A Phase 1, Open-label, Dose-escalation Study of SNX 5422 and Everolimus in Subjects With Neuroendocrine Tumors.
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- Esanex Inc.
- 入组人数
- 19
- 试验地点
- 5
- 主要终点
- Number of patients with dose limiting toxicities
研究概览
简要总结
Study is designed to determine the maximum tolerated dose (MTD) of SNX-5422 when given in combination with everolimus.
详细描述
Heat shock protein 90 (Hsp90) plays a central role in the maturation and maintenance of numerous proteins, for example HER2 and mutated EGFR, that are critical for tumor cell viability and growth; SNX-5422 is a pro-drug of SNX-2112, a potent, highly selective, small-molecule inhibitor of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 has been found to be expressed in 95% of subjects with pancreatic neuroendocrine tumors.
This study will determine the MTD of SNX-5422 when given in combination with everolimus in patients with neuroendocrine tumors.The clinical starting dose of 50 mg/m2 qod for SNX-5422 in combination with daily everolimus is 50% of the SNX-5422 qod mono-therapy MTD. The choice to continue once every other day SNX-5422 dosing is based on the safety and efficacy profiles from prior studies, so that drug holidays are interspersed into weekly dosing. The planned subsequent dose levels are 75% and 100% of the SNX-5422 qod mono-therapy MTD.
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
- •Males or non-pregnant, non-breastfeeding females 18 years-of-age or older.
- •Archived neuroendocrine tumor sample or biopsy sample (will also be used for genetic testing).
- •Pathologic evidence of chemo-resistant Small Cell Lung cancer (relapse <90 days after 1st line), chemo-sensitive Small Cell Lung Cancer (relapse >90 days after first line), locally advanced metastatic neuroendocrine tumor of gastro-entero, pancreatic, pulmonary (other than Small Cell Lung) or thymic origin, or advanced renal cell carcinoma for which everolimus is indicated.
- •Measurable (RECIST) indicator lesion not previously irradiated.
- •Life expectancy of at least 3 months.
- •No more than 4 prior lines of systemic anti-cancer therapy.
- •Karnofsky performance score ≥
- •Adequate baseline laboratory assessments, including
- •Absolute neutrophil count (ANC) ≥1.5 x 109/L.
- •WBC >3000/microliter
- •Platelet count of ≥100 x 109/L.
- •Total bilirubin level ≤1.5 times institutional upper limit of normal (ULN), alanine aminotransferase or aspartate aminotransferase ≤2 x ULN
- •Hemoglobin ≥9 mg/dL.
- •Creatinine <1.5 X upper limit of normal or estimated plasma creatinine clearance of ≥40 mL/min
- •Signed informed consent form
- •Recovered from toxicities of previous anticancer therapy
- •Subjects with reproductive capability must agree to practice adequate contraception methods.
排除标准
- •Subjects in whom everolimus is contraindicated.
- •Subjects with clinically significant interstitial lung disease, or obstructive disease without sufficient reserve
- •Carcinoid with hormone related symptoms
- •Neuroendocrine cancer of the thyroid or thymus.
- •Rare pancreatic neuroendocrine cancers such as, insulinomas, glucagonomas, gastrinomas.
- •Prior treatment with any Hsp90 inhibitor.
- •Prior failed treatment with mTOR inhibitors
- •CNS metastases that are symptomatic and /or requiring escalating doses of steroids.
- •Major surgery or significant traumatic injury within 4 weeks of starting study treatment.
- •Conventional chemotherapy or radiation within 4 weeks.
- •Palliative radiation within 2 weeks.
- •The need for treatment with medications with clinically-relevant metabolism by the cytochrome P450 (CYP) 3A4 isoenzyme within 3 hours before or after administration of SNX-5422
- •Screening ECG QTc interval ≥470 msec for females, ≥450 msec for males.
- •At increased risk for developing prolonged QT interval, including hypokalemia or hypomagnesemia, unless corrected to within normal limits prior to first dose of SNX-5422; congenital long QT syndrome or a history of torsade de pointes; currently receiving anti-arrhythmics or other medications that may be associated with QT prolongation.
- •Patients with chronic diarrhea or with Grade 2 or greater diarrhea despite appropriate medical management.
- •Gastrointestinal diseases or conditions that could affect drug absorption, including gastric bypass.
- •Gastrointestinal diseases that could alter the assessment of safety, including irritable bowel syndrome, ulcerative colitis, Crohn's disease, or hemorrhagic coloproctitis.
- •History of documented adrenal dysfunction not due to malignancy.
- •Known seropositive for human immunodeficiency virus (HIV) or hepatitis C virus (HCV).
- •History of chronic liver disease.
- •Active hepatitis A or B.
- •Current alcohol dependence or drug abuse.
- •Use of an investigational treatment from 30 days prior to the first dose of SNX-5422 and during the study.
- •Glaucoma, retinitis pigmentosa, macular degeneration, or any retinal changes detected by ophthalmological examination.
- •Other serious concurrent illness or medical condition.
- •Psychological, social, familial, or geographical reasons that would hinder or prevent compliance with the requirements of the protocol or compromise the informed consent process.
研究组 & 干预措施
SNX-5422
Open-label administration of SNX-5422 capsules dosed in the morning once every other day (qod) for 21 days (11 doses), followed by a 7 day drug free period. Dose escalation will be based on safety defined as 1 or less dose limiting toxicities during the first 28 day cycle at any dose level. Dose escalation will not exceed a dose of 100 mg/m2 SNX-5422 qod even if the MTD has not been identified. Subjects will receive daily oral everolimus in the PM about the same time every day for 28 days.
干预措施: SNX-5422 (Drug)
结局指标
主要结局
Number of patients with dose limiting toxicities
时间窗: First 28 day cycle
Number of patients with dose limiting toxicities defined as adverse events or laboratory abnormalities of Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 ≥ Grade 3 that are not clearly related to disease progression or delay by more than 4 weeks in receiving the next scheduled cycle due to persisting toxicities and attributable to the combination of SNX-5422 and everolimus despite optimal medical supportive management.
次要结局
- Changes in ECG, vital signs, laboratory or physical examination(Every 4 weeks)
- Number of patients with adverse events as a measure of tolerability(Every 4 weeks)
- Tumor response(Every 8 weeks)