Clinical trial NCT01879085: Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma
Official title: Phase 1b/2 Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Sarcoma
Keywords: advanced
metastatic
unresectable
soft
tissue
sarcomas
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2013-06-17
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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

Detailed description: 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

Primary outcomes:
measure: Phase I: Recommended Phase II Dose of Vorinostat
timeFrame: During Cycle 1 of treatment
measure: Six-month Progression-free Survival (PFS)
timeFrame: Up to 6 months (per patient)
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: Up to 7 years and 7 months
measure: Progression-free Survival (PFS)
timeFrame: Up to 7 years and 7 months
measure: One-year Progression-free Survival (PFS)
timeFrame: Up to one year (per patient)
measure: Overall Survival (OS)
timeFrame: Up to 7 years and 7 months
measure: Six-month Overall Survival (OS)
timeFrame: Up to 6 months (per patient)
measure: One-year Overall Survival (OS)
timeFrame: Up to one year (per patient)
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Hillman Cancer Center
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Melissa Burgess, MD
role: PRINCIPAL_INVESTIGATOR
References: