A Pilot Study of Sirolimus (Rapamycin, Rapamune[Registered Trademark]) in Subjects With Cowden Syndrome or Other Syndromes Characterized by Germline Mutations in PTEN
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 18
- 试验地点
- 1
- 主要终点
- Biochemical Changes in Benign and Malignant Tumor Tissues as Assessed by Immunohistochemistry.
研究概览
简要总结
Background:
People with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) hamartomatous tumor syndromes (PHTS) have a mutation in one of their genes called PTEN that can lead to benign tumors called hamartomas throughout the body. This puts them at increased risk for breast, thyroid and endometrial cancer.
People with a PTEN mutation have increased activity of proteins such as protein kinase B (AKT) and mammalian target of rapamycin (mTOR), which may be responsible for tumor growth and their increased risk of these cancers.
Experiments show that a drug called sirolimus, which is used to prevent the immune system from rejecting transplanted organs, can inhibit cancer cell growth by blocking the mTOR protein.
Objectives:
To test the ability of sirolimus to decrease the activity of proteins that are regulated by mTOR in both benign and cancerous tumor tissue.
Eligibility:
People 18 years of age and older with Cowden syndrome or other PHTS.
Design:
Sirolimus treatment. Patients take sirolimus once a day in 28-day treatment cycles. Patients who do not have cancer take the drug for a total of two cycles (56 days) unless they develop unacceptable side effects. Those who have cancer may continue sirolimus beyond cycle 2 until their disease worsens or they develop unacceptable side effects.
Evaluations. Patients come to the clinic for a history and physical examination on day 1 of every treatment cycle, then every month for the first two months off therapy, and then at 6 and 12 months. In addition, they have the following procedures:
- Positron emission tomography (PET) scan and neuropsychological testing before starting treatment.
- Clinical photography (photographic documentation of skin lesions) before starting treatment. Patients who do not have cancer have repeat photography at 2 and 8 weeks and then, if the lesions shrink or go away while on therapy, again every month for the first 2 months off sirolimus, then at 6 months and 1 year. Patients who have cancer and continue treatment beyond 8 weeks have repeat photography every 8 weeks while on the study.
- Digital dermoscopy (skin lesion examination using a high resolution camera). This is done at the same intervals as clinical photography.
- Multiple biopsies of the skin and lower intestine, and possibly the tumor in patients with cancer, before starting treatment, at 2 weeks of treatment and at 8 weeks of treatment.
- Blood and urine tests every week while on treatment for the first two cycles, then every 4 weeks for patients who continue treatment beyond two cycles.
- Imaging studies, such as computerized tomography (CT), ultrasound or magnetic resonance imaging (MRI) in patients with cancer before starting treatment and again every two cycles to monitor the tumor size and location.
详细描述
Background:
- PTEN (phosphatase and tensin homolog deleted on chromosome 10) is a tumor suppressor gene whose function is frequently lost through genetic and epigenetic mechanisms in cancer. Loss of PTEN increases activation of the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway, which increases cellular proliferation and survival.
- Germline mutations in PTEN are associated with a number of hamartomatous syndromes, of which Cowden Syndrome (CS) is the prototype. The set of syndromes that are defined by germline PTEN mutations has been labeled PTEN Hamartomatous Tumor Syndromes or PHTS.
- Patients with PHTS suffer increased morbidity and mortality. Benign tumors such as hamartomas occur in virtually every organ, most commonly in the skin and the gastrointestinal tract, which prompts frequent monitoring and resection and causes psychological and physical stressors on patients with this condition.
- Cowden syndrome (CS) patients develop thyroid, breast, and endometrial cancers at an earlier age than the general population, and have an overall increased incidence of these cancers compared to the general population. These patients have increased morbidity from heightened surveillance and diagnostic procedures.
- No medical therapies exist for PHTS patients.
- Because tumors from PHTS patients show increased activation of the PI3K/Akt/mTOR pathway, inhibitors of this pathway might have activity in patients with PHTS.
- Sirolimus (rapamycin) is a specific inhibitor of mTOR that is Food and Drug Administration (FDA)-approved and is preferentially effective in cells with mutant PTEN.
- We hypothesize that sirolimus will have activity in patients with PHTS, as measured by biochemical techniques that will assess mTOR inhibition and clinical tests that will assess the growth and metabolism of benign and malignant tumors.
Objectives:
- The primary endpoint will be inhibition of the mTOR pathway in tissues obtained before and after therapy, as assessed using immunohistochemistry in benign as well as malignant tumors.
- Secondary endpoints will include inhibition of the mTOR pathway in peripheral blood mononuclear cells (PBMCs) as assessed by immunoblotting, changes and duration of change in benign or malignant tumor size as assessed by computed tomography (CT), serial digital photography, digital dermoscopy, changes in tumor metabolism as assessed by positron emission tomography (PET), changes in lymphocyte counts, as well as changes in neuropsychological testing.
Eligibility:
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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Sirolimus Patients
sirolimus 6 mg by mouth loading dose and 2 mg by mouth daily in a 28 day treatment cycle. Patients who do not have cancer take the drug for a total of two cycles (56 days) unless they develop unacceptable side effects. Those who have cancer may continue sirolimus beyond cycle 2 until their disease worsens or they develop unacceptable side effects.
干预措施: fludeoxyglucose F 18 (Radiation)
Sirolimus Patients
sirolimus 6 mg by mouth loading dose and 2 mg by mouth daily in a 28 day treatment cycle. Patients who do not have cancer take the drug for a total of two cycles (56 days) unless they develop unacceptable side effects. Those who have cancer may continue sirolimus beyond cycle 2 until their disease worsens or they develop unacceptable side effects.
干预措施: sirolimus (Drug)
Sirolimus Patients
sirolimus 6 mg by mouth loading dose and 2 mg by mouth daily in a 28 day treatment cycle. Patients who do not have cancer take the drug for a total of two cycles (56 days) unless they develop unacceptable side effects. Those who have cancer may continue sirolimus beyond cycle 2 until their disease worsens or they develop unacceptable side effects.
干预措施: Clinical Videography (Other)
结局指标
主要结局
Biochemical Changes in Benign and Malignant Tumor Tissues as Assessed by Immunohistochemistry.
时间窗: Baseline, day 14, and day 56
A biochemical change is defined as a decrease in certain protein levels (e.g. P-AKT (phosphorylated AKT), total S6, P-S6, and P-4E-BP1) important in cell growth. These are measured by collecting tissue samples which stained and protein levels are measured under the microscope. Scoring will be based on distribution and intensity of staining. Distribution will be scored as 0 (0%), 1 (1% to 50%), and 2 (51% to 100%) to indicate the percentage of positive cells of interest in a single core. The intensity of the signal will be scored as 1 (weak), 2 (moderate), and 3 (strong). The distribution score and intensity score will be summed into a total score (TS).
Number of Participants With Adverse Events
时间窗: 47 months
Here is the number of participants with adverse events
次要结局
未报告次要终点
研究者
Arun Rajan, M.D.
Principal Investigator
National Institutes of Health Clinical Center (CC)