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.
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. TERTIARY OBJECTIVES: I. To perform mass spectrometry imaging (MSI) to qualitatively assess the ability of MLN0128 (TAK-228) to penetrate the blood brain barrier and enter tumor tissue in enhancing and non-enhancing regions of the tumor. (Part I) II. To determine ex-vivo sensitivity of tumor neurosphere cultures (patient derived cell lines \[PDCL\]) established from surgical specimens to MLN0128 (TAK-228). (Part II) III. To explore the potential association of tumor genotype with progression-free survival among patients treated with MLN0128 (TAK-228). (Part II) IV. To determine the ability of MLN0128 (TAK-228) to inhibit TORC1/2 as determined by modulation of additional TORC1/2 markers in RPPA assays. (Part II) OUTLINE: PART I: COHORT A: Patients receive sapanisertib orally (PO) once daily (QD) for 7-9 days (including 2-4 hours before surgery). On day 0, patients undergo surgery. Within 45 days after surgery, patients receive sapanisertib PO QD. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If patients do not demonstrate adequate sapanisertib tumor tissue concentrations, patients are enrolled in Cohort B. COHORT B: Patients receive sapanisertib PO 2-4 hours before surgery on day 0. Within 45 days after surgery, patients receive sapanisertib PO once weekly. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PART II: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive sapanisertib PO according to the results from Part I. Patients also undergo surgery on day 0. Within 30 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. ARM II: Patients undergo surgery on day 0. Within 30 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. After completion of study treatment, patients are followed up at 30 days, every 2 months for 2 years, and then every 6 months thereafter.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
UCSF Medical Center-Parnassus
San Francisco, California, United States
Proportion of patients who achieve a drug concentration >= 70 nM in contrast enhancing tumor tissue
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.
Time frame: Up to 2 years
Difference in ratio of the S6 phosphorylation over the total between the two groups
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.
Time frame: Up to 2 years
Difference of the pS6 concentration between the two groups
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.
Time frame: Up to 2 years
Sapanisertib concentration in non-enhancing tumor
Will be summarized using descriptive statistics or two-group comparison between groups. The Spearman correlation coefficient might be used to assess potential correlations between pathway modulation scores and tumor growth measured by KI67 (proliferation) and cleaved caspase 3 (apoptosis/cell death).
Time frame: Up to 2 years
Sapanisertib concentration in blood
Will be summarized using descriptive statistics or two-group comparison between Groups A and B. The Spearman correlation coefficient might be used to assess potential correlations between pathway modulation scores and tumor growth measured by KI67 (proliferation) and cleaved caspase 3 (apoptosis/cell death).
Time frame: Up to 2 years
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Undergo surgery
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Henry Ford Hospital
Detroit, Michigan, United States
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
Case Western Reserve University
Cleveland, Ohio, United States
Cleveland Clinic Foundation
Cleveland, Ohio, United States
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
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
Will be summarized using descriptive statistics or two-group comparison between Groups A and B. The Spearman correlation coefficient might be used to assess potential correlations between pathway modulation scores and tumor growth measured by KI67 (proliferation) and cleaved caspase 3 (apoptosis/cell death).
Time frame: Up to 2 years
Pharmacodynamic marker such as pS6 (by immunohistochemistry), p4EBP, pmTOR, and AKTpSer473 compared to the control
Will be summarized using descriptive statistics or two-group comparison between Groups A and B. The Spearman correlation coefficient might be used to assess potential correlations between pathway modulation scores and tumor growth measured by KI67 (proliferation) and cleaved caspase 3 (apoptosis/cell death).
Time frame: Up to 2 years
Incidence of toxicity graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0
All treatment or surgically related adverse events will be reported descriptively. A proportion of toxicity grade \>= 3 will be estimated using binomial distribution.
Time frame: Up to 30 days
Tumor response
The proportion of patients who had tumor response (partial response + complete response) during the course of treatment will be estimated using the exact binomial distribution.
Time frame: Up to 2 years
Progression-free survival (PFS)
PFS along with 95% confidence interval will be estimated using Kaplan-Meier method.
Time frame: Time from date of post-surgical treatment start to the date progressive disease was defined, assessed up to 2 years
Overall survival (death)
Overall survival along with 95% confidence interval will be estimated using Kaplan-Meier method.
Time frame: Time from the date of post-surgical treatment start to the date death occurred, assessed up to 2 years