Combination of Everolimus and 177Lu-DOTATATE in the Treatment of Grades 2 and 3 Refractory Meningioma: a Phase IIb Clinical Trial
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 28
- 试验地点
- 4
- 主要终点
- RANO criteria (Response assessment in neuro oncology criteria)
研究概览
简要总结
Meningioma, the most common intracranial primary tumor of the central nervous system predominantly affects people in their fifties. Meningiomas are generally subdivided into two entities: a priori non-aggressive meningiomas (grade 1), and meningiomas at high risk of aggressive behavior (grade 2/atypical and 3/anaplastic). The current conventional treatments for meningioma are surgery and radiotherapy. When these treatments are no longer feasible, meningiomas are considered refractory irrespectively of grade, and in these rare entities, the therapeutic arsenal is reduced to the few treatments that have shown limited efficacy. Refractory, and particularly grades 2 and 3 meningiomas, have very poor prognoses with a progression-free survival at 6 months (PFS-6) of 26%. The European Response Assessment in Neuro-Oncology group (RANO) recommends that in any new, grades 2 and 3 meningioma, therapy that achieves a PFS-6 >30% in phase II trials be considered promising.
In Nuclear Medicine, Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE, currently used on a compassionate basis in refractory meningioma, deploys an octreotide-like effect, and appears very promising, with preliminary PFS-6 of 94% and an overall survival at 12 months (OS-12) of 88% in grade 1 meningioma. However, its PFS-6 is reduced to 28% with an OS-12 of 65% in WHO grades 2 and 3 meningioma. Recently the non-radiolabeled octreotide and everolimus combination however achieved a PFS-6 of 55% and an OS-12 of 75% in a population of 90% WHO grades 2 and 3 meningioma.
详细描述
Meningioma, the most common intracranial primary tumor of the central nervous system predominantly affects people in their fifties. Meningiomas are generally subdivided into two entities: a priori non-aggressive meningiomas (grade 1), and meningiomas at high risk of aggressive behavior (grade 2/atypical and 3/anaplastic). The current conventional treatments for meningioma are surgery and radiotherapy. When these treatments are no longer feasible, meningiomas are considered refractory irrespectively of grade, and in these rare entities, the therapeutic arsenal is reduced to the few treatments that have shown limited efficacy. Refractory, and particularly grades 2 and 3 meningiomas, have very poor prognoses with a progression-free survival at 6 months (PFS-6) of 26%. The European Response Assessment in Neuro-Oncology group (RANO) recommends that in any new, grades 2 and 3 meningioma, therapy that achieves a PFS-6 >30% in phase II trials be considered promising.
In Nuclear Medicine, Peptide Receptor Radionuclide Therapy (PRRT) with 177Lu-DOTATATE, currently used on a compassionate basis in refractory meningioma, deploys an octreotide-like effect, and appears very promising, with preliminary PFS-6 of 94% and an overall survival at 12 months (OS-12) of 88% in grade 1 meningioma. However, its PFS-6 is reduced to 28% with an OS-12 of 65% in WHO grades 2 and 3 meningioma. Recently the non-radiolabeled octreotide and everolimus combination however achieved a PFS-6 of 55% and an OS-12 of 75% in a population of 90% WHO grades 2 and 3 meningioma.
Our research hypothesis is that 177Lu-DOTATATE PRRT, a vector targeting somatostatin type 2 receptor (octreotide type) with a high-energy β-emitting radioactive label, when combined with everolimus, an mTOR protein inhibitor with radiosensitizing properties, will potentiate the effects of the non-radiolabeled octreotide + everolimus combination and increase PFS-6 in refractory grades 2 and 3 meningioma patients.
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 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Adult patient < 80 years old, who received a complete comprehensive briefing about the trial and signed the informed consent
- •Eligible patient for compassional access program (National Multidisciplinary Neuro-Oncology board to Lutathera ® traitement
- •WHO performance status ≤ 3
- •Patient with grade 2 and 3 meningioma, substantiated by histology, not amenable to surgery or radiotherapy, with clinical or radiological progression
- •Clinical deterioration or at least 10% of tumor growth rate, defined as the product of the two largest diameters of the target lesion within 6 months
- •Expressing somatostatin receptors as determined by 68Ga-DOTATOC PET (lesion uptake ≥ liver uptake and/or 1.7 fold SUVpeak of the controlateral meninges).
- •Patient that underwent a brain MRI and 68Ga-DOTATOC PET within the last 2 months.
- •Effective contraception required for women of childbearing age.
- •Patient with social security cover.
排除标准
- •Hypersensitivity to everolimus.
- •Contraindication to 177Lu-DOTATATE: renal failure GFR<40 mL/min/1.73m2 (calculated by the CKD-Epi Formula), hepatic failure total bilirubin >3N, heart failure NYHA III or IV.
- •Patients should not take the following treatments:
- •Other rapamycin derivatives (sirolimus, temsirolimus, deforolimus).
- •Other immunosuppressants
- •Co-administration with potent inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) : Ketoconazole , itraconazole, posaconazole, voriconazole, telithromycin, clarithromycin, Nefazodone, Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir.
- •If everolimus is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate.
- •Contraindication to MRI or 68Ga-DOTATOC PET/CT.
- •Person referred to and L. 3212-1 and L. 3213-1 (psychiatric care).
- •Women of childbearing age without effective contraception
- •Patient unable to attend follow-ups over a 12-month period.
- •Patients who participate in an interventional clinical research trial for the duration of the ELUMEN study.
- •Individuals referred to in Articles 10, 31, 32, 33 and 34 of Regulation (EU) No 536/
- •Pregnant woman, birthing or breastfeeding mother
- •Minor (not emancipated)
- •Adult subject to a legal protection measure (such as guardianship, conservatorship)
- •Adult who is unable to give consent
研究组 & 干预措施
Patient treat with everolimus
The product Everolimus is an oral drug.The dosage is 7.5 mg.
干预措施: Everolimus (Drug)
结局指标
主要结局
RANO criteria (Response assessment in neuro oncology criteria)
时间窗: 7 months
Progression Free Survival (PFS) from the start of treatment according to the RANO criteria (Response assessment in neuro oncology criteria)
次要结局
- Overall Survival(12 months)
- Tumor growth rate(6 months)
- Progression Free Survival(1 month)
- Number and types of grade 1, 2, 3 or 4 adverse events according to the CTCAE(180 days)
- Questionnaire(6 moniths)
研究者
Antoine VERGER
Principal Investigator
Central Hospital, Nancy, France