Multicentric Study on Indigenous and Affordable Microspheres for Selective Internal Radiation Therapy (SIRT) of Unresectable Liver Cancer
试验速览
- 阶段
- 1 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 18
- 试验地点
- 5
- 主要终点
- Number of Participants with Dose-Limiting Toxicity (DLT) as assessed by CTCAE v4.0
研究概览
简要总结
Primary liver tumors, with hepatocellular carcinoma (HCC) accounting for 80%, represent 6% of global cancer incidence and 9% of global cancer-associated mortality.HCC remains the leading causes of cancer-related deaths worldwide, due to late diagnosis. Although local-stage liver tumors are curable with tumor resection or livertransplantation, 65-70% of diagnosed cases are not suitable for resection due to large or multifocal lesions. For these patients, local therapies such as transcatheterarterial chemoembolization (TACE) or selective internal radiation therapy (SIRT) are appropriate at intermediate stages. In cases of advanced and metastatic livertumors, systemic therapies like sorafenib are the standard approach. Selective Intra-arterial Radionuclide Therapy (SIRT) offers a promising treatment for inoperableliver tumors by delivering beta-emitting radiolabeled microspheres directly to tumor sites through the liver's dual blood supply. However, the high cost of standard90Y-microspheres has limited accessibility for patients. This current project aims to develop, optimize, and validate the indigenously prepared microspheres forradiolabeling with 188Re from commercially available generator and indigenously produced radionuclide 177Lu (BARC Mumbai) for SIRT in liver cancer. With hightransformational impact, the current multicentric research will lead to a potentially safe, effective, and promising low-cost SIRT solution for low-income settings.Through collaboration across multiple centers, the study will evaluate the efficacy of microspheres labelled with both radionuclides. By establishing these accessibleSIRT options, this project strives to reduce financial barriers to treatment, advancing the goals of "Jai Anusandhan" towards building innovative therapeutics throughcollaborative research project and improving outcomes for patients with limited options.
详细描述
Study Objective: Phase-1 Dose-escalation of 188Re-microspheres with comparator arm (Safety and primary efficacy)
Study Design: This is an open-label, multi-centric, randomized, dose escalation Phase I study with an active comparator arm (90Y-Theraspheres). The study will be initiated at PGIMER, Chandigarh, India and the other participating centres (AIIMS, New Delhi, India and TMH, Mumbai, India) would be added in a phased manner.
Study Settings:
The study will be conducted in the Department of Nuclear Medicine, PGIMER Chandigarh, which will serve as the coordinating and primary executing department, in collaboration with the Departments of Hepatology, Gastroenterology, and Phase I Centre of Clinical Pharmacology Unit, PGIMER Chandigarh, for patient screening, eligibility confirmation, therapeutic drug and dosimetry-related expertise, and overall conduct of Selective Internal Radiation Therapy (SIRT) in patients with hepatocellular carcinoma (HCC).
Study Design:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 90 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age greater than or equal to 18 years (male or female)
- •Histologically or radiologically confirmed diagnosis of HCC deemed inoperable
- •Barcelona Clinic Liver Cancer stage B with ECOG performance status between 0 and 2
- •At least one measurable lesion with longest diameter greater than or equal to 5 cm on cross sectional imaging
- •Portal vein thrombosis may be present or absent
- •Laboratory criteria:
- •Serum creatinine less than or equal to 1.5 mg per dL
- •Total bilirubin less than or equal to 2.0 mg per dL
- •AST or ALT less than or equal to 5 times upper limit of normal
- •Leukocyte count greater than or equal to 1500 per microliter
- •Platelet count greater than or equal to 50000 per microliter
- •Prothrombin time less than or equal to 1.3 times control or INR less than or equal to 1.5
- •Karnofsky performance status greater than 70
- •Ability and willingness to provide written informed consent for participation in the IEC approved protocol
排除标准
- •Women of childbearing potential who are unwilling or unable to use effective contraception or who are pregnant or lactating
- •Child Pugh class C liver function
- •Presence of extrahepatic metastases
- •Severe chronic pulmonary disease with hypoxemia or NYHA class three or four heart failure
- •Myocardial infarction within the past six months
- •Unstable arrhythmia or symptomatic cardiac disease
- •Any other serious uncontrolled illness that in the investigator's opinion would compromise study participation
- •History of other malignancy except adequately treated basal cell carcinoma or cervical carcinoma in situ within the last five years
- •Major surgery within four weeks prior to enrolment
- •Active uncontrolled bacterial infection requiring systemic therapy
- •Liver rupture, tumor penetration of the liver capsule, tumor invasion of the biliary system, or biliary obstruction
- •Known allergy or hypersensitivity to any component of the investigational or comparator microspheres
- •Prior treatment with Selective Internal Radiation Therapy (SIRT)
- •Estimated overall survival less than one month
研究组 & 干预措施
188Re-SIRT
The experimental arm will evaluate the safety, tolerability, biodistribution, and preliminary efficacy of indigenous 188Re-Microspheres for SIRT in unresectable HCC. Participants will be enrolled in three dosing cohorts (80-100 Gy, 100-150 Gy, 150-200 Gy) with 4 patients receiving 188Re-Microspheres per cohort. Pre-therapy assessments will include clinical evaluation, laboratory tests, serology, Child-Pugh score, AFP, portal vein status, and triple-phase CT/MRI/PET-CT. Lung shunt study using 99mTc-Microspheres will be performed on day of SIRT to calculate the 188Re-Microspheres activity required for intended dose. 188Re-Microspheres will be delivered via single femoral artery catheter under DSA, followed by post-therapy SPECT/CT for biodistribution and dosimetry. Patients will be monitored for laboratory parameters, adverse events, and tumor response up to 12 weeks using mRECIST. Dose escalation will proceed only if dose-limiting toxicity is not observed in more than 1 of 3 patients.
干预措施: 188Re-Microspheres (Device)
90Y-SIRT
The comparator arm aims to compare the safety, tolerability, biodistribution, and preliminary efficacy of 188Re-Microspheres with the standard-of-care 90Y-Microspheres for SIRT in unresectable HCC. Tumor dose escalation will be conducted in a phased manner across three groups receiving 80-100, 100-150, and 150-200 Gy. Prior to therapy, patients will undergo clinical evaluation, laboratory investigations, serological testing, and imaging with triple phase CT/MRI/PET-CT. 99mTc-MAA will be administered via trans-arterial catheter placed by femoral artery puncture under DSA at least one week prior to SIRT for lung shunt estimation and determination of the therapeutic dose of 90Y-Theraspheres. On the day of SIRT, the patient will be catheterized again, and the calculated Y90-Theraspheres dose will be delivered under DSA. Post-therapy PET-CT will be performed to assess biodistribution. Dose escalation will proceed only if dose-limiting toxicity is not observed in more than 1 of 3 patients.
干预措施: 90Y-Theraspheres (Device)
结局指标
主要结局
Number of Participants with Dose-Limiting Toxicity (DLT) as assessed by CTCAE v4.0
时间窗: Day 1 - Day 28 Post-SIRT
Microspheres cold-kit is unique, GMP-grade innovative formulation with enhanced shelf-life and affordability. The clinical validation of 188Re-Microspheres across a broad spectrum of patients nationwide (Pan India) will ensure market readiness. Once available, this cost-effective treatment has the potential to benefit a large number of patients with HCC who previously had limited access to such therapies. The primary endpoint will be assessment of Dose-Limiting Toxicity (DLT) from Day 1 to Day 28. Proportion of patients experiencing more than or equal to 1 treatment related DLT within 28 days post-SIRT, adjudicated per CTCAE v5.0 by the Safety Review Committee, will be noted.
次要结局
- Change From Baseline in Blood Pressure(Five time-points: Baseline and Week 2, 4, 8, 12 post-SIRT)
- Change From Baseline in Body Temperature(Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT)
- Change From Baseline in Heart Rate(Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT)
- Incidence of Clinically Significant ECG Rhythm Abnormalities(Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT)
- Change From Baseline in ECG Interval Parameters(Five time-points: Baseline and Weeks 2, 4, 8, 12 post-SIRT)
- Change From Baseline in ECOG Performance Status Score(Baseline and Weeks 2, 4, 8, 12 post-SIRT)
- Number of Participants With Grade ≥3 Laboratory Abnormalities as Assessed by CTCAE v5.0(Five time-points: Baseline and Week 2, 4, 8, 12 post-SIRT)
- Systemic Exposure to Radioactivity(Five time-points: Hour 0, 2, 12, 24, and 48)
- Quantitative Estimation of Post-therapy Biodistribution and Absorbed Dose Using SPECT/CT(Day 0, Day 1, Day 2)
- Evaluation of Preliminary Therapeutic Efficacy of 188Re-SIRT via Radiologic Response(Single time-point: Week 8 post-SIRT)
- Evaluation of Preliminary Therapeutic Efficacy of 188Re-SIRT via Biochemical Response(Three time-points: Baseline, Week 8 and Week 12 post-SIRT)
- Change From Baseline in Quality of Life Scores as Measured by the World Health Organization Quality of Life-BREF (WHOQOL-BREF)(Baseline, 1 month, and 3 months post-SIRT)
- Change From Baseline in Hepatocellular Carcinoma-Specific Symptom Scores as Measured by the EORTC QLQ-HCC18(Baseline, 1 month, and 3 months post-SIRT)
- Proportion of Participants Meeting Composite Procedural Safety Criteria for SIRT(Single time-point: Immediately after performing SIRT)
研究者
Jaya Shukla
Professor
Post Graduate Institute of Medical Education and Research, Chandigarh