A Phase II/III Randomized, Open-Label Study of Toca 511, A Retroviral Replicating Vector, Combined With Toca FC With Temozolomide and Radiation Followed by Adjuvant Temozolomide and Toca FC Compared to Temozolomide and Radiation Followed by Adjuvant Temozolomide in Patients With Newly Diagnosed Glioblastoma
试验速览
- 阶段
- 2 期
- 状态
- 撤回
- 发起方
- NRG Oncology
- 主要终点
- Progression free survival (PFS) (Phase II)
研究概览
简要总结
This phase II/III trial studies how well vocimagene amiretrorepvec (Toca 511) and extended release flucytosine (Toca FC) work when added to the usual treatment (temozolomide and radiation therapy) in treating patients with newly diagnosed glioblastoma. Toca 511 is a live virus that has been built to carry a gene into tumor cells. This gene carries instructions that cause the tumor cells to turn Toca FC, typically used to treat fungal infections, into a drug that may kill the tumor cells. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving Toca 511 and Toca FC in addition to the usual treatment (temozolomide and radiation therapy) may help shrink or stabilize cancer or extend the life of patients with newly diagnosed glioblastoma.
详细描述
PRIMARY OBJECTIVES:
I. To compare the progression-free survival (PFS) of patients with newly diagnosed glioblastoma treated with Toca 511 at the time of tumor resection followed by Toca FC in combination with standard of care (SOC) treatment to patients with newly diagnosed glioblastoma treated with SOC after tumor resection. (Phase II) II. To compare the overall survival (OS) from time of randomization of all patients with newly diagnosed glioblastoma treated with Toca 511 at the time of tumor resection followed by Toca FC in combination with SOC treatment to patients with newly diagnosed glioblastoma treated with SOC after tumor resection. (Phase III)
SECONDARY OBJECTIVES:
I. To evaluate the safety of each arm as administered in this study. II. To compare the OS between arms (only for phase II part of the study). III. To compare the PFS between arms using Response Assessment in Neuro-Oncology (RANO) (only for phase III part of the study).
IV. To evaluate the objective response rate (ORR) in patients with measurable disease at the post-surgical scan.
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
- •Presumptive diagnosis of glioblastoma based on magnetic resonance imaging (MRI) imaging within 14 days prior to registration.
- •NOTE: Patients who undergo treatment with Toca 511 whose final pathology shows diagnosis other than glioblastoma (e.g. anaplastic astrocytoma or oligodendroglioma or any other histology) will be treated with Toca FC and chemoradiation; however they will not be analyzed in the primary endpoint. The outcomes of these patients will be reported descriptively. Similarly the patients with anaplastic astrocytoma or oligodendroglioma or any other histology treated on the standard-of-care arm will be reported separately and they are allowed to receive the treatment per choice of the treating physician/ investigator (for e.g. radiation therapy [RT] plus temozolomide or RT plus procarbazine-lomustine-vincristine [PCV])
- •In addition, patients who have undergone biopsy with diagnosis of glioblastoma and who have never received any chemotherapy and/or radiation and are candidates for >= 80% resection of enhancing region are eligible
- •The tumor must be unifocal, confined to the supratentorial compartment and based on the pre-operative evaluation, the patient is a candidate for >= 80% resection of enhancing region
- •Measurable disease preoperatively, defined as at least 1 contrast enhancing lesion, with 2 perpendicular measurements of at least 1 cm, as per Response Assessment in Neuro-Oncology (RANO) criteria
- •The hematoxylin and eosin (H&E) slide and formalin-fixed paraffin-embedded (FFPE) tumor tissue block must be available to be sent for mandatory central pathology review after registration
- •Patients must be able to undergo an evaluation by MRI within 96 hours post surgery to assess extent of resection
- •Karnofsky performance status >= 70 within 14 days prior to registration
- •History/physical examination within 14 days prior to registration
- •Platelet count >= 100,000/mm^3 (within 14 days prior to registration)
- •Hemoglobin (Hgb) >= 10 g/dL (within 14 days prior to registration)
- •Absolute neutrophil count (ANC) >= 1,500/mm^3 (within 14 days prior to registration)
- •Absolute lymphocyte count (ALC) >= 1000/mm^3 (within 14 days prior to registration)
- •Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert?s syndrome) (within 14 days prior to registration)
- •Alanine aminotransferase (ALT) =< 2.5 x ULN (within 14 days prior to registration)
- •Estimated glomerular filtration rate of at least 50 mL/min by the Cockcroft Gault formula (within 14 days prior to registration)
- •Women of childbearing potential (women who have not had >=12 months of non therapy induced amenorrhea or are not surgically sterile) must have had a negative serum pregnancy test within 14 days prior to registration and must agree to use a birth control method in addition to barrier methods (condoms or diaphragm) during treatment with temozolomide
- •If the patient is randomized to arm 2, the patient or patient?s partner must be willing to use barrier method of contraception for 12 months after receiving Toca 511 and 1 month after stopping Toca FC or until there is no evidence of the virus in the patient?s blood, whichever is longer
- •The patient or a legally authorized representative must provide study-specific informed consent prior to registration
排除标准
- •History of prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years
- •A contrast enhancing brain tumor on MRI that is any of the following:
- •Multi focal (defined as 2 separate areas of contrast enhancement measuring at least 10 mm in 2 planes that are not contiguous on either fluid attenuated inversion recovery [FLAIR] or T2 hyperintensity);
- •Associated with either diffuse subependymal or leptomeningeal dissemination; or
- •> 50 mm in any dimension
- •Active infection (excluding skin or toenail infections) requiring systemic antibiotic, antifungal or antiviral therapy within 28 days prior to registration
- •Bleeding diathesis, or must take anticoagulants, or antiplatelet agents, including nonsteroidal anti inflammatory drugs (NSAIDs), at the time of the scheduled resection that cannot be stopped for surgery
- •Known human immunodeficiency virus (HIV) positive status
- •History of allergy or intolerance to flucytosine
- •Swallowing difficulty that would prevent patient from being able to swallow either temozolomide or Toca FC or severe active mal-absorption
- •Patients who are breast feeding or lactating
- •Intent to undergo treatment with the Gliadel wafer at the time of this surgery or has received the Gliadel
- •Prior to registration, steroid treatment beyond a maximum of 8 mg/day of dexamethasone (or equivalent) or a total of 8 weeks (56 days) is excluded
- •Severe pulmonary, cardiac or other systemic disease, specifically:
- •New York Heart Association > =Class II congestive heart failure within 6 months (180 days) prior to registration, unless asymptomatic and well controlled with medication
- •Uncontrolled or significant cardiovascular disease, clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes), clinically significant pulmonary disease (such as >= grade 2 dyspnea)
- •Any other disease that as per investigator assessment may affect the patient?s compliance or place the patient at higher risk of potential treatment complications
研究组 & 干预措施
Arm I (surgery, radiation therapy, temozolomide)
Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Arm I (surgery, radiation therapy, temozolomide)
Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Radiation Therapy (Radiation)
Arm I (surgery, radiation therapy, temozolomide)
Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: NovoTTF-100A Device (Device)
Arm I (surgery, radiation therapy, temozolomide)
Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Arm I (surgery, radiation therapy, temozolomide)
Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Quality-of-Life Assessment (Other)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Questionnaire Administration (Other)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Radiation Therapy (Radiation)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Vocimagene Amiretrorepvec (Biological)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Extended Release Flucytosine (Drug)
Arm I (surgery, radiation therapy, temozolomide)
Beginning on week 5 following standard of care surgery, patients undergo radiation therapy over 30 fractions 5 days per week for up to 6 weeks, and receive temozolomide PO QD for up to 49 days. At the discretion of treating physician, patients may also receive novoTTF-100A (Optune) device 0-7 weeks following radiation and temozolomide treatment. One month following completion of radiation therapy, patients continue to receive temozolomide PO QD on days 1-5. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
干预措施: Temozolomide (Drug)
Arm II (Toca 511, Toca FC, radiation therapy, temozolomide)
Patients receive vocimagene amiretrorepvec via intracranial injection during surgery on day 1. Beginning on week 5 following surgery, patients receive extended release flucytosine PO TID for 7 consecutive days every 7 weeks. Patients also undergo radiation therapy and receive temozolomide as in arm I. After completion of radiation therapy and at the discretion of the treating physician, patients may continue to receive extended release flucytosine PO TID for 7 consecutive days every 8 weeks in the absence of disease progression or unacceptable toxicity.
干预措施: Temozolomide (Drug)
结局指标
主要结局
Progression free survival (PFS) (Phase II)
时间窗: Time from randomization to the first documented progressive disease (PD) as determined by central review, or death due to any cause, whichever occurs first, assessed for up to 5 years
Analysis of treatment comparison between the experimental and standard-of-care arms will be performed once the required number of centrally-reviewed PFS events is reached . The Kaplan-Meier method will be used to calculate the PFS rates for each of the two arms. Hazard ratio (HR) on the treatment effect will be calculated using the stratified Cox proportional hazard model. A one-sided stratified log-rank test will be used to test the difference in PFS between the two arms.
Overall survival (OS) (Phase III)
时间窗: The time from randomization to death due to any cause, assessed up to 5 years
Analysis of the treatment comparison between the experimental and standard of care arms will be performed once the required number of deaths is reached. The Kaplan-Meier method will be used to calculate the OS rates for each of the two arms. The primary endpoint will be assessed using a one-sided stratified log-rank test, incorporating only stratification factors, to test the difference in OS between the two arms. Hazard ratio (HR) on the treatment effect will be calculated using the stratified Cox proportional hazard model adjusting for stratification factors. In addition to assessing the effect of treatment arm, IDH mutation status, MGMT status, the interaction between MGMT status and treatment arm, extent of resection, and use of Optune (in only the standard-of-care arm) will be assessed using a log-rank test and Cox proportional hazards models.
次要结局
- Incidence of grade 3 or higher adverse events(Until death, assessed up to 5 years)
- Overall survival (OS) (Phase II)(The time from randomization to death due to any cause, assessed up to 5 years)
- Progression free survival (PFS) (Phase III)(Time from randomization to the first documented PD as determined by central review, or death due to any cause, whichever occurs first, assessed for up to 5 years)
- Objective response rate (ORR)(Up to 18 months)