Phase II Study of CTLA-4 Blockade and Low Dose Cyclophosphamide in Patients With Advanced Malignant Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 终止
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- The Anti-tumor Activity of the Combination of Low Dose Cyclophosphamide and CTLA-4 Blockade Using Objective Response Rate (ORR)
研究概览
简要总结
The purpose of this study is to see whether the combination of low-dose Cyclophosphamide and Anti-CTLA4 (Ipilimumab) will stop tumor growth in patients with advanced skin cancer. The investigators expect to see an increase in response rate of the combination over Anti-CTLA-4 alone and estimate a response rate of approximately 20 % in the proposed population.
详细描述
The transient removal of CTLA-4-mediated inhibition (CTLA-4 blockade) can induce effective anti-tumor immunity. Efficacy of CTLA-4 blockade as a single agent has been shown in melanoma 53. It has been hypothesized that anti-CTLA-4 antibody might deplete Treg cells 54, inducing autoimmunity. However, patients receiving Ipilimumab have not shown a decrease in Treg number or function in peripheral blood 55.
This trial will answer the question if the combination of Anti-CTLA 4 (following a well established regimen of Ipilimumab) and Cyclophosphamide (given at immunomodulatory doses) will result in antitumor activity in patients with metastatic melanoma due to synergistic immunomodulating effects by overcoming tolerance.
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
- •Men & women, ages ≥18
- •Willing/able to give written informed consent.
- •Histologic diagnosis of unresectable AJCC Stage III/IV malignant melanoma
- •At least 2wks must have elapsed since last chemotherapy, immunotherapy, hormonal therapy, radiotherapy or major surgery & beginning of protocol therapy. At least 6wks for nitrosoureas, mitomycin C, & liposomal doxorubicin
- •Toxicity related to prior therapy must either have returned to ≤ grade 1 or baseline.
- •Two punch tumor biopsy at Screening and Wk12 (4mm diameter) must be provided for immune analysis/staining if patients have accessible disease. Biopsies are optional during the Maintenance Period.Site of tumor biopsy s/n be only site of measurable disease. Minimum of 5 out of 1st 10 patients in stage I of the protocol must have biopsy accessible disease.
- •Patients must have measurable disease defined as @ least 1 lesion that can be accurately measured in @ least 1 dimension (longest diameter to be recorded) as >20 mm with conventional techniques or as >10 mm with spiral CT scan.
- •Required values for initial laboratory tests:
- •WBC ≥ 2000/uL
- •ANC ≥ 1000/uL
- •Platelets ≥ 50 x 103/uL
- •Hemoglobin ≥ 9.5 g/dL
- •Creatinine ≤ 3.0 x ULN
- •AST/ALT ≤ 2.5 x ULN for patients without liver metastasis, ≤ 5 x ULN for patients with liver metastasis
- •Bilirubin ≤ 3.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
- •Life expectancy of at least 4mos
- •Patients w/stable, treated central nervous system (CNS) metastasis are eligible
- •ECOG Performance Status Score 0-1
- •Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout study & for up to 26wks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized.
- •WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not post-menopausal. Post-menopause is defined as:
- •Amenorrhea ≥ 12 consecutive months w/o another cause, or
- •For women with irregular menstrual periods and taking hormone replacement therapy (HRT), documented serum follicle-stimulating hormone (FSH) level ≥ 35 mIU/mL.
- •Women who are using oral contraceptives, other hormonal contraceptives (vaginal products/skin patches/implanted/injectable products), mechanical products such as an intrauterine device or barrier methods (diaphragm/condoms/ spermicides) to prevent pregnancy,are practicing abstinence or where their partner is sterile (eg vasectomy) should be considered to be of childbearing potential.
- •WOCBP must have a negative urine or serum pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) w/in 72hrs before the start of ipilimumab.
- •Men of fathering potential must be using an adequate method of contraception to avoid conception throughout the study [and up to 26wks after last dose of investigational product] in a way that risk of pregnancy is minimized.
排除标准
- •Any other malignancy from which patient has been disease-free for less than 5yrs, with the exception of adequately treated & cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix.
- •Autoimmune disease: Patients with a history of inflammatory bowel disease, including ulcerative colitis and Crohn's Disease, are excluded from this study, as are patients with a history of symptomatic disease (eg rheumatoid arthritis, systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune vasculitis [eg Wegener's Granulomatosis]); motor neuropathy considered of autoimmune origin (eg Guillain-Barre Syndrome and Myasthenia Gravis).
- •Any underlying medical or psychiatric condition, which in the opinion of investigator will make administration of ipilimumab hazardous or obscure interpretation of AEs, like a condition associated with frequent diarrhea.
- •Uncontrolled or significant cardiovascular disease
- •Any non-oncology vaccine therapy used for prevention of infectious diseases (for up to 1mo before/after any dose of ipilimumab).
- •History of prior treatment with ipilimumab or prior CD137 agonist or CTLA 4 inhibitor or agonist.
- •Concomitant therapy with any of following: IL 2, interferon, other non-study immunotherapy regimens; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids (>60mg prednisone/day).
- •Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (eg infectious) illness.
- •Women of childbearing potential (WOCBP), defined above who:
- •are unwilling/unable to use an acceptable method of contraception to avoid pregnancy for their entire study period and for at least 26wks after cessation of study drug, or
- •have a positive pregnancy test at baseline, or
- •are pregnant or breastfeeding.
- •Persons of reproductive potential who are unwilling to use an adequate method of contraception throughout treatment & for at least 26wks after ipilimumab is stopped.
研究组 & 干预措施
Cyclophosphamide, Ipilimumab
Treatment:
Cyclophosphamide 300 mg/m2 po - Day 1 of Weeks 1, 4, 7, and 10, for a total of 4 doses; (premedication prior to each dose of Cyclophosphamide 8mg Zofran po, then prn)
Ipilimumab 10 mg/kg iv - Day 3 of Weeks 1, 4, 7, and 10 for a total of 4 doses Maintenance treatment will be given on Weeks 24, 36, and 48 Ipilimumab 10 mg/kg iv
干预措施: Cyclophosphamide (Drug)
结局指标
主要结局
The Anti-tumor Activity of the Combination of Low Dose Cyclophosphamide and CTLA-4 Blockade Using Objective Response Rate (ORR)
时间窗: 12 weeks
Objective response rate (ORR) using mWHO RC. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
次要结局
- T Regulatory Cell Profile in Peripheral Blood(Week 60)
- Progression-free Survival(Week 60)
研究者
Nina Bhardwaj
Director, Tumor Vaccine Program
Icahn School of Medicine at Mount Sinai