Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma

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

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.

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