A Phase I Open-Label Safety and Pharmacokinetic Study of Escalating Doses of SGT-53 for Infusion in Subjects With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- Safety will be assessed by analysis of adverse experiences, clinical laboratory tests, and physical examinations.
研究概览
简要总结
This is a Phase Ib study as a continuation of the original Phase I protocol. The purpose of this Phase Ib study is to evaluate the safety of a single course of SGT-53 in combination with docetaxel and determine the recommended Phase II doses of SGT-53 and docetaxel in combination for evaluation in subsequent clinical studies for the treatment of solid tumors.
详细描述
The p53 gene is a vital tumor suppressor gene in humans. Numerous human tumors possess a loss or mutation of wild type p53 (wtp53). In addition to playing a crucial role in cell cycle control, the p53 gene is a critical component in two of the pathways involved in regulating tumor cell growth: cell death (apoptosis) and the regulation of angiogenesis. The loss of such critical tumor suppressor activity is believed to be responsible for p53's involvement in such a broad array of human tumors and resistance to chemo/radiotherapy. SGT-53 is a complex composed of a wild type p53 gene (plasmid DNA) encapsulated in a liposome that is targeted to tumor cells by means of an anti-transferrin receptor single-chain antibody fragment (TfRscFv) attached to the outside of the liposome. Pre-clinical studies have indicated that SGT-53 could sensitize tumors to the effects of radiation/chemotherapy.
The Phase 1a portion of this clinical study was designed to evaluate the safety and maximum tolerated dose (MTD) of SGT-53. In addition, pharmacokinetics of escalating doses of SGT-53 will be measured and correlated with tumor response and toxicity.
The Phase Ib portion of this clinical study is designed to evaluate the safety of SGT-53 in combination with docetaxel, determine the recommended Phase II doses of these two agents, and evaluate the effect of the combination of SGT-53 and docetaxel on tumor size or progression.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •* Have a biopsy confirmed diagnosis thereby providing histological diagnosis of a solid tumor malignancy.
- •* Have been offered all standard or approved therapies for which they would be considered eligible and have specifically declined or decided to postpone.
- •* Have solid tumors that can be measured on physical examination or by radiographic imaging studies.
- •* Have a tumor for which docetaxel would be an appropriate therapeutic agent (Phase Ib only).
- •* Patients (n=3) entered in phase Ib MTD dose expansion require biopsy accessible lesion in addition to measurable lesion and must consent to biopsy of tumor and normal skin.
- •* Previous docetaxel allowed if \> 6 months prior to study entry (Phase Ib only).
- •* Be 18 years old or older.
- •* Have an ECOG performance study of 0, 1 or 2 for Phase Ia, 0-1 for Phase Ib.
- •* Be able to give informed consent.
- •* Have recovered from any previous therapy side effects or toxicities prior to initiating protocol study infusions.
- •* Have a life expectancy of more than 12 weeks.
- •* Female subjects of childbearing potential must have a negative pregnancy test within 7 days before initiation of study drug dosing. Postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential.
- •* Male and female subjects of reproductive potential must agree to use measures (e.g., condoms or birth control pills) to avoid pregnancy throughout the study and for 3 months following discontinuation of the study drug.
- •* Organ function characterized by \/= 10.0 gm/dL
- •* Absolute neutrophil count \> 1500/mm3
- •* White blood cell count \> 3000/mm3
- •* Platelet count \>/= 100,000/mm3
- •* PT/PTT \< 1.5 times the upper limit of normal
- •* LDH \/= 50 ml/minute
排除标准
- •* Have hematological malignancy
- •* Prior hypersensitivity reaction to docetaxel (Phase Ib only)
- •* Are pregnant or lactating women
- •* Have signs and symptoms consistent with an active infection
- •* Fever (\> 38.1 C)
- •* Treated with antibiotics for infection within one-week prior to study entry
- •* Known HIV infection
- •* Have any history of psychiatric disorders that would interfere with informed consent or follow-up.
- •* Have any other concurrent disease that, in the judgment of the investigator, would contraindicate the administration of study drug or interfere with the study evaluations.
- •* Have fasting glucose levels \>/= 180 mg/dL.
- •* Have diastolic blood pressure of \> 90 mm Hg resting at baseline despite medication. (Acceptable if on hypertensive medication and diastolic blood pressure is \/= grade 2 based upon CTCAE v 3.0).
- •* Requiring renal dialysis.
- •* Receiving systemic steroids or other chronic immunosuppressive medications (e.g., tacrolimus, cyclosporine) within 30 days prior to study entry
- •* Receiving hematopoietic growth factors
- •* Receiving anticoagulants other than to maintain patency of venous access lines
- •* Received an investigational drug within 30 days prior to study entry
- •* Received radiation treatment \< 4 weeks prior to study entry
- •* Had prior exposure to gene vector delivery products within the last 6 months
- •* Received treatment with chemotherapeutic agents \< 4 weeks prior to study entry except for mitomycin C or nitrosurea where subjects who received mitomycin C or nitrosoureas \< 6 weeks prior to study entry are not eligible.
研究组 & 干预措施
SGT-53
SGT-53 (2.4mg DNA/infusion) will be administered in a standard 3x3 dose escalation design in combination with docetaxel 40mg/m2 starting dose, cohort 1, cycle 1. This protocol will allow for both inter- and intra-patient dose escalations. SGT-53 will be administered weekly, day 1 except weeks 1, 4 & 7 when it will be administered biweekly on days 1 & 4. Docetaxel will be administered every 3 weeks (weeks 1, 4 & 7) on day 3. Patients completing cohort 1, cycle 1 without DLT at docetaxel 40mg/m2 will be allowed to dose escalate to 60mg/m2 in cycles 2 and 3. Cohort 2 (2.4mg DNA/infusion;75mg/m2 Docetaxel) will open 3 weeks after demonstration of 0/3 or ≤1/6 DLTs at docetaxel 60mg/m2. Cohort 3 (3.6mg DNA/infusion; 75mg/m2 Docetaxel) will open after demonstration of 0/3 or ≤1/6 DLTs at SGT-53 2.4mg DNA/infusion and docetaxel 75mg/m2. If necessary, the dose of docetaxel in cycle 2 and 3 may be reduced to 60mg/m2.
干预措施: SGT-53 (Genetic)
结局指标
主要结局
Safety will be assessed by analysis of adverse experiences, clinical laboratory tests, and physical examinations.
时间窗: 7 weeks
次要结局
- Determine the presence of exogenous wtp53 in tumor(Week 5 or Week 6)
- Pharmacokinetic parameters(6 weeks)
- Tumor Response(Week 6 for Phase Ia, and weeks 9 for Phase Ib)