Randomized Phase 2 Clinical Trial of Repeated Intratumoral and Cervical Perilymphatic Lerapolturev Injections Versus Lomustine in Recurrent Glioblastoma (GBM)
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 发起方
- 入组人数
- 92
- 试验地点
- 1
- 主要终点
- Proportion of patients at each dose level who experienced a dose-limiting toxicity - Stage 1
研究概览
简要总结
The purpose of this research study is to determine the safety and efficacy of administering two doses of lerapolturev in residual disease (within tumor margins) after surgery, followed later by repeated injections of lerapolturev in the subcutaneous area (under the skin) around the lymph nodes of the head and neck for adult patients diagnosed with recurrent glioblastoma at the Preston Robert Tisch Brain Tumor Center (PRTBTC) at Duke.
详细描述
The study will be conducted in two stages: Approximately twelve patients with recurrent supratentorial glioblastoma will enroll in stage 1.
Stage 1 is a safety lead-in which will assess the safety of lerapolturev when infused twice, 4 days apart, via Convection Enhanced Delivery (CED) in the residual disease of recurrent Glioblastoma (GBM) patients following maximal safe resection of the enhancing/necrotic portion of the disease recurrence.
A tissue biopsy of the area infused will be recommended 5 weeks (± 1 week) after the 2nd lerapolturev infusion via CED, if imaging changes suggest tumor progression vs. immune effect on the MRI obtained 4-5 weeks after the 2nd lerapolturev infusion via CED.
Stage 2 is a Phase 2 randomized clinical trial to compare the efficacy and safety of two treatment regimens for recurrent GBM patients who undergo maximal safe resection for their recurrence. Approximately eighty patients with recurrent supratentorial glioblastoma will enroll in stage 2 of the study.
Stage 2 has 2 arms and is randomized, like the flip of a coin. Arm 1 is Lerapolturev and Arm 2 is Lomustine. After the recurrent tumor has been removed by surgery, subjects will be randomly assigned to receive either the FDA-approved chemotherapy (lomustine) or the study drug (lerapolturev). Subjects receive lerapolturev infused in the residual disease via CED twice, 4-day apart. About 1 week after the 2nd lerapolturev infusion, subjects will start subcutaneous (under the skin) injections of lerapolturev into the area of the cervical lymph nodes (head and neck) nearest to their tumor weekly for 4 weeks and afterward every 3 weeks for about a year.
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 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age ≥ 18 years old at the time of entry into the study.
- •Histopathologically confirmed recurrent supratentorial glioblastoma (WHO grade 4) (high grade glioma with molecular features of glioblastoma will be eligible).
- •Karnofsky Performance Score (KPS) ≥ 70%
- •Hemoglobin ≥ 9 g/dl prior to biopsy
- •Platelet count ≥ 100,000/µl unsupported is necessary for eligibility on the study; however, because of risks of intracranial hemorrhage with catheter placement, platelet count ≥ 125,000/µl is required for the patient to undergo biopsy and catheter insertion, which can be attained with the help of platelet transfusion.
- •Neutrophil count ≥ 1000 prior to biopsy
- •Creatinine ≤ 1.5 x normal range prior to biopsy
- •Total bilirubin ≤ 1.5 x ULN prior to biopsy (Exception: Participant has known or suspected Gilbert's Syndrome for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.)
- •AST/ALT ≤ 2.5 x ULN
- •Prothrombin and Partial Thromboplastin Times ≤ 1.2 x normal prior to biopsy. Patients with prior history of thrombosis/embolism are allowed to be on anticoagulation, understanding that anticoagulation will be held in the perioperative period per the neurosurgical team's recommendations. Low molecular weight heparin (LMWH) is preferred. If a patient is on warfarin, the international normalized ratio (INR) is to be obtained and value should be below 2.0 prior to biopsy.
- •At the time of biopsy, prior to administration of the 1st infusion of lerapolturev via CED, the presence of recurrent tumor must be confirmed by histopathological analysis.
- •Able to undergo brain MRI with and without contrast
- •Prior CDC-recommended vaccination series against PV and has received a boost immunization with trivalent Poliovirus Vaccine Inactivated (IPOL®) (Sanofi-Pasteur SA) at least 1 week, but less than 6 weeks, prior to administration of lerapolturev. Note: Patients who are unsure of their prior vaccination status must provide evidence of anti-PV immunity prior to enrollment, as applicable.
- •Patient or partner(s) meets one of the following criteria:
- •Non-childbearing potential (i.e., not sexually active, physiologically incapable of becoming pregnant, including any female who is post-menopausal or surgically sterile, or any male who has had a vasectomy). Surgically sterile females are defined as those with a documented hysterectomy and/or bilateral oophorectomy or tubal ligation. Postmenopausal for purposes of this study is defined as 1 year without menses.; or
- •Childbearing potential and agrees to use one of the following methods of birth control: approved hormonal contraceptives (e.g. birth control pills, patches, implants, or infusions), an intrauterine device, or a barrier method of contraception (e.g., a condom or diaphragm) used with spermicide.
- •A signed informed consent form approved by the Institutional Review Board (IRB) will be required for patient enrollment into the study. Patients must be able to read and understand the informed consent document and must sign the informed consent indicating that they are aware of the investigational nature of this study
排除标准
- •Females who are pregnant or breast-feeding
- •Patients with an impending, life-threatening cerebral herniation syndrome, based on the assessment of the study neurosurgeons or their designate
- •Patients with severe, active co-morbidity, defined as follow:
- •Patients with an active infection requiring intravenous treatment or having an unexplained febrile illness (Tmax > 99.5°F/37.5°C)
- •Patients with known immunosuppressive disease or known human immunodeficiency virus infection
- •Patients with unstable or severe intercurrent medical conditions such as severe heart disease (New York Heart Association Class 3 or 4)
- •Patients with known lung (forced expiratory volume in the first second of expiration (FEV1) < 50%) disease or uncontrolled diabetes mellitus
- •Known albumin allergy
- •History of agammaglobulinemia
- •Patients may not have received chemotherapy or bevacizumab ≤ 4 weeks [except for nitrosourea (6 weeks), or metronomic dosed chemotherapy such as daily etoposide or cyclophosphamide (1 week)] prior to starting the study drug unless patients have recovered from side effects of such therapy
- •Patients may not have received immunotherapy ≤ 4 weeks prior to starting the study drug unless patients have recovered from side effects of such therapy
- •Patients may not have received treatment with tumor treating fields (e.g., Optune®) ≤ 1 week prior to starting the study drug
- •Patients may not be less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation
- •Patients who have not completed all standard of care treatments, including surgical procedure and radiation therapy (Please note: For patients under 65 years old, standard radiation therapy is typically at least 59 Gy in 30 fractions over 6 weeks. For patients 65 years or older, standard RT is often reduced to a minimum 40 Gy in 15 fractions over 3 weeks.)
- •If the MGMT promoter in their tumor is known to be unmethylated, patients are not mandated to have received chemotherapy prior to participating in this trial
- •If the MGMT promoter in their tumor is known to be methylated or the MGMT promoter methylation status is unknown at time of screening, patients must have received at least one chemotherapy regimen prior to participating in this trial
- •Patients with neoplastic lesions in the brainstem, cerebellum, or spinal cord; radiological evidence of active (growing) disease (active multifocal disease); extensive subependymal disease (tumor touching subependymal space is allowed); tumor crossing the midline or leptomeningeal disease
- •Patients on greater than 4 mg per day of dexamethasone within the 2 weeks prior to the 1st lerapolturev infusion via CED
- •Patients with worsening steroid myopathy (history of gradual progression of bilateral proximal muscle weakness, and atrophy of proximal muscle groups)
- •Patients with prior, unrelated malignancy requiring current active treatment with the exception of cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
- •Patients with active autoimmune disease requiring systemic immunomodulatory treatment within the past 3 months
- •Patients with known history of hypersensitivity to lomustine, dacarbazine, or any components of lomustine
研究组 & 干预措施
Lerapolturev Arm (Stage 2 - Arm 1)
Lerapolturev (intratumoral) will be given by Convection Enhanced Delivery (CED), infused twice, 4 days apart, in the remaining disease of recurrent Glioblastoma (rGBM) subjects following maximal safe resection of their disease recurrence. This will be followed by subcutaneous injections of lerapolturev in the cervical perilymphatic (CPL) area on the same side as their tumor, weekly for 4 weeks and afterward every 3 weeks for about a year.
干预措施: Lerapolturev (Drug)
Lomustone (Stage 2 Arm 2)
Following maximal safe resection of their tumor recurrence subjects will receive Lomustine as a single oral dose of 110 mg/m2 every six weeks for up to 9 cycles.
干预措施: Lomustine Pill (Drug)
Lerapolturev Arm (Stage 1)
Lerapolturev (intratumoral) will be dosed by Convection Enhanced Delivery (CED), infused twice, 4 days apart, in the remaining disease of recurrent Glioblastoma (rGBM) subjects following maximal safe resection of the disease recurrence.
To assess treatment response and/or immunologic responses in the brain, a tissue biopsy of the area infused will be recommended 5 weeks (± 1 week) after the 2nd lerapolturev infusion via CED, in the event that changes suggestive of tumor progression are seen on the MRI obtained 4-5 weeks after the 2nd lerapolturev infusion via CED.
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干预措施: Lerapolturev (Drug)
结局指标
主要结局
Proportion of patients at each dose level who experienced a dose-limiting toxicity - Stage 1
时间窗: Up to 1 year
Dose-limiting toxicities (DLTs) are defined as any of the following events that are possibly, probably, or definitely attributable to study treatment (i.e., lerapolturev) during dose escalation (Stage 1): * Any Grade 3 or any Grade 4 toxicity within 2 weeks, including cerebral edema or worsening neurologic symptoms * Any life-threatening event within 2 weeks * Treatment-related death at least possibly, probably, or definitely attributable to study treatment * Any grade 2 or higher serious cytokine release syndrome at least possibly, probably, or definitely attributable to study treatment, particularly those affecting vital organs (e.g., cardiac, hepatic, renal, CNS) occurring within 2 weeks of the infusion
Proportion of patients who experience an unacceptable toxicity - Stage 2
时间窗: Up to 1 year
Unacceptable toxicity is defined as any of the following events that are possibly, probably, or definitely attributable to study treatment: * Any Grade 3 or any Grade 4 toxicity within 2 weeks, including cerebral edema or worsening neurologic symptoms * Any life-threatening event within 2 weeks * Treatment-related death at least possibly, probably, or definitely attributable to study treatment * Any grade 2 or higher serious cytokine release syndrome at least possibly, probably, or definitely attributable to study treatment, particularly those affecting vital organs (e.g., cardiac, hepatic, renal, CNS) occurring within 2 weeks of the infusion
Overall survival (OS) - Stage 2
时间窗: 2 years
Median OS, where OS is defined as the time between randomization and death
次要结局
- Progression free survival (PFS)(2 years)
研究者
Darell Bigner
Professor of Neurosurgery
Duke University