A Phase II Trial With the HIV Protease Inhibitor Indinavir for the Treatment of Classical Kaposi's Sarcoma
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 28
- 试验地点
- 9
- 主要终点
- Assessment of clinical response every 3 months during treatment and every 6 months during follow-up based on the recommendations of ACTG.
研究概览
简要总结
Recent studies have described a reduced incidence or the regression of Kaposi's sarcoma (KS) in HIV-infected patients treated with the highly active anti-retroviral therapy (HAART) that contains at least one inhibitor of the HIV protease (HIV-PI) such as Indinavir. Experimental studies have shown that part of the anti-KS actions of HIV-PI are not related to their antiretroviral actions, but, at least in part, to their capability of blocking angiogenesis and tumor growth.
This study will be conducted on HIV-negative (classical) KS patients to prove that Indinavir has anti-angiogenic and anti-KS effects in humans independently of its antiretroviral activity.
详细描述
Kaposi's sarcoma (KS) is a rare vascular tumor affecting elderly individuals from Mediterranean countries (CKS), post transplant patients and, with increased incidence and aggressiveness, HIV-infected individuals (AIDS-KS). No definitive cure has been established for KS and all conventional therapies result in low response rate, high toxicity and tumor relapse.
Antiretroviral therapies including a HIV protease inhibitor (HIV-PI) have reduced AIDS-KS incidence and induce KS regression in treated patients. This cannot be explained solely with drug-mediated HIV suppression and immune reconstitution. We have shown that HIV-PI such as Indinavir or Saquinavir block KS-like lesions in mice by inhibiting angiogenesis and tumor cell invasion through a blockade of matrix metalloprotease 2 (MMP2) proteolytic activation.
Based on these data, a proof-of-concept clinical study on HIV-negative (classic) KS (C-KS) patients was planned to prove that Indinavir has anti-angiogenic and anti-KS effects in humans independently of its antiretroviral activity.
Recent concepts in the evaluation of non cytotoxic anti-cancer drugs such as anti-angiogenic agents suggest novel criteria for the design of clinical studies due to the specific mechanism of action of these drugs. In particular, the use of the conventional evaluation criteria based on cytotoxic actions may mislead the interpretation of the therapeutic efficacy of non cytotoxic agents. The study was therefore designed to compare the clinical response to Indinavir in early-stage vs. late-stage KS and by relating it to key biological endpoints and plasmatic drug concentrations. This was also motivated by the rareness of C-KS and by ethical reasons which prevented the inclusion of a control group.
Patients will be treated per os with 800 mg x 2/daily of Indinavir for 12 months. Follow-up will be one year.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 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 documented diagnosis of classical KS
- •Be HIV-negative
- •Be 18 years old and over
- •Have one or more of the following: a minimum of 3 measurable progressive lesions; all stages of complicated KS, i.e. showing functional impotency of the affected limbs, lymphedema, lymphorrea or pain; visceral disease; lack of response to conventional therapy (radiotherapy, chemotherapy); contraindication to conventional therapies-
排除标准
- •Presence of life-threatening lesions or other concomitant illness, neoplasia or any other clinical condition threatening the health of the patient or his compliance to the treatment
- •Inability to provide informed consent
- •Concomitant treatment (within 30 days of initiating study treatment) with systemic immunomodulatory agents (e.g., glucocorticoids as immunosuppressive agents, interferons) or chemotherapy
- •Pregnancy
- •Impaired clinical conditions (Karnofsky's index <60
- •Diabetes, history of nephrolithiasis or monolateral nephropathy
- •Difficulty swallowing capsules/tablets
- •Any clinically significant laboratory findings obtained during screening, including:
- •Alkaline phosphatase (AP) >2 fold upper limit of normal (ULN)
- •Aspartate aminotransferase (AST)
- •Alkaline aminotransferase (ALT)
- •Gamma-glutamyl transferase (gamma-GT) or total bilirubin >3 fold the ULN
- •Serum creatinine >1.2 mg/d for women and >1.4 mg/dL for men or creatinine clearance > 100 +/- 25
- •Pancreatic amylase >1.5 folds ULN
- •Hemoglobin <10.0 g/dL for males, <9.0 g/dL for females
- •Platelet count <75.000/cubic millimeter (mm3)
- •Neutrophil count <850/mm3
结局指标
主要结局
Assessment of clinical response every 3 months during treatment and every 6 months during follow-up based on the recommendations of ACTG.
次要结局
- Monthly evaluation of toxicity and of biological endpoints every 3 months and their correlation with drug plasma levels