Pilot Study of MLN0128 (TAK-228) in Preoperative Recurrent Glioblastoma (GBM) Patients
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 40
- 试验地点
- 10
- 主要终点
- Proportion of patients who achieve a drug concentration >= 70 nM in contrast enhancing tumor tissue
研究概览
简要总结
This partially randomized pilot phase I trial studies how much sapanisertib reaches the brain tumor and how well it works when given before and after surgery in treating patients with glioblastoma that has grown or come back and requires surgery. Sapanisertib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
详细描述
PRIMARY OBJECTIVES:
I. To evaluate the penetration of sapanisertib (MLN0128 [TAK-228]) across the blood brain barrier and achieve a concentration of 70 nM in tissue resected from a contrast enhancing region of the tumor in 60% of recurrent glioblastoma (GBM) patients. (Part I) II. To determine the ability of MLN0128 (TAK-228) to inhibit TOR complex (TORC)1/2 in the enhancing components of the tumor as determined by modulation of RPS6 phosphorylated Ser-235 (pS235) in reverse phase protein array (RPPA) assays. (Part II)
SECONDARY OBJECTIVES:
I. To evaluate the penetration of MLN0128 (TAK-228) across the blood brain barrier by determining its concentration in tissue resected from a non-contrast enhancing region of the tumor. (Part I) II. To assess the plasma pharmacokinetics of MLN0128 (TAK-228) in patients with recurrent GBM. (Part I) III. To determine the ability of MLN0128 (TAK-228) to inhibit TORC1/2 in the non-enhancing components of the tumor as determined by modulation of RPS6 pS235 in RPPA assays. (Part II) IV. To assess the ability of MLN0128 (TAK-228) to inhibit TORC1/2 by evaluating pharmacodynamics (PD) markers by immunohistochemistry such as pS235, pS236, phosphorylated 4E-binding protein (p4EBP), phosphorylated-mechanistic target of rapamycin (serine/threonine kinase) (pmTOR), and AKTpSer473. (Phase II) V. To evaluate the safety profile of MLN0128 (TAK-228) in pre-operative patients with recurrent GBM.
VI. To estimate response rate, progression-free survival, and overall survival.
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
- •Patients must have histologically proven glioblastoma or gliosarcoma which is progressive or recurrent following radiation therapy +/- chemotherapy
- •Patients must have measurable, supratentorial contrast-enhancing progressive or recurrent glioblastoma or gliosarcoma by magnetic resonance imaging (MRI) imaging within 21 days of starting treatment; patient must be able to tolerate MRIs
- •Patients may have had treatment for no more than 2 prior relapses
- •Patients must have recovered from severe toxicity of prior therapy; the following intervals from previous treatments are required to be eligible:
- •12 weeks from the completion of radiation
- •6 weeks from a nitrosourea chemotherapy or mitomycin C
- •3 weeks from a non-nitrosourea chemotherapy
- •4 weeks from any investigational (not Food and Drug Administration [FDA]-approved) agents
- •2 weeks from administration of a non-cytotoxic, FDA-approved agent except bevacizumab/vascular endothelial growth factor receptor (VEGFR) inhibitors (e.g., erlotinib, hydroxychloroquine, etc.)
- •6 weeks from bevacizumab/VEGFR inhibitors
- •Patients must be undergoing surgery that is clinically indicated as determined by their care providers
- •Patients must be eligible for surgical resection according to the following criteria:
- •Part 1 Patients: Expectation that the surgeon is able to resect at least 350 mg of tumor from enhancing tumor and at least 350 mg from non-enhancing tumor with low risk of inducing neurological injury
- •Part 2 Patients: Expectation that the surgeon is able to resect at least 1000 mg from enhancing tumor and at least 350 mg from non-enhancing tumor with low risk of inducing neurological injury
- •Patients must have a Karnofsky performance status >= 60% (i.e. the patient must be able to care for himself/herself with occasional help from others)
- •Absolute neutrophil count >= 1,500/mcL
- •Platelets >= 100,000/mcL
- •Hemoglobin >= 9 g/dL
- •Total bilirubin =< 1.5 x upper limit of normal (ULN)
- •Fasting serum glucose =< 130 MG/DL
- •HbA1c =< 7.0%
- •Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 × institutional upper limit of normal
- •Creatinine =< institutional upper limit of normal OR
- •Creatinine clearance >= 50 ml/min/1.73 m^2 for patients with creatinine levels above institutional normal
- •Activated partial thromboplastin time (APTT)/partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal
- •Patients must be able to provide written informed consent
- •Women of childbearing potential must have a negative serum pregnancy test prior to study entry; women of childbearing potential and men must agree to practice 1 highly effective method of contraception and 1 additional effective (barrier) method, at the same time, prior to study entry, for the duration of study participation, and through 90 days (or longer, as mandated by local labeling [e.g. USPI, SmPC, etc.]) after the last dose of study drug; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use highly effective barrier contraception prior to the study, for the duration of study participation, and through 120 days after the last dose of study drug
- •Patients must have no concurrent malignancy except curatively treated basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix, breast, or bladder; patients with prior malignancies must be disease-free for >= five years
- •Patients must be able to swallow whole capsules
- •Patients enrolled in Part 2 must have at least 20 (preferably 40) slides of archival tumor tissue from a prior surgery demonstrating GBM; patients enrolled in Part 1 will not be required to have archival tissue
- •Patients with controlled diabetes are allowed on study; controlled diabetes is defined as < 130 ml/dL for the sake of this study
排除标准
- •Patients receiving any other investigational agents are ineligible
- •Patients with a history of allergic reactions attributed to compounds of similar chemical or biologic composition to MLN0128 (TAK-228) are ineligible
- •Patients may not have had prior treatment with mTOR, peptidase inhibitor 3, skin-derived (PI3) kinase or Akt inhibitors
- •Patients on enzyme-inducing anti-epileptic drugs (EIAED) are not eligible for treatment on this protocol; patients may be on non-enzyme inducing anti-epileptic drugs or not be taking any anti-epileptic drugs; patients previously treated with EIAED may be enrolled if they have been off the EIAED for 10 days or more prior to the first dose of MLN0128 (TAK-228)
- •Patients must not have evidence of significant hematologic, renal, or hepatic dysfunction
- •Patients must not have evidence of significant intracranial hemorrhage
- •Patients with a history of any of the following within the last 6 months prior to study entry are ineligible:
- •Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures
- •Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures
- •Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia)
- •Placement of a pacemaker for control of rhythm
- •New York Heart Association (NYHA) class III or IV heart failure
- •Pulmonary embolism
- •Patients with known significant active cardiovascular or pulmonary disease at the time of study entry are ineligible
- •Patients with baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes) are ineligible
- •Patients with known diabetes mellitus which is poorly controlled (defined as hemoglobin A1c [HbA1c] > 7%) are ineligible; subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion have been met
- •Patients who have initiated treatment with bisphosphonates less than 30 days prior to the first administration of MLN0128 (TAK-228) are ineligible; concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to the first administration of MLN0128 (TAK-228)
- •For weekly MLN0128 (TAK-228) dose cohorts, patients taking proton pump inhibitors (PPIs) are ineligible unless these patients are able to switch to a histamine (H2) blocker and/or antacid
- •Patients with known manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128 (TAK-228) are ineligible
- •Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, are ineligible
- •Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with this agent
- •Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
- •Subjects taking strong CYP3A4 and CYP2C19 inhibitors and/or inducers should be considered with caution; alternative treatments that are less likely to affect MLN0128 (TAK-228) metabolism, if available, should be considered; if a subject requires treatment with 1 or more of the strong CYP3A4 and CYP2C19 inhibitors and/or inducers, the study doctor should be consulted
研究组 & 干预措施
Arm I (sapanisertib before and after surgery)
Patients receive sapanisertib PO according to the results from Part I. Patients also undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm I (sapanisertib before and after surgery)
Patients receive sapanisertib PO according to the results from Part I. Patients also undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm I (sapanisertib before and after surgery)
Patients receive sapanisertib PO according to the results from Part I. Patients also undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Sapanisertib (Drug)
Arm I (sapanisertib before and after surgery)
Patients receive sapanisertib PO according to the results from Part I. Patients also undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
Arm II (sapanisertib after surgery)
Patients undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Laboratory Biomarker Analysis (Other)
Arm II (sapanisertib after surgery)
Patients undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Pharmacological Study (Other)
Arm II (sapanisertib after surgery)
Patients undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Sapanisertib (Drug)
Arm II (sapanisertib after surgery)
Patients undergo surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO according to the results from Part I. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
干预措施: Therapeutic Conventional Surgery (Procedure)
结局指标
主要结局
Proportion of patients who achieve a drug concentration >= 70 nM in contrast enhancing tumor tissue
时间窗: Up to 2 years
The proportion of patients who achieve a drug concentration \>= 70 nM in contrast enhancing tumor tissue will be calculated and the 90% confidence interval will be estimated using binomial distribution.
Difference in ratio of the S6 phosphorylation over the total between the two groups
时间窗: Up to 2 years
Two sample t-test will be used for the hypothesis testing of a difference in ratio of the S6 phosphorylation over the total between the two groups.
Difference of the pS6 concentration between the two groups
时间窗: Up to 2 years
Two sample t-test will be used for the hypothesis testing of a difference in ratio of the S6 phosphorylation over the total between the two groups. A "heat map" or "heat map visualization" may also be used to present and examine possible difference in clustering signaling pathway activation between the groups.
次要结局
- Sapanisertib concentration in blood(Up to 2 years)
- Sapanisertib concentration in non-enhancing tumor(Up to 2 years)
- Inhibition TORC1/2 in the non-enhancing components of the tumor as determined by modulation of RPS6 pS235 in reverse phase protein array (RPPA) assays(Up to 2 years)
- Pharmacodynamic marker such as pS6 (by immunohistochemistry), p4EBP, pmTOR, and AKTpSer473 compared to the control(Up to 2 years)
- Progression-free survival (PFS)(Time from date of post-surgical treatment start to the date progressive disease was defined, assessed up to 2 years)
- Incidence of toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0(Up to 30 days)
- Tumor response(Up to 2 years)
- Overall survival (death)(Time from the date of post-surgical treatment start to the date death occurred, assessed up to 2 years)