A Phase I/II, Open-Label Study of JX-594 (Thymidine Kinase-deleted Vaccinia Virus Plus GM-CSF) Administered by Intratumoral Injection in Patients With Unresectable Stage 3 or Stage 4 Malignant Melanoma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 10
- 试验地点
- 5
- 主要终点
- Response rate for injected tumor(s)
研究概览
简要总结
The purpose of this research study is to find out whether JX-594 (Pexa-Vec) is safe and effective for treating surgically unresectable malignant melanoma.
详细描述
Cancer of the skin is the most common of all cancers, probably accounting for more than 50% of all cancers. Melanoma accounts for about 4% of skin cancer cases but causes a large majority of skin cancer deaths. The American Cancer Society estimates that about 62,190 new melanomas will be diagnosed in the United States during 2006.
DTIC is the only chemotherapy drug approved by the FDA for the treatment of metastatic melanoma. The reported response rates are 5-20% without any evidence of prolonged survival in randomized clinical trials versus best supportive care. The median overall survival for melanoma patients treated with DTIC alone is approximately 8 months; PFS and TTP following treatment with DTIC is approximately 7 weeks, and the objective response rate for DTIC alone (CR+PR) is less than 10% (Millward, 2004). Other chemotherapy agents including cisplatin and carboplatin, BCNU, vindesine, paclitaxel, docetaxel, and vinorelbine have also been tested but none have improved upon the very modest activity of DTIC.
Melanoma may be the optimal target for JX-594 immunotherapy because of the relatively high rate of accessible disease for injection, the positive response of melanoma seen with IL-2 immunotherapy, and the lack of effective, tolerable therapy for patient with metastatic melanoma. Furthermore, it is speculated that JX-594 replication targets the EGFR pathway, which is highly expressed in melanocytes.
Results from an initial Phase I/II study suggest that intratumoral injection of JX-594 is safe and effective in treating both injected and distant disease in patients with surgically incurable metastatic melanoma. Response of both injected tumors (in 5 of 7 patients) and response of at least one non-injected tumor (in 4 of 7 patients) was demonstrated, including two patients who achieved a partial response (6 + months) and a complete response (4 + months) to JX-594 treatment. Particularly noteworthy is that efficacy and gene expression occurred despite pre-treatment vaccination (and, therefore, pre-existing anti-vaccinia immunity) in all patients.
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
- •Histologically-confirmed, Stage 3 or Stage 4 malignant melanoma
- •At least one tumor mass measurable by CT/MRI and/or physical examination that can be injected by direct visualization or by ultrasound-guidance
- •Anticipated survival of at least 16 weeks
- •Cancer is not surgically resectable for cure
- •KPS score of ≥ 70 (refer to APPENDIX E: KARNOFSKY PERFORMANCE STATUS (KPS))
- •Age ≥18 years
- •Men and women of reproductive potential must be willing to follow accepted birth control methods during treatment and for 3 months after the last treatment with JX-594
- •The ability to understand and willingness to sign an Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written informed consent form
- •Able to comply with study procedures and follow-up examinations
- •Adequate liver function: Total bilirubin ≤ 2.0 x ULN; AST, ALT ≤ 2.0 x ULN
- •Adequate bone marrow function: WBC > 3,500 cells/mm3 and < 50,000 cells/mm3; ANC > 1,500 cells/mm3; Hemoglobin > 10 g/dL; Platelet count > 125,000 plts/mm3
- •Acceptable coagulation status: INR < (ULN + 10%)
- •Acceptable kidney function: Serum creatinine < 2.0 mg/dL
排除标准
- •Target tumor(s) adherent to and/or invading a major vascular structure (e.g. carotid artery)
- •Pregnant or nursing an infant
- •Known infection with HIV
- •Systemic corticosteroid or other immunosuppressive medication use within 4 weeks of first treatment with JX-594
- •Clinically significant active infection or uncontrolled medical condition (e.g. pulmonary, neurological, cardiovascular, gastrointestinal, genitourinary) considered high risk for investigational new drug treatment Significant immunodeficiency due to underlying illness and/or medication (e.g. systemic corticosteroids)
- •History of eczema that at some stage has required systemic therapy
- •Clinically significant and/or rapidly accumulating ascites, peri-cardial and/or pleural effusions (e.g. requiring drainage for symptom control)
- •Severe or unstable cardiac disease which includes, but is not limited to, any of the following within 6 months prior to screening: myocardial infarct, unstable angina, congestive heart failure, myocarditis, arrhythmias diagnosed and requiring medication, or any clinically-significant change in cardiac status
- •Treatment of the target tumor(s) with radiotherapy, chemotherapy, surgery, or an investigational drug within 4 weeks of screening (6 weeks in case of mitomycin C or nitrosoureas)
- •Experienced a severe reaction or side-effect as a result of a previous smallpox vaccination
- •Inability or unwillingness to give informed consent or comply with the procedures required in this protocol
- •Patients with household contacts who are pregnant or nursing an infant, children < 5 years old, have history of eczema that at some stage has required systemic therapy, or have a significant immunodeficiency due to underlying illness (e.g. HIV) and/or medication (e.g. systemic corticosteroids) will be excluded unless alternate living arrangements can be made during the patient's active dosing period and for three weeks following the last dose of study medication.
结局指标
主要结局
Response rate for injected tumor(s)
时间窗: Initial response assessment at 6 weeks
Number of Participants With Objective Response in Injected Tumor(s)
时间窗: Initial response assessment after six weeks (Day 43)
Response was evaluated at the participant level based on the sum of the longest diameters of the injected target tumors. Tumor assessments were performed using RECIST criteria. Complete response (CR): all lesions disappear; Partial response (PR): maximum diameter decrease of \> 30% of the longest diameter (LD) of target lesions using the baseline LD; Progressive disease (PD): increase of \>20% in the sum of LD target lesions using the smallest sum LD recorded since treatment started; Stable disease (SD): unable to categorize as PR or PD using as reference the lobe with the smallest diameter at baseline.
次要结局
- Safety, as determined by incidence of treatment-related adverse events, serious adverse events (SAEs), and clinically-significant changes from baseline in routine laboratory parameters(Safety evaluation throughout study period)
- Best overall response for entire disease burden (RECIST criteria)(Initial response assessment after six weeks)
- Progression-free survival (PFS)(Follow-up every three weeks until new therapy or disease progression)
- Response rate of non-injected tumor(s)(Initial response assessment at six weeks)
- Incidence of Treatment-related Adverse Events (AEs) and Serious Adverse Events (SAEs)(Up to Day 64)
- Best Overall Response for Entire Disease Burden (RECIST Criteria)(Initial response assessment after six weeks (Day 43))
- Progression-free Survival(From first study treatment until objective evidence of disease progression or death, up to 20.5 months)
- Number of Participants With Objective Response in Non-injected Tumor(s)(Initial response assessment after six weeks (Day 43))