study of vorinostat in combination with gemcitabine and docetaxel in advanced sarcoma

Conditions: Sarcoma

Summary: this is a phase ib/ii experimental, open-label, dose escalation, active treatment study designed to determine the safety, tolerability, and recommended dose of the combination. during the phase 2 portion of the study, we will assess progression-free survival (pfs), overall survival (os),overall response rate (orr), correlative endpoints, dna methylation measured by microarray, and expression level of the genes as measured by microarray

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 (exploratory aim). 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.

Eligibility criteria:
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

Keywords: advanced metastatic unresectable soft tissue sarcomas