Safety and Tolerability of Everolimus as Second-line Treatment in Poorly Differentiated Neuroendocrine Carcinoma / Neuroendocrine Carcinoma G3 (WHO 2010) and Neuroendocrine Tumor G3 - an Investigator Initiated Phase II Study
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- Incidence of adverse events (AEs)
研究概览
简要总结
The study is designed as an open-label, prospective, single arm, multicenter study of everolimus in histologically confirmed, neuroendocrine carcinoma G3 /neuroendocrine tumor G3 after failure of first-line platin-based chemotherapy (open-label pilot study).
The aim of this study is to provide a second line therapy to patients with any type of platinum based first line chemotherapy, to gather data on disease control rate and progression free survival.
详细描述
As more efficient drugs are urgently needed for the treatment of neuroendocrine tumors the investigator evaluated phosphorylated Mammalian target of rapamycin (mTOR) and effectors in a series of NEC G3 at the Charité Center. Everolimus showed antiproliferative effects in bronchial NET.
In a second approach the data of this study should be the basis to generate another study to further explore everolimus as maintenance therapy in NEC G3/ NET G3.
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
- •Signed written informed consent
- •Male or female ≥ 18 years of age
- •Patients with poorly differentiated neuroendocrine carcinoma, neuroendocrine carcinoma G3 (NEC - G3 according to WHO 2010) or well or moderately differentiated neuroendocrine carcinoma (NET - G1 / G2) that switched to G3 (confirmed by histology) or neuroendocrine tumor G3 (NET G3) and disease progression as measured by RECIST 1.1
- •Progression during or after treatment with first-line platinbased chemotherapy. In NET G3 that switched from NET G2 the line of therapy is determined from the time of revised histology (confirming a G3 NEN)
- •Measurable disease according to RECIST 1.1
- •Performance Status according to Eastern Cooperative Oncology Group (ECOG) status 0 - 2 (Karnofsky Performance status ≥ 80%)
- •Women of child-bearing potential must have a negative pregnancy test
- •Laboratory requirements:
- •Hematology
- •Absolute neutrophil count ≥ 1.5 x 109/L
- •Platelet count ≥ 100 x 10^9/L
- •Leukocyte count ≥ 3.0 x 10^9/L
- •Hemoglobin ≥ 9 g/dL or 5.59 mmol/L
- •Hepatic Function
- •Total bilirubin ≤ 1.5 time the upper limit normal (ULN)
- •Aspartate Aminotransferase (AST) ≤ 3 x ULN in absence of liver metastases, or ≤ 5 x ULN in presence of liver metastases
- •Alanine Aminotransferase (ALT) ≤ 3 x ULN in absence of liver metastases, or ≤ 5 x ULN in presence of liver metastases
- •Renal Function
- •Creatinine clearance ≥ 50 mL/min according to cockroft-Gault formula
- •Metabolic Function
- •Magnesium ≥ lower limit of normal
- •Calcium ≥ lower limit of normal
- •CRP (PCT if CRP is elevated to exclude infection)
- •negative urinary screening test for leukocytes and nitrite (U - stix) to exclude urinary tract infection
排除标准
- •Known or suspected allergy or hypersensitivity reaction to any of the components of study treatment or their excipients.
- •Previous therapy with mTOR inhibitor
- •Radiotherapy :
- •Concurrent radiotherapy involving target lesions used for this study.
- •Concurrent palliative radiation (but radiation for non-target lesions is allowed if other target lesions are available outside the involved field)
- •previous pre-operative or post-operative radiotherapy within 3 months before study treatment
- •History of other malignant tumors within the last 5 years, except basal cell carcinoma or curatively excised cervical carcinoma in situ
- •Known brain metastases unless adequately treated (surgery or radiotherapy) with no evidence of progression and neurologically stable off anticonvulsants and steroids
- •Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1 year before enrolment
- •Inadequate pulmonary function according to the Investigator's judgment, history of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis or evidence of interstitial lung disease on baseline chest CT scan
- •Known active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) or HIV infection
- •Serious concomitant disease or medical condition that in the judgment of the investigator renders the patient at high risk from treatment complication
- •Any systemic disease requiring oral intake of corticosteroids (except for replacement therapy of corticosteroids - hydrocortisone in case of adrenal or pituitary insufficiency)
- •Hearing loss ≥ Grade 3 (CTCAE v4.03)
- •Patient pregnant or breast feeding, or planning to become pregnant within 8 weeks after the end of treatment
- •Patient (male or female) is not willing to use highly effective methods of contraception (per institutional standard) during treatment and for 8 weeks (male or female) after the end of treatment.
- •Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 28 days prior to treatment start
- •Concurrent treatment with inhibitors (e.g. itraconazole, ketoconazole) and inducers (e.g. phenytoin, rifampicin) of Cytochrome P450 3A4 (CYP3A4) and / or the multidrug efflux pump P-glycoprotein (PgP).
- •Known drug abuse/alcohol abuse
- •Peripheral polyneuropathy ≥ Grade 2 (CTCAE v4.03)
- •Active chronic inflammatory bowel disease
- •Any condition which might interfere with study objectives (e.g. infections) or would limit the patient's ability to complete the study in the opinion of the investigator
- •Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities. (AMG §40, Abs. 1 No. 4)
- •Affected persons who might be dependent on the sponsor or the investigator
研究组 & 干预措施
Single Arm
Patients receive Everolimus orally, 10 mg/day.
The end of study will be performed when tumor progression has been observed for 28 patients. Patients who are still under treatment at that time may continue with chemotherapy at the discretion of the investigator, but will be excluded from the study.
干预措施: Everolimus (Afinitor®) (Drug)
结局指标
主要结局
Incidence of adverse events (AEs)
时间窗: approx. 18 month
Incidence of adverse events (AEs) overall and by severity, and serious adverse events (SAEs). Severity will be assessed using the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) for Adverse Events, version 4.03 (CTCAEv4.03). To evaluate tolerability and safety of everolimus in second-line treatment of poorly differentiated neuroendocrine carcinoma / neuroendocrine carcinoma G3 according to WHO 2010 and neuroendocrine tumors G3.
次要结局
- Progression free survival (PFS)(approx. 18 month)
- Overall Survival (OS)(approx. 18 month)
- Disease control rate (DCR)(approx. 18 month)
- chromogranin A & B(approx. 12 month)
- neuron-specific enolase(approx. 12 month)
- Duration of response (DR)(approx. 18 month)
- Time to Progression (TTP)(approx. 18 month)
- progastrin releasing peptide(approx. 12 month)
- Objective response rate (ORR)(approx. 18 month)
- Correlation mTOR pathway components in tumor tissue to tumor response(approx. 18 month)
- Quality of life(approx. 18 month)