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

Phase 1

Completed

Conditions: Sarcoma

Interventions: Drug: Docetaxel
Drug: Gemcitabine
Drug: Vorinostat
Drug: Pegfilgrastim

Registration Number: NCT01879085

Lead Sponsor: Melissa Burgess, MD

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 37

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Combination therapy	Docetaxel	Dose Level\\Docetaxel IV\\ Gemcitabine IV\\Vorinostat PO\\Pegfilgrastim 1\\75 mg/m2\\900 mg/m2\\300 mg once daily\\6 mg on day 9 2\\75 mg/m2\\900 mg/m2\\200 mg twice daily\\6 mg on day 9 3\\75 mg/m2\\900 mg/m2\\300 mg twice daily\\6 mg on day 9 4\\75 mg/m2\\900 mg/m2\\400 mg twice daily\\6 mg on day 9
Combination therapy	Vorinostat	Dose Level\\Docetaxel IV\\ Gemcitabine IV\\Vorinostat PO\\Pegfilgrastim 1\\75 mg/m2\\900 mg/m2\\300 mg once daily\\6 mg on day 9 2\\75 mg/m2\\900 mg/m2\\200 mg twice daily\\6 mg on day 9 3\\75 mg/m2\\900 mg/m2\\300 mg twice daily\\6 mg on day 9 4\\75 mg/m2\\900 mg/m2\\400 mg twice daily\\6 mg on day 9
Combination therapy	Pegfilgrastim	Dose Level\\Docetaxel IV\\ Gemcitabine IV\\Vorinostat PO\\Pegfilgrastim 1\\75 mg/m2\\900 mg/m2\\300 mg once daily\\6 mg on day 9 2\\75 mg/m2\\900 mg/m2\\200 mg twice daily\\6 mg on day 9 3\\75 mg/m2\\900 mg/m2\\300 mg twice daily\\6 mg on day 9 4\\75 mg/m2\\900 mg/m2\\400 mg twice daily\\6 mg on day 9
Combination therapy	Gemcitabine	Dose Level\\Docetaxel IV\\ Gemcitabine IV\\Vorinostat PO\\Pegfilgrastim 1\\75 mg/m2\\900 mg/m2\\300 mg once daily\\6 mg on day 9 2\\75 mg/m2\\900 mg/m2\\200 mg twice daily\\6 mg on day 9 3\\75 mg/m2\\900 mg/m2\\300 mg twice daily\\6 mg on day 9 4\\75 mg/m2\\900 mg/m2\\400 mg twice daily\\6 mg on day 9

Primary Outcome Measures

Name	Time	Method
Phase I: Recommended Phase II Dose of Vorinostat	During Cycle 1 of treatment	Recommended Phase ll dose of vorinostat that can be safely combined with gemcitabine and docetaxel. Gemcitabine and docetaxel were given at a fixed dose while vorinostat was dose-escalated using a standard '3+3' design. Dose-limiting toxicity (DLT) is defined as specific study drug-related events experienced during Cycle 1; only DLTs observed in a patient during the first cycle of treatment will be used for the dose escalation decision.
Six-month Progression-free Survival (PFS)	Up to 6 months (per patient)	Proportion of participants whose disease does not progress within 6 months of start of treatment (number of patients without progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.

Secondary Outcome Measures

Name	Time	Method
One-year Overall Survival (OS)	Up to one year (per patient)	Proportion of participants alive at one year from the start of treatment.
Progression-free Survival (PFS)	Up to 7 years and 7 months	The median length of time from the beginning of study treatment that patients remain alive without progression of their disease (cancer). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.
One-year Progression-free Survival (PFS)	Up to one year (per patient)	Proportion of participants whose disease does not progress within one year of start of treatment (number of patients with progressive disease/total number of patients). Per RECIST v1.1, progressive disease (PD) is defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. For non-target lesions, PD: Unequivocal progression of existing non-target lesions. The appearance of one or more new lesions is also considered progression.
Objective Response Rate (ORR)	Up to 7 years and 7 months	Number of patients with Complete response \[CR\] + partial response \[PR\], per RECIST v1.1 criteria . Per RECIST v1.1, CR: Disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to \<10 mm. For non-target lesions: Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10mm short axis);PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters
Six-month Overall Survival (OS)	Up to 6 months (per patient)	Proportion of participants alive at six months from the start of treatment.
Overall Survival (OS)	Up to 7 years and 7 months	The median length of time from the start of treatment that diagnosed study participants remain alive.