A Two-Part, Phase 1/2a Trial to Determine the Maximum Tolerated Dose, Safety, and Tolerability of Rhenium (186Re) Obisbemeda (Rhenium-186 NanoLiposome, 186RNL) Delivered Via Convection Enhanced Delivery (CED) in Supratentorial Recurrent, Refractory, or Progressive Pediatric Ependymoma and High-Grade Glioma (HGG)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 56
- 试验地点
- 1
- 主要终点
- Maximum Tolerated Dose (MTD)
研究概览
简要总结
Pediatric patients 6-21 years of age with supratentorial recurrent, refractory, or progressive pediatric ependymoma and high-grade glioma (HGG) will be included in this study of treatment with Rhenium-186 Nanoliposome (186RNL). Phase 1 of the study will look to determine the maximum tolerated dose (MTD) of 186RNL in this patient population. Phase 2 of the study will use the recommended dose determined in Phase 1 to continue to look at overall response rate and progression-free survival following 186RNL treatment.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 6 Years 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •6 years to 21 years* of age.
- •Lesion number and size:
- •Phase 1a/b only: A single lesion (less than or equal to) ≤3.5 cm (longest axis) and volume of (less than or equal to) ≤22.4 mL as the largest tumor (subsequent to individual Cohort lesion size requirements).
- •Phase 2a only: A single lesion or any number of multiple lesions separated by (less than or equal to) ≤3 cm; each lesion (less than or equal to) ≤3.5 cm (longest axis) and volume of (less than or equal to) ≤22.4 mL as the largest tumor.
- •a) Documented recurrent, refractory, or progressive ependymoma or HGG not eligible for resection or no longer receiving standard of care.
- •i) Phase 2a only: May include patients with recurrent, refractory, or progressive ependymoma or HGG where SOC surgery could be safely delayed four (4) weeks post-infusate.
- •b) Documented histologically confirmed high-grade glioma [following 2021 WHO CNS5 glioma nomenclature, e.g., Anaplastic astrocytoma, Anaplastic pleomorphic xanthoastrocytoma (PXA), Anaplastic ganglioglioma, Anaplastic oligodendroglioma, Glioblastoma, Diffuse midline glioma, H3K27M mutant].
- •Karnofsky Performance Status ≥
- •For subjects <16 years of age, Lansky score ≥
- •Acceptable liver function:
- •Bilirubin ≤ 1.5 times the upper limit of normal
- •AST (SGOT) and ALT (SGPT) ≤ 3.0 times the upper limit of normal (ULN)
- •6) Acceptable renal function:
- •Serum creatinine ≤1.5xULN
- •7. Acceptable hematologic status (without hematologic support):
- •ANC ≥1000 cells/uL
- •Platelet count ≥100,000/uL
- •Hemoglobin ≥9.0 g/dL
- •8. All subjects of childbearing potential must have a negative serum pregnancy test, and subjects must agree to use effective means of contraception (for example, surgical sterilization or the use of barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel or an IUD) with their partner from entry into the study through 6 months after the last dose.
- •9. Life expectancy of at least 2 months.
- •*Will consider treatment of subjects up to 25 years of age on a per-patient basis if no other co-morbidities are present that require subspecialty consultation outside of neurosurgical and oncologic care.
排除标准
- •Spinal disease.
- •Infratentorial location of tumor.
- •Involvement of the leptomeninges.
- •Serious intercurrent illness, as determined by the treating physician, which would compromise either patient safety or study outcomes such as:
- •Hypertension (two or more blood pressure readings performed at screening of systolic blood pressure (SBP) or diastolic blood pressure (DBP) above 95th percentile for age) despite optimal treatment.
- •Active medically significant infection unresponsive to antibiotics (e.g., non-healing wound, ulcer), uncontrolled systemic infection, or bone fracture.
- •Clinically significant cardiac arrhythmias.
- •Untreated hypothyroidism.
- •Congestive heart failure.
- •Myocarditis.
- •Inherited bleeding diathesis or coagulopathy with the risk of bleeding.
- •Known active malignancy other than ependymoma or high-grade glioma.
- •Any of the following prior anticancer therapy:
- •Prior treatment with Bevacizumab or other VEGF agents within 12 months prior to study registration.
- •Non-standard radiation therapy such as brachytherapy, systemic radioisotope therapy, or intra-operative radiotherapy (IORT) to the target site at any time prior to study registration.
- •Standard radiation therapy within 12 weeks prior to study registration.
- •Any systemic therapy within 28 days or 2 half-lives, whichever is longer, prior to study registration (this may include investigational agents, small-molecule kinase inhibitors, non-cytotoxic hormonal therapy, biologic agents, metronomic/protracted low-dose chemotherapy, etc.).
- •Nitrosoureas or mitomycin C within 42 days prior to study registration.
- •Psychiatric illness/social situations that would limit compliance with the study requirements.
- •A tumor located within 1.0cm of a ventricle AND it is determined by the surgeon, PI, and Sponsor to be a risk for drug extravasation to the subarachnoid space if given catheter placement and drug administration.
- •A tumor within 1.5cm of critical structures, including the optic chiasm, optic nerves, or brainstem.
- •Evidence of acute intracranial or intratumoral hemorrhage either by magnetic resonance imaging (MRI) or computerized tomography (CT) scan (subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin are eligible).
- •Treatment with antiepileptic medications must have a two-week history of a stable dose of antiepileptic without seizures prior to study registration.
- •Patients with corticosteroid requirements to control cerebral edema must be maintained at a stable or decreasing dose for a minimum of two weeks without progression of clinical symptoms prior to study registration.
研究组 & 干预措施
Phase 1b
Phase 1b continued dosing escalation will be defined following review of the safety data from Phase 1a.
干预措施: Rhenium-186 Nanoliposome (Drug)
Phase 2
The Phase 2 expansion study will utilize the maximum tolerable dose (MFD) determined from the Phase 1 dose escalation study. If no maximal tolerable dose is found, tumors may be treated up to an estimated total absorbed dose of 176 Gy. Varying concentrations of 186RNL infusate (0.5-2.5 mCi/mL) may be used to achieve this maximum tolerable dose while maintaining total tumor volume coverage. Phase 2a will enroll an additional 12 patients with a diagnosis of recurrent, refractory, or progressive ependymoma and an additional 20 patients with a diagnosis of recurrent, refractory, or progressive HGG.
干预措施: Rhenium-186 Nanoliposome (Drug)
Phase 1a - Cohort A
Up to six subjects will be enrolled in Cohort A. Tumor size will be limited to a maximum diameter of (less than or equal to) ≤2 cm and a maximum volume of (less than or equal to) ≤4.2 mL. Up to two CED catheters will be utilized in Cohort A at the discretion and consensus of the PI, neurosurgeon, and/or study team. The concentration of 186RNL infusate in Cohort A is 0.5 mCi/mL, with a corresponding estimated absorbed dose of ~87.5Gy.
干预措施: Rhenium-186 Nanoliposome (Drug)
Phase 1a - Cohort B
Up to six subjects will be enrolled in Cohort B. Tumor size will be limited to a maximum diameter of 3.5 cm in the longest axis and a maximum volume of 22.4 mL. Up to 5 total catheters may be used for Cohort B at the discretion and consensus of the PI, neurosurgeon, and/or study team to ensure total tumor volume coverage. The concentration of 186RNL infusate in Cohort B is 1.0 mCi/mL with a corresponding estimated absorbed dose of ~176Gy (~2x Cohort A).
干预措施: Rhenium-186 Nanoliposome (Drug)
结局指标
主要结局
Maximum Tolerated Dose (MTD)
时间窗: 28 days
Determine the maximum tolerated dose (MTD) of 186RNL administered by convection-enhanced delivery (CED) in subjects with supratentorial recurrent, refractory, or progressive pediatric ependymoma or HGG.
Overall Response Rate (ORR) by RANO in Ependymoma
时间窗: 90 days
Determine the best overall response rate (ORR) by Radiographic Assessment in Neuro-Oncology (RANO) criteria following 186RNL administration in subjects with supratentorial recurrent, refractory, or progressive pediatric ependymoma.
Progression-Free Suvival at 12 months (PFS12) in HGG
时间窗: 12 months
Determine progression-free survival at 12 months (PFS12) in subjects with supratentorial recurrent, refractory, or progressive pediatric HGG.
次要结局
- Safety of 186RNL Dose(28 days)
- Dose Distribution of 186RNL(8 days)
- Progression-Free Survival at 24 Months (PFS24) in Ependymoma(24 months)
- Overall Response Rate (ORR) by RANO in HGG(90 days)
- Overall Survival at 24 Months (OS24)(24 months)
- Neuropsychologic Outcome(1 year)
- Neuropsychologic Outcome(12 months)