A Pilot Trial to Evaluate the Molecular Effects of RO4929097 as Neoadjuvant Therapy for Resectable Stage IIIB, IIIC or IV Melanoma
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Molecular effects of notch-signaling inhibition
研究概览
简要总结
This pilot phase II trial is studying how well RO4929097 works in treating patients with stage III, or stage IV melanoma that can be removed by surgery. RO4929097 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth
详细描述
PRIMARY OBJECTIVES:
I. Evaluate the molecular effects of Notch signaling inhibition using gamma-secretase inhibitor RO4929097 (RO4929097) in patients with resectable stage IIIB, IIIC, or IV intact melanoma tumors in the neoadjuvant setting.
SECONDARY OBJECTIVES:
I. Assess any indication of clinical activity of RO4929097 in these patients. II. Assess the effect of RO4929097 on Akt-mediated downstream biomarkers in melanoma tissue.
III. Assess the effect of RO4929097 on the melanoma stem cell subpopulation. IV. Identify patient-specific micro-RNA signatures that may correlate with response to therapy, recurrence, and overall 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 or cytologically confirmed melanoma
- •Stage IIIB, IIIC, or IV disease
- •Disease that is deemed resectable by surgical consultation
- •Patients must agree to pretreatment biopsies of their tumor
- •Measurable disease defined as ≥ 1 lesion that can be accurately measured in ≥ 1 dimension (longest diameter to be recorded) as ≥ 20 mm by conventional techniques OR as ≥ 10 mm by spiral CT scan
- •Measurable lesions must be deemed resectable
- •Skin metastases must be photographed and measured
- •No non-target disease
- •No known brain metastases
- •Life expectancy > 3 months
- •ECOG performance status 0-2 (Karnofsky 60-100%)
- •WBC ≥ 3,000/mm³
- •ANC ≥ 1,500/mm³
- •Platelet count ≥ 75,000/mm³
- •Hemoglobin > 10 g/dL
- •Total bilirubin ≤ 1.5 times upper limit of normal (ULN)
- •AST and ALT ≤ 2.5 times ULN
- •Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
- •Fertile patients must agree to use 2 forms of contraception (i.e., barrier contraception and 1 other method of contraception) for ≥ 4 weeks prior to, during, and for ≥ 12 months post-treatment
- •Negative pregnancy test
- •Not pregnant or nursing
- •No history of allergic reactions attributed to compounds of similar chemical or biological composition of gamma-secretase inhibitor RO4929097 or other agents used in the study
- •No malabsorption syndrome or other condition that would interfere with intestinal absorption
- •Able to swallow tablets
- •No known history of hepatitis or have a history of liver disease or other forms of cirrhosis
- •No uncontrolled hypocalcemia, hypomagnesemia, hyponatremia, hypophosphatemia, or hypokalemia despite adequate electrolyte supplementation
- •No uncontrolled intercurrent illness including, but not limited to, any of the following:
- •Ongoing or active infection
- •Symptomatic congestive heart failure
- •Unstable angina pectoris
- •Cardiac arrhythmia other than chronic
- •Unstable atrial fibrillation
- •Psychiatric illness and/or social situations that would limit compliance with study requirements
- •No baseline QTcF > 450 msec (male) or QTcF > 470 msec (female)
- •No history of cancer within the past 5 years except curatively treated basal or squamous cell cancer of the skin, in situ cervical cancer, or lobular carcinoma in situ of the breast
- •No other concurrent anticancer agents or therapies
- •More than 4 weeks since prior immunotherapy or local radiotherapy and recovered
- •No prior chemotherapy for melanoma
- •No concurrent medications with narrow therapeutic indices that are metabolized by cytochrome P450 (CYP450), including warfarin sodium (Coumadin®)
- •No concurrent medications that are strong inducers/inhibitors or substrates of CYP3A4
- •No concurrent combination antiretroviral therapy for HIV-positive patients
- •No concurrent ketoconazole or grapefruit juice while taking gamma-secretase inhibitor RO4929097
- •No concurrent granulocyte colony-stimulating factors
- •No other concurrent investigational agents
排除标准
- 未提供
研究组 & 干预措施
Treatment (gamma-secretase inhibitor RO4929097, surgery)
Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Within 35-56 days after completion of therapy, patients with stable or responsive disease undergo surgery. Patients may continue RO4929097 for 28 days after surgery in the absence of disease progression or unacceptable toxicity.
干预措施: gamma-secretase/Notch signalling pathway inhibitor RO4929097 (Drug)
Treatment (gamma-secretase inhibitor RO4929097, surgery)
Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Within 35-56 days after completion of therapy, patients with stable or responsive disease undergo surgery. Patients may continue RO4929097 for 28 days after surgery in the absence of disease progression or unacceptable toxicity.
干预措施: pharmacological study (Other)
Treatment (gamma-secretase inhibitor RO4929097, surgery)
Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Within 35-56 days after completion of therapy, patients with stable or responsive disease undergo surgery. Patients may continue RO4929097 for 28 days after surgery in the absence of disease progression or unacceptable toxicity.
干预措施: therapeutic conventional surgery (Procedure)
Treatment (gamma-secretase inhibitor RO4929097, surgery)
Patients receive oral RO4929097 once daily on days 1-3, 8-10, and 15-17. Within 35-56 days after completion of therapy, patients with stable or responsive disease undergo surgery. Patients may continue RO4929097 for 28 days after surgery in the absence of disease progression or unacceptable toxicity.
干预措施: laboratory biomarker analysis (Other)
结局指标
主要结局
Molecular effects of notch-signaling inhibition
时间窗: Up to 2 years
All statistics will be descriptive.
次要结局
- Toxicity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0(2 years)
- Response rate (complete or partial response) according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1(Up to 2 years)
- Change in Akt-mediated downstream biomarkers by immunohistochemistry (IHC)(From baseline to 4 weeks at the time of surgery)
- Change in stem cell subpopulation(From baseline to 4 weeks at the time of surgery)
- Correlation between patient-specific micro-RNA signatures with response to therapy, recurrence and overall survival(At baseline and at 4 weeks at the time of surgery)
- Correlation of circulating melanoma endothelial cells (CECs) and circulating progenitor (CEPs) cell levels in the blood with recurrence and/or survival(Up to 2 years)
- Correlation between shedding of collagen cryptic epitopes with response and risk of recurrence(Up to 2 years)
- Pharmacokinetics of RO4929097(At days 1 and 10)
- Pharmacodynamics of RO4929097(At days 1 and 10)
- Impact of RO4929097 on serum markers of angiogenesis(Up to 2 years)
- Correlation between serum autoimmune biomarkers and clinical response(Up to 2 years)