Terbium-161 DOTATATE in Metastatic Neuroendocrine Tumors: Assessment of Safety and Efficacy
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 20
- 试验地点
- 2
- 主要终点
- Disease control rate
研究概览
简要总结
Gastro-enteropancreatic Neuro-endocrine tumors (GEP-NETs) are rare slow-growing cancers which commonly involve the abdominal organs like liver, stomach, intestines and pancreas. Their incidence has been documented to have increased over the last decade, thus resulting in treatment options being developed to treat these cancers. These cancers spread commonly to the liver, followed by lungs, bones and other sites. Depending on the extent of disease seen on scan, treatment is planned. Patients are advised Peptide Receptor Radionuclide Therapy (PRRT), which is the current standard of treatment for metastatic GEP-NETs. Radio-isotopes labeled to octreotide analogs bind to somatostatin receptors on surface of cancer cells and deliver radiation to the cancer cells when injected into the body. Lu-177 (Lutetium-177) is one such radioisotope which has been used for tagging to the octreotide and is known as Lu-177 DOTATATE PRRT, which is now routinely used in clinical practice. Terbium-161 is another radioisotope which can be labeled to octreotide and used for PRRT. It has advantages over Lu-177 such that it specifically reaches the tumor sites and does not affect the surrounding normal cells, due to its higher penetrating capacity and shorter range of travel. This will benefit patients as the effectiveness of PRRT will be higher with lesser side effects. However, the investigators can only do this by performing a study. Response to treatment can be evaluated by performing scans and side effects, if any can be studied by performing blood tests.
详细描述
Targeted radionuclide therapy (TRT) is a nuclear medicine technique that uses radiopharmaceuticals (RPs) with high affinity to receptors or antigens on the surface of tumor cells to achieve a therapeutic effect. TRT causes less collateral damage than external beam radiotherapy (EBRT) because the RPs are selectively taken up by tumors and their metastases, delivering high doses of radiation to cancer cells and minimizing doses to normal tissues.NETTER-1 and 2 trials have already established PRRT (Peptide Receptor Radionuclide Therapy) with Lutetium-177 (Lu-177) DOTATATE as first line TRT in metastatic well-differentiated gastro-enteropancreatic neuroendocrine tumors(GEP-NETs).
While Lu-177 as a radioisotope is safe and indigenously produced by BARC, the recent global shortage of this isotope has led to development of Terbium-161 (Tb-161). Terbium-161 belongs to the same family of Lanthanides as Lu-177 and offers the same physical characteristics.
The superiority of Tb-161 over Lu-177 evolves from its basic property of emission of Auger electrons (AE).(4) Most important characteristics of radioisotopes in Nuclear Medicine or Radiation Oncology are linear energy transfer and range; which are determinants of cell-damage to the target cell and normal cell, respectively. Compared to beta-emissions (as in Lu-177), AEs are most lethal to cancer cells when emitted near the cell nucleus and especially when incorporated into DNA. AEs cause DNA damage both directly and indirectly via water radiolysis. AEs can also kill targeted cancer cells by damaging the cell membrane and producing more targeted and lethal effects. Moreover, the important point is that since the range of delivery of this energy is relatively shorter as compared to beta-emitters, hence there is negligible bystander and crossfire effect, thereby causing no damage to surrounding cells.
Monte-Carlo simulations: Larauze et al assessed absorbed doses from simulations performed with CELLDOSE, which is a homemade Monte Carlo track-structure code for simulating the transport of electrons in water, based on differential and total interaction cross sections describing the elastic scattering, electronic excitation, and ionization. Absorbed doses to cell nuclei and cell membranes (with an intranuclear radionuclide location, only nuclear absorbed doses were assessed) were assessed. In this tumor cluster model, when all cells were targeted, and depending on the location of the radionuclide, Tb-161 delivered a 2- to 3-fold higher nuclear absorbed doses than Lu-177 but also 2- to 6-fold higher absorbed doses to cell membranes. Interaction of ionizing radiation with the cell membrane induces sphingomyelin hydrolysis to ceramide, initiating apoptosis.
Spoormans et al performed cellular dosimetry to quantify the absorbed dose to the cell nucleus and compared dose-response curves to evaluate differences in relative biological effectiveness in vitro, between Tb-161 and Lu-177. (7) Tb-161-DOTATATE and delivered a 3.6 times higher dose to the nucleus, respectively, than their Lu-177-labeled counterparts on saturated receptor binding. This increased nucleus-absorbed dose was mainly due to the additional emission of internal conversion electrons by Tb-161.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or female, age greater than 18 years
- •Histopathological diagnosis of well-differentiated GEP-NET
- •Positive Ga-68-DOTANOC PET/CT, Krennings score >/=3
- •Locally advanced/inoperable disease or metastatic disease
- •Patient who have shown disease progression with Lu-177 DOTATATE PRRT
- •Karnofsky performance-status score of at least 60 or ECOG performance status </=2
- •Life expectancy greater than 6 months
排除标准
- •Serum creatinine level of more than 1.6 mg/dl or a creatinine clearance of less than 50 ml/min
- •Hemoglobin level of less than 8.0 g per deciliter
- •Red blood cell count less than 300,000/cubic millimeter
- •White cell count of less than 2000 per cubic millimeter
- •Platelet count of less than 75,000 per cubic millimetre
- •Total bilirubin level of more than 3 times the upper limit of the normal range
- •Serum albumin level > 3.0 g/dl
- •Pregnancy and Lactation
- •Patients with concurrent malignancies
研究组 & 干预措施
Terbium 161 DOTATATE PRRT
Peptide Receptor Radionuclide Therapy with 7.4 GBq of Terbium 161 DOTATATE administered every 6-8 weeks
干预措施: Terbium 161 (Drug)
结局指标
主要结局
Disease control rate
时间窗: 4-6 weeks
Disease control rate will be measured as a primary endpoint. It is percentage of patients achieving complete or partial response or stable disease on Ga-68 DOTATATE PET/CT. Response assessment will be done using RECIST 1.1 for solid tumors. Non-PD (non-disease progression) after one session of Tb-161 therapy will be eligible for the second session. Patients showing CR with no residual measurable disease will not undergo a second session of therapy. Patients with PD after 1 cycle of Tb-161 DOTATATE therapy will not continue in the study
次要结局
- Quality of Life assessment(Before therapy, at 4 weeks and 8 weeks after each therapy session.)
- Safety Assessment(2 weeks, 4 weeks and 6 weeks after each therapy)
- Quality of Life assessment using QLQ-GI.NET21 questionnaire(Before therapy, at 4 weeks and 8 weeks after each therapy session.)
研究者
Ameya Puranik
Professor
Tata Memorial Hospital