A Phase 2 Study - Clinical Trial Assessing Efficacy and Safety of the mTOR Inhibitor Sirolimus in the Treatment of Complicated Vascular Anomalies
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 61
- 试验地点
- 4
- 主要终点
- Overall Response by Radiologic Evaluation, Quality of Life Assessment, and Functional Impairment Score
研究概览
简要总结
The purpose of this study is to determine if the use of sirolimus in the treatment of children and young adults with complicated vascular anomalies will prove to be safe and provide objective response resulting in improved clinical status and quality of life.
Funding Source - FDA OOPD (Food and Drug Administration - Office of Orphan Products Development)
详细描述
Patients with vascular anomalies (VA) have a spectrum of diseases that can be broadly classified into vascular tumors and malformations. Complicated vascular anomalies can cause disfigurement, chronic pain, and organ dysfunction with significant morbidity and mortality. Despite the severity of potential complications, we lack uniform guidelines for the treatment and response to treatment of children and young adults with these diseases. There are pre-clinical and clinical data supporting the essential regulatory function of the PI3K/Akt/mTOR pathway in vascular growth and organization, and suggest a therapeutic target for patients with complicated vascular anomalies. The overall goal of this trial is to objectively determine the effectiveness and safety of the mTOR inhibitor Rapamycin* in the treatment of children and young adults diagnosed with complicated vascular anomalies. We propose a Phase 2 trial with the diagnostic, therapeutic and response criteria experimentally determined in this study used as a framework for future Phase 3 clinical trials.
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
- — 至 31 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Inclusion will be strictly limited to children and young adults with vascular anomalies with complications that require systemic therapy for control.
- •Diagnosis: All patients must have one of the following vascular anomalies as determined by clinical, radiographic and histologic criteria (when possible):
- •Kaposiform Hemangioendotheliomas with Kasabach-Merritt Phenomenon
- •Kaposiform Hemangioendotheliomas without Kasabach-Merritt Phenomenon
- •Tufted Angioma with Kasabach-Merritt Phenomenon
- •Tufted Angioma without Kasabach-Merritt Phenomenon
- •Capillary Lymphatico-Venous Malformation (CLVM)
- •Venous Lymphatic Malformation (VLM)
- •Microcystic Lymphatic Malformation (MLM)
- •Multifocal Lymphangiomatosis and Thrombocytopenia (MLT)/Cutaneovisceral Angiomatosis and Thrombocytopenia (CAT)
- •Capillary Lymphatic Arterial Venous Malformations (CLAVM)
- •PTEN Overgrowth syndrome with vascular anomaly
- •Lymphangiectasia Syndromes
- •If archived tissue is available, histological diagnosis will be confirmed by the pathology lab at the enrolling site.
- •Complications: Patients must have vascular anomalies that have potential to cause significant morbidity. In addition to the above diagnosis, one or more of the following criteria needs to be met:
- •Coagulopathy
- •Chronic pain
- •Recurrent cellulitis (>3 episodes/year)
- •Ulceration
- •Visceral and/or bone involvement
- •Cardiac dysfunction
- •Age: Patients must be 0 - 31 years of age at the time of study entry. Enrollment includes patients of both genders and all ethnic groups.
- •Organ function requirements:
- •Adequate liver function defined as:
- •Total bilirubin (sum of conjugated and unconjugated) ≤1.5 x ULN for age, and
- •SGPT (ALT) <5 x ULN for age, and
- •Serum albumin > or = 2 g/dL.
- •Fasting LDL and cholesterol:
- •Fasting LDL cholesterol of <160 mg/dL
- •Patients taking a cholesterol lowering agent must be on a single medication and on a stable dose for at least 4 weeks
- •Adequate Bone Marrow Function defined as:
- •Peripheral absolute neutrophil count (ANC) > or = 1000/microL
- •Hemoglobin > or = 8.0 gm/dL (may receive RBC transfusions)
- •Platelet count > or = 50,000/microL (transfusion independent defined as not receiving a platelet transfusion within a 7 day period prior to enrollment)
- •Note: There is NO platelet requirement for patients with Kasabach-Merritt Phenomenon
- •Adequate Renal Function Defined as:
- •A serum creatinine based on age as follows:
- •≤ 5 years of age maximum serum creatinine (mg/dL) of 0.8
- •6 < age ≤ 10 years of age maximum serum creatinine (mg/dL) of 1.0
- •11 < age ≤ 15 years of age maximum serum creatinine (mg/dL) of 1.2
- •> 15 years of age maximum serum creatinine (mg/dL) of 1.5
- •AND cystatin C equal to or less than the upper limit of normal for the patient. If cystatin C does not initially meet this criterion, it may be repeated or a more sensitive screening by nuclear GFR must be ≥ 70 ml/min.
- •Urine protein to creatinine ratio (UPC) < 0.3 g/l
- •Performance Status: Karnofsky > or = 50 (>10 years of age) and Lansky > or = 50 for patients < or = 10 years of age
- •Prior therapy requirements:
- •Patients who have undergone surgical resection or interventional radiology procedures for disease control are eligible if they meet all inclusion criteria after surgery/procedure
- •Surgery: At least 2 weeks since undergoing any major surgery
- •Steroids: Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. Other patients, such as vascular tumor patients, need to be on a weaning dose of steroids (steroid use defined as intravenous or oral steroids required for more than one day).
- •Myelosuppressive chemotherapy: Must not have received within 4 weeks of entry onto this study.
- •Hematopoietic GFs: At least 7 days since the completion of therapy with a GF that supports platelet, red or white cell number or function.
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排除标准
- •Dental braces or prosthesis only if it interferes with radiologic analysis of vascular anomaly.
- •Concurrent severe and/or uncontrolled medical disease which could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe infection, severe malnutrition, chronic liver or renal disease, active upper GI tract ulceration).
- •Chronic treatment with systemic steroids or another immunosuppressive agent. Patients with endocrine deficiencies are allowed to receive physiologic or stress doses of steroids if necessary. Patients with the diagnosis of a vascular tumor (KHE, TA) can be on a weaning dose of steroids.
- •Patients who require medications that inhibit/induce CYP3A4 enzyme activity to control concurrent medical conditions.
- •Known history of HIV seropositivity or known immunodeficiency. Testing is not required unless a condition is suspected.
- •Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of sirolimus (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection). A gastric tube or nasogastric tube is allowed.
- •Women who are pregnant or breast feeding.
- •Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method during the period they are receiving the study drug and for 3 months thereafter. Abstinence is an acceptable method of birth control. Women of childbearing potential will be given a pregnancy test within 7 days prior to administration of sirolimus and must have a negative urine or serum pregnancy test.
- •Patients who have received prior treatment with an mTOR inhibitor.
- •Patients unwilling or unable to comply with the protocol, or who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study.
- •Patients who currently have an uncontrolled infection, defined as receiving intravenous antibiotics.
研究组 & 干预措施
Sirolimus
Single arm using Sirolimus 0.8 mg/m2 per dose twice daily, Liquid form (1mg/ml) Length: 12 cycles of 28 day cycles
干预措施: sirolimus (Drug)
结局指标
主要结局
Overall Response by Radiologic Evaluation, Quality of Life Assessment, and Functional Impairment Score
时间窗: 12 months
Measures were determined by 3 distinct methods: radiologic evaluation, functional impairment score (clinical measurement of disease), and health-related quality of life. (HRQOL). The most common radiologic evaluation was MRI but other studies including CT and X-rays were included. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0 (3-18 years) ad infant Scales (\< or = to 2 years) and the Functional Assessment of Chronic Illness System (\> 18 years). Third method was the functional impairment score which was adopted from the measure of organ function that have been validated in the quantification of adverse even results from medical therapies and procedures. Patients needed to have complete response, normalization in quality of life and functional impairment score to have a complete response. In order to have a partial response they needed to have improvement in all three areas of assessment and not worsening of any others.
Overall Response by Radiologic Evaluation, Quality of Life Assessment, and Functional Impairment Score
时间窗: 6 months
Measures were determined by 3 distinct methods: radiologic evaluation, functional impairment score (clinical measurement of disease), and health-related quality of life. (HRQOL). The most common radiologic evaluation was MRI but other studies including CT and X-rays were included. HRQOL was assessed using the Pediatric Quality of Life Inventory 4.0 (3-18 years) ad infant Scales (\< or = to 2 years) and the Functional Assessment of Chronic Illness System (\> 18 years). Third method was the functional impairment score which was adopted from the measure of organ function that have been validated in the quantification of adverse even results from medical therapies and procedures. Patients needed to have complete response, normalization in quality of life and functional impairment score to have a complete response. In order to have a partial response they needed to have improvement in all three areas of assessment and not worsening of any others.
次要结局
未报告次要终点
研究者
Denise Martin Adams
Denise Adams, MD/Medical Director, Hemangioma Vascular Malformation Center, Cincinnati Children's Hospital Medical Center
Boston Children's Hospital