Phase 1b/2 Study of Vorinostat in Combination With Gemcitabine and Docetaxel in Advanced Sarcoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 37
- 试验地点
- 1
- 主要终点
- Phase I: Recommended Phase II Dose of Vorinostat
研究概览
简要总结
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
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically confirmed soft tissue sarcoma with evidence of metastatic or unresectable disease.
- •Patients must have measurable disease by RECIST 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
- •Women of Child bearing potential MUST use contraceptives.
- •Ability to understand and the willingness to sign a written informed consent document.
排除标准
- •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
研究组 & 干预措施
Combination therapy
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
干预措施: Docetaxel (Drug)
Combination therapy
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
干预措施: Gemcitabine (Drug)
Combination therapy
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
干预措施: Vorinostat (Drug)
Combination therapy
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
干预措施: Pegfilgrastim (Drug)
结局指标
主要结局
Phase I: Recommended Phase II Dose of Vorinostat
时间窗: 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)
时间窗: 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.
次要结局
- Progression-free Survival (PFS)(Up to 7 years and 7 months)
- One-year Progression-free Survival (PFS)(Up to one year (per patient))
- Overall Survival (OS)(Up to 7 years and 7 months)
- Objective Response Rate (ORR)(Up to 7 years and 7 months)
- Six-month Overall Survival (OS)(Up to 6 months (per patient))
- One-year Overall Survival (OS)(Up to one year (per patient))
研究者
Melissa Burgess, MD
Assistant Professor of Medicine Division of Hematology/Oncology
University of Pittsburgh