Sapanisertib Before and After Surgery in Treating Patients With Recurrent Glioblastoma

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.

Inclusion Criteria:

- 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

Exclusion Criteria:

- 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