A Phase 1, Open-Label, Dose-Ranging Study to Assess the Safety and Immunologic Activity of APN401
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 17
- 试验地点
- 2
- 主要终点
- Incidence of adverse events of APN401, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
研究概览
简要总结
This phase I trial studies the side effects and best dose of small interfering ribonucleic acid (siRNA)-transfected peripheral blood mononuclear cells APN401 (APN401) in treating patients with melanoma, kidney, or pancreatic cancer, or other solid tumors that have spread to other parts of the body or that cannot be removed by surgery. There are factors in immune cells in the blood that inhibit their ability to kill cancers. Treating white blood cells with one of these factors in the laboratory may help the white blood cells kill more cancer cells when they are put back in the body.
详细描述
PRIMARY OBJECTIVES:
I. To determine the toxicities and establish the maximal tolerated dose (MTD) of APN401.
II. To determine the effects of APN401 on immune response.
SECONDARY OBJECTIVES:
I. To document clinical response and survival.
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 metastatic or inoperable solid tumors that are no longer responding to standard therapies; preference will be made to patients with melanoma, renal cell, and pancreatic cancer; patients with other types of solid tumors will require approval by the principal investigator
- •Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST)
- •Patients with treated, stable, and asymptomatic brain metastases are eligible
- •Must be at least 4 weeks since treatment with chemotherapy, biochemotherapy, immunotherapy, and/or radiation and recovered from any clinically significant toxicity experienced; must be at least 4 weeks and have recovered from major surgery
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
- •White blood cells (WBC) >= 3000/uL
- •Platelets >= 100,000/uL
- •Hematocrit >= 28%
- •Creatinine =< 1.6 mg/dL
- •Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 2.5 x upper limit of normal
- •Bilirubin =< 1.6 mg/dL (except patients with Gilbert's syndrome, who must have a total bilirubin less than 3.0 mg/dL)
- •Albumin >= 3.0 g/dL
- •International normalized ratio (INR) =< 1.5
排除标准
- •Women must not be pregnant or breastfeeding; all women of childbearing potential must have a blood test within 72 hours prior to randomization to rule out pregnancy; women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception; women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for 12 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized; sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be of childbearing potential; women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential
- •Untreated, progressing, or symptomatic brain metastases
- •Autoimmune disease, as follows: patients with a history of inflammatory bowel disease are excluded as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [e.g., Wegener's granulomatosis]); patients with motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome and myasthenia gravis) are excluded; patients with a history of autoimmune thyroiditis are eligible if their current thyroid disorder is treated and stable with replacement or other medical therapy
- •Any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix
- •Other ongoing systemic therapy for cancer, including any other experimental treatment; these include concomitant therapy with any of the following: interleukin (IL)-2, interferon, ipilimumab or other immunotherapy; cytotoxic chemotherapy; and targeted therapies
- •Ongoing requirement for an immunosuppressive treatment, including the use of glucocorticoids or cyclosporine, or with a history of chronic use of any such medication within the last 4 weeks before enrolment; patients are excluded if they have any concurrent medical condition that requires the use of systemic steroids (the use of inhaled or topical steroids is permitted)
- •Infection with human immunodeficiency virus (HIV)
- •Active infection with hepatitis B; active or chronic infection with hepatitis C
- •Clinically significant pulmonary dysfunction, as determined by medical history and physical examination; patients with a history of pulmonary dysfunction must have pulmonary function tests with a forced expiratory volume in 1 second (FEV1) >= 60% of predicted and a diffusing capacity of the lung for carbon monoxide (DLCO) >= 55% (corrected for hemoglobin)
- •Clinically significant cardiovascular abnormalities (e.g., congestive heart failure or symptoms of coronary artery disease), as determined by medical history and physical examination; patients with a history of cardiac disease must have a normal cardiac stress test (treadmill, echocardiogram, or myocardial perfusion scan) within the past 6 months of study entry
- •Active infections or oral temperature > 38.2º Celsius (C) within 48 hours of study entry
- •Systemic infection requiring chronic maintenance or suppressive therapy
- •Patients are excluded for any underlying medical or psychiatric condition, which in the opinion of the investigator, will make treatment hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent rashes or diarrhea
研究组 & 干预措施
Treatment (APN401)
Patients receive autologous siRNA-transfected peripheral blood mononuclear cells APN401 IV over 30 minutes.
干预措施: laboratory biomarker analysis (Other)
Treatment (APN401)
Patients receive autologous siRNA-transfected peripheral blood mononuclear cells APN401 IV over 30 minutes.
干预措施: siRNA-transfected peripheral blood mononuclear cells APN401 (Biological)
结局指标
主要结局
Incidence of adverse events of APN401, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
时间窗: Up to 2 years
Adverse events will be categorized by organ system and severity and summarized as frequency counts and percentages.
Maximum tolerated dose of siRNA-transfected peripheral blood mononuclear cells APN401, defined as the dose in which the number of patients with dose limiting toxicity is less than or equal to one out of six
时间窗: 14 days
Overall survival
时间窗: From the initial infusion to confirmation of progression or death, assessed up to 5 years
Standard survival analysis techniques using Kaplan Meier methods will be used.
Immune response, measured by change in blood Th1-associated cytokines production in response to anti-CD3/28 stimulation or >= tumor antigens post-therapy
时间窗: Baseline to week 9
Summarized as medians and ranges. The effects of treatment on these markers individually will be analyzed using paired t-tests (possibly after transformation, e.g., logarithmic) or the non-parametric counterpart. Differences between dose levels at particular time points will be analyzed using analysis of variance and 2-sample t-tests, and differences over time will be analyzed using longitudinal methods such as repeated measures. The association between the markers (baseline and changes) and objective response will also be examined.
Clinical response assessed by RECIST
时间窗: Up to 5 years
Summarized as frequency counts and percentages.
Progression-free survival
时间窗: From the initial infusion to confirmation of progression or death, assessed up to 5 years
Standard survival analysis techniques using Kaplan Meier methods will be used.
次要结局
未报告次要终点