A Phase II Study in Relapsing Glioblastoma of Intraarterial Concurrent Chemoradiation Therapy Using IA Carboplatin

Université de Sherbrooke1 个研究点分布在 1 个国家目标入组 35 人开始时间: 2018年7月10日最近更新: 2025年8月11日

适应症

干预措施

试验速览

阶段: 1 期
状态: 招募中
发起方: Université de Sherbrooke
入组人数: 35
试验地点: 1
主要终点: Response on MRI using the RANO Criteria

研究概览研究设计入排标准研究组 & 干预措施结局指标研究者研究点记录与标识符相似试验

研究概览

简要总结

Treatment of glioblastoma involves an optimal surgery, followed by a combination of radiation and temozolomide chemotherapy. Progression-free survival (PFS) with this treatment is only 6.9 months and relapse is the norm. The rationale behind the fact that limited chemotherapy agents are available in the treatment of malignant gliomas is related to the blood-brain barrier (BBB), which limits drug entry to the brain. Intraarterial (IA) chemotherapy allows to circumvent this. Using IA delivery of carboplatin, the investigators have observed responses in 70% of patients for a median PFS of 5 months. Median survival from study entry was 11 months, whereas the overall survival 23 months. How can this be improved? By coupling radiation with a chemotherapeutic which is also a potent radiosensitizer such as carboplatin.

Study design: In this phase I/II trial, patients will be treated at recurrence; a surgery will be performed for cytoreduction and to obtain tumor sample, followed with a combination of re-irradiation and IA carboplatin chemotherapy. A careful escalation scheme from 1.5Gy/fraction up to 3.5Gy/fraction will allow the investigators to determine the optimal re-irradiation dose (10 fractions of radiation over 2 weeks). Toxicity will be assessed according to the NCIC common toxicity criteria. Combined with radiation, patients will receive 2 treatments of IA carboplatin, 400 mg/m2, 4 hours prior to the first and the sixth radiation fraction. IA treatments will then be continued on a monthly basis, up to a total of 12 months, or until progression.

Outcome measurements: Tumor response will be evaluated using the RANO criteria by magnetic resonance imaging monthly. The investigators will also acquire a sequence that enables the measurement of cerebral blood flow, cerebral blood volume and blood vessel permeability that are all relevant to understand the delivery of therapeutics to the CNS. Primary outcome will be OS and PFS. Secondary outcome will be QOL, neurocognition, and carboplatin delivery.

In vitro intracellular carboplatin accumulation: Tumor samples from re-operation will be be analyzed for intracellular Pt concentration by ICP-MS. The amount of Pt bound to DNA will be measured. The level of apoptosis will be determined for each of the sample.

Putting together these data will allow to correlate clinical and radiological response to QOL, NC (MOCA), and to delivery surrogates for the IA infusion and intracellular penetration of carboplatin.

详细描述

A phase II study in relapsing glioblastomas (GBM) using concurrent intraarterial carboplatin chemoradiation therapy.

BACKGROUND - Contemporary treatment of GBM brain tumors involves a first-line treatment in which the patient receives a surgical procedure followed by a combination of radiation and temozolomide-based chemotherapy1. Unfortunately, this regimen improves patient survival only modestly, with a progression-free survival (PFS) of 6 months, and an overall survival of 14 months. Glioblastoma remains an incurable disease characterized by relapse and disease progression. There is no established second-line treatment for relapsing GBM, and the most used (BCNU chemotherapy) results in a PFS of only 2 months. As the investigators have shown, treatment can be considerably improved by circumventing the limitation of chemotherapeutic agents(CA) to cross the blood-brain barrier (BBB) and enter the central nervous system (CNS).

The investigators have focused their research on 3 essential aspects of GBM treatment: 1) alternate delivery approaches to bypass the BBB; 2) magnetic resonance imaging (MRI) to characterize tumor blood supply and predict therapeutics delivery to the tumor; 3) synergestic interplay of radiation and platinum drugs to improve brain tumor therapy. This is the first study to ever attempt bridging these 3 aspects within the same project.

Alternate delivery approaches to bypass the BBB.

Although different approaches have been tested in the researcher's lab to bypass the BBB, the most applicable to the clinic is the intraarterial infusion of chemotherapy (IA). It allows to circumvent the BBB via the first pass effect, resulting in a local plasma peak concentration increase of the CA by up to a 5-fold factor, maximizing CNS drug exposure. It also decreases systemic distribution of the CA thereby reducing toxicities and side effects. Over the last 15 years, the principal investigator has treated more than 720 patients using this IA approach, 422 of which had glioblastoma. This is the largest of such series. Based on this extensive experience, the investigators have convincingly shown that the procedure is safe and well tolerated. Using IA carboplatin in GBM relapse, a response in 70% of patients, and a 22 months overall survival + an increase in PFS to 5 months has been observed. This represents an impressive survival increase of 9 months. Time is ripe to improve these results in hope to cure this hard-to-treat cancer someday; hence the 2 additional measures discussed next.

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: 18 Years 至 —（Adult, Older Adult）
性别: All
接受健康志愿者: 否

入选标准

•Histological diagnosis of glioblastoma multiforme
•Radiological progression on an MRI scan, according to the RANO criteria, in the context of a known glioblastoma multiforme, already treated with the Stupp protocol of combined radiotherapy-Temozolomide, and progressing. This implies a measurable disease on MRI.
•Prior radiotherapy and temozolomide, as per the Stupp protocol, no sooner than 4 weeks, is permitted.
•18 of age and over
•Performance status: Karnofsky 60-100%
•Haematopoietic parameters at enrolment:
•Platelet counts > 100,000/mm^3
•Hemoglobin > 8 g/dL
•Absolute neutrophil count > 1,500/mm^3
•No impaired bone marrow function
•Hepatic parameters at enrolment:
•Bilirubin ≤ 2 times normal value
•AST and ALT ≤ 2 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2 times ULN (unless attributed to tumor)
•No impaired hepatic function
•Renal parameters at enrollment:
•No impaired renal function
•Creatinine no greater than 1.5 fold of the normal value
•Creatinine clearance > 30 ml/min.
•Written informed consent obtained
•Patient should be either sterile or else use a contraceptive strategy (for at least 2 months prior to study accrual).

排除标准

•Presence of a severe psychiatric or medical condition that would interfere with treatment administration or study enrolment.
•Presence of an active auto-immune disease.
•Occurrence of another malignancy within the past 5 years except curatively treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
•Pregnancy (as objectivated by a positive b-HCG) or actively nursing
•Presence of an uncontrolled systemic infection