- Patients who are receiving any other investigational agents.

- Patients with known brain metastases.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to gemcitabine, docetaxel, vorinostat, or G-CSF.

- Patients who have received and progressed on the combination of gemcitabine and
docetaxel in the metastatic setting.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant and breastfeeding women

- Patients taking concomitant HDAC inhibitors.

- HIV-positive patients on combination antiretroviral treatment