A Phase I Trial to Determine the Maximum Tolerated Dose and Patient-specific Dosimetry of Fractionated Intracavitary Radioimmunotherapy With Lu-177 Labeled 6A10 Fab-fragments in Patients With Glioblastoma After Standard Treatment
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 15
- 试验地点
- 11
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
Locoregional, intracavitary radioimmunotherapy (iRIT) with a newly developed radioimmunoconjugate (Lu-177 labeled 6A10-Fab-fragments) will be used to prevent or postpone tumour recurrence in patients with GBM following standard therapy .
Following study objectives will be analyzed:
- Determining the Maximum Tolerated Dose (MTD)
- Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher
- Determining absorbed dose to the 2 cm shell of the resection cavity (based on a series of SPECT/CTs of the head 2h,24h,48h, 72h p.i. and on day 5-7)
- Determining absorbed dose values for the kidneys, the liver, the active marrow (based on a series of SPECT/CTs of the abdomen 2h,24h,48h, 72h p.i. and on day 5-7)
- Determining 24 weeks Progression-Free-Survival (PFS), defined from the day of inclusion
详细描述
In glioblastoma (GBM), tumour recurrence occurs adjacent to the initial tumor resection cavity in about 85% of cases (Albert et al., 1994; Bashir et al., 1988; Nestler et al., 2015). Therefore, local treatment concepts seem crucial for effective recurrence treatment strategies. We consider locoregional, intracavitary radioimmunotherapy (iRIT) to be a new therapeutic approach to delay or prevent the development of local tumour regrowth in GBM patients. By applying a radioimmunoconjugate (RIC) into the surgically created resection cavity (RC) the blood-brain barrier can effectively be by-passed, allowing the a deposit of high radiation doses locally while sparing sensitive organs like the bone marrow and the kidneys. LuCaFab (Lu-177 labeled 6A10- Fab-fragment) is a carbonic anhydrase XII-specific antibody Fab fragment developed by Helmholtz Munich, labeled with ITM's highly pure medical radioisotope, lutetium-177. (ITM IsotopeTechnologies Munich SE). Patients with GBM after standard therapy (surgery by radio-chemotherapy concomitant and adjuvant chemotherapy) Are eligible for the study. Patients will receive the calculated total doses of Lu-177-labeled 6A10-Fabs in three fractions with an interval of 4 weeks between injections, administered into the tumour cavity via an implanted reservoir. A patient specific dosing strategy will be applied and will depend on the individual RC volume. This investigator-initiated trial is sponsored by the University Hospital Münster, conducted in hospitals in Münster, Essen, Cologne, and Wuerzburg, and supported by ITM and Helmholtz Munich.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Written patient consent after comprehensive information
- •Age between 18 and 80 years
- •Primary supratentorial high grade glioma after standard therapy (fluorescence-guided surgery, radio-chemotherapy, concomitant + adjuvant chemotherapy), with no or stable small tumor residue (residual contrast enhancement of up to 5cm3) at earliest 6 weeks after completion of radiotherapy
- •Histological verification of glioblastoma and CA 12-expression of tumor cells confirmed
- •Karnofsky-score ≥ 60
- •Volume of resection cavity 2,5-25 cm3
- •Male and female patients with reproductive potential must use an approved contraceptive method
- •Pre-menopausal female patients with childbearing potential: a negative serum pregnancy test must be obtained prior to treatment start
- •Adequate bone marrow reserve: white blood cell (WBC) count ≥3000/μl, granulocyte count >1500/μl, platelets ≥100000/μl, hemoglobin ≥ 10 g/dl
- •Adequate liver function: bilirubin < 1.5 times above upper limit of normal range (ULN), alanine transaminase (ALT/SGPT) and aspartate transaminase (AST/SGOT) < 3 times ULN. In the case of documented or suspected Gilbert's disease bilirubin < 3 times ULN.
- •Blood clotting: INR (=PT) and PTT within acceptable limits according to the investigator
- •Adequate renal function: creatinine < 3 times above ULN; eGFR > (or equal) 60 ml/min
排除标准
- •Patient unable to undergo imaging by CT, PET or contrast-enhanced MRI for whatever reason (i.e., pacemaker)
- •Resection cavity with intraventricular access
- •Significant leakage of radioactivity into CSF spaces or ventricles
- •Other actively treated invasive malignancy
- •Breastfeeding women
- •Past medical history of diseases with poor prognosis, e.g., severe coronary heart disease, heart failure (NYHA III/IV), severe and poorly controlled diabetes, immune deficiency, residual deficits after stroke, severe mental retardation, pre-existing neurological diseases except those related to glioblastoma or other serious concomitant systemic disorders incompatible with the study (at the discretion of the investigator)
- •Any active infection (at the discretion of the investigator)
- •Previous participation in a registered clinical trial with therapeutic intervention less than 6 weeks prior to enrolment (date of informed consent)
- •Allergy against known constituents of study medication
研究组 & 干预措施
Lu-177-labeled-6A10Fab-fragments
The patient will receive a predetermined dose of Lu-177-labeled- 6A10Fab-fragments via the intracavitary reservoir. Patients will receive 3 RIT-cycles with an interval of 4 weeks. The total activity, adjusted to the volume of the RC, will be injected in 3 fractions with 50%, 25% and 25% of the total activity to achieve the desired boost to the 2 cm margin.
干预措施: Lu-177 labeled 6A10-Fab-fragments (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: Through study completion, ca 1 ½ years
Determine maximum tolerated dose (MTD) and safety of adjuvant radio-immunotherapy (RIT) with Lu-177 labeled 6A10-Fab-fragments
Safety of the adjuvant radio-immunotherapy
时间窗: Through study completion, ca 1 ½ years
Determining safety by assessing all new neurological, hematological and other AEs CTC grade 2 or higher
次要结局
- Evaluation of pharmacokinetics of Lu-177 labeled 6A10 Fab fragments(After first application: 2 ,24 ,48, 72 hours post injection and on day 5-7. After second and third application.)
- Progression-free survival (PFS)(Through study completion, an average of 18 months)
研究者
Univ.-Prof. Dr. med. Walter Stummer
Scientific
Universitaetsklinikum Muenster AöR