TORC1/2 Inhibitor INK128 Before and After Surgery in Treating Patients With Recurrent Glioblastoma
Conditions
Adult Giant Cell Glioblastoma - Adult Glioblastoma - Adult Gliosarcoma - Recurrent Adult Brain Neoplasm
Conditions: official terms
Brain Neoplasms - Glioblastoma - Gliosarcoma
Study Type
Interventional
Study Phase
N/A
Study Design
Allocation: Randomized, Endpoint Classification: Bio-availability Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Intervention
Name: Laboratory Biomarker Analysis Type: Other
Name: Pharmacological Study Type: Other
Name: Therapeutic Conventional Surgery Type: Procedure
Name: TORC1/2 Inhibitor INK128 Type: Drug
Overall Status
Recruiting
Summary
This partially randomized pilot trial studies how much TORC1/2 inhibitor INK128 reaches the brain tumor and how well it works when given before and after surgery in treating patients with glioblastoma that has grown or recurred and requires surgery. TORC1/2 inhibitor INK128 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.
Detailed Description
PRIMARY OBJECTIVES:

I. To evaluate the penetration of MLN0128 (TORC1/2 inhibitor INK128) 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 to inhibit TOR complex (TORC)1/2 in the enhancing components of the tumor as determined by modulation of ribosomal protein S6 (RPS6) phosphorylated Ser-235 (pS235) in reverse phase protein array (RPPA) assays. (Part II)

SECONDARY OBJECTIVES:

I. To evaluate the penetration of MLN0128 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 in patients with recurrent GBM. (Part I) III. To determine the ability of MLN0128 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 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 v-akt murine thymoma viral oncogene homolog 1 (AKT)pSer473. (Phase II) V. To evaluate the safety profile of MLN0128 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 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. (Part II) III. To explore the potential association of tumor genotype with progression-free survival among patients treated with MLN0128. (Part II) IV. To determine the ability of MLN0128 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 TORC1/2 inhibitor INK128 orally (PO) once daily (QD) for 7-9 days (including 2-4 hours before surgery). On day 0, patients undergo surgery. Within 30 days after surgery, patients receive TORC1/2 inhibitor INK128 PO QD. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. If patients do not demonstrate adequate TORC1/2 inhibitor INK128 tumor tissue concentrations, patients are enrolled in Cohort II.

COHORT B: Patients receive TORC1/2 inhibitor INK128 PO 2-4 hours before surgery on day 0. Within 30 days after surgery, patients receive TORC1/2 inhibitor INK128 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 TORC1/2 inhibitor INK128 PO according to the results from Part I. Patients also undergo surgery on day 0. Within 30 days after surgery, patients receive TORC1/2 inhibitor INK128 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 TORC1/2 inhibitor INK128 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 every 2 months for 2 years and then every 6 months thereafter.
Criteria for eligibility
Healthy Volunteers: No
Maximum Age: N/A
Minimum Age: 18 Years
Gender: Both
Criteria: 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 (e.g., erlotinib, hydroxychloroquine, etc.)

- 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)

- 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/1.73m^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 use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and through 30 days 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 adequate contraception prior to the study, for the duration of study participation, and through 30 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

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 are ineligible

- Patients may not have had prior treatment with mTOR, peptidase inhibitor 3, skin-derived (PI3) kinase or Akt inhibitors

- Patients may not have had prior treatment with bevacizumab/vascular endothelial growth factor receptor (VEGFR) 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

- 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 are ineligible; concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to the first administration of MLN0128

- For weekly MLN0128 dose cohorts, patients taking proton pump inhibitors (PPIs) are ineligible unless these patients are able to switch to an H2 blocker and/or antacid; concurrent PPI use is allowed for patients enrolled on the daily MLN0128 dose cohorts

- 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 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 MLN0128

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

- Subjects taking strong cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) and cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) inhibitors and/or inducers should be considered with caution; alternative treatments that are less likely to affect MLN0128 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
Locations
University of Alabama at Birmingham Cancer Center
Birmingham, Alabama, United States
Status: Recruiting
Contact: Louis B. Nabors - 205-934-0309
UCLA / Jonsson Comprehensive Cancer Center
Los Angeles, California, United States
Status: Recruiting
Contact: Phioanh (. Nghiemphu - 310-825-5321 - PNghiemphu@mednet.ucla.edu
Johns Hopkins University/Sidney Kimmel Cancer Center
Baltimore, Maryland, United States
Status: Recruiting
Contact: Stuart A. Grossman - 410-955-8804 - jhcccro@jhmi.edu
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
Status: Recruiting
Contact: Eudocia Q. Lee - 877-442-3324
Henry Ford Hospital
Detroit, Michigan, United States
Status: Active, not recruiting
Wake Forest University Health Sciences
Winston-Salem, North Carolina, United States
Status: Recruiting
Contact: Glenn J. Lesser - 336-713-6771
Cleveland Clinic Foundation
Cleveland, Ohio, United States
Status: Recruiting
Contact: David M. Peereboom - 866-223-8100
University of Pittsburgh Cancer Institute (UPCI)
Pittsburgh, Pennsylvania, United States
Status: Recruiting
Contact: Frank S. Lieberman - 412-647-8073
Start Date
May 2014
Sponsors
National Cancer Institute (NCI)
Source
National Cancer Institute (NCI)
Record processing date
ClinicalTrials.gov processed this data on July 28, 2015
ClinicalTrials.gov page