Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

Phase 2

Completed

Conditions: Oligodendrogliomas
Astrocytoma, Grades II, III and IV
Glioblastoma Multiforme
Giant Cell Glioblastoma
Glioma

Interventions: Drug: LB-100

Registration Number: NCT03027388

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: Background:

The brain is separated from the rest of the blood stream by the blood-brain barrier. This is like a filter that protects the brain. But is also a challenge when medicines need to get into the brain. Researchers want to give the new drug LB100 to people before brain tumor surgery. They will measure how much LB100 is in the blood and how much gets into the brain. This may help with the use of LB100 to treat brain tumors in the future.

Objective:

To see if LB100 can pass into the brain.

Eligibility:

People at least 18 years old with a brain tumor that requires surgery.

Design:

Participants will be screened with:

Physical exam

Medical history

Blood tests

Neurosurgery evaluation

Scans

Heart tests

Tumor sample. This can be from a previous procedure.

Participants will have their brain surgery at the Clinical Center.

Participants will get a dose of the study drug through a plastic tube in a vein for 2 hours during surgery.

Participants will have blood taken 7 times in the 8 hours after getting the study drug.

Tumor samples will be taken during surgery.

Participants will have a heart test after getting the study drug. Sticky pads on the skin will measure electrical activity of the heart.

Two-three weeks after leaving the hospital, participants will have a follow-up visit. They will have a physical exam and blood tests.

One month after surgery, they will be contacted in person or by phone to see how they are doing.

Detailed Description: Background:

* Primary gliomas are an incurable disease in spite of aggressive multimodality therapy consisting of craniotomy, irradiation, and chemotherapy. Therapeutic options for patients with recurrent glioma are limited, and there is an unmet need to identify more effective agents.

* LB100, a water-soluble small molecule novel protein phosphatase 2A (PP2A) inhibitor, was commercially developed through a Cooperative Research and Development Agreement (CRADA) based on our previous intramural research. This compound has shown to be effective in a variety of cancer types in both in vitro and in vivo models. Preclinical studies indicate LB100 has in vitro and in vivo activity as a single agent as well as potentiating the effect of cytotoxic agents including temozolomide, docetaxel, doxorubicin, and ionizing radiation. LB100 is active in combination with temozolomide or doxorubicin against xenografts of glioblastoma, neuroblastoma, pheochromocytoma, breast cancer, fibrosarcoma, and melanoma.

* A complete phase I study of LB100 has established its safety and the recommended phase II dose (2.33 mg/m\^2, daily for three days every 3 weeks).

* Although it is a polar compound, rodent studies suggest LB100 has activity in the brain.

* Whether LB100 can across the human blood brain barrier (BBB), and at what concentration relative to the plasma level is not known. Characterizing these parameters is important because:

* 1) Our ongoing in vitro studies indicate that LB100 has distinct mechanisms of action at different drug concentrations (e.g., nM versus uM);

* 2) There are other brain tumors lacking effective medical therapies but without a BBB. Characterizing the LB100 BBB penetration profile will assist in defining its optimal clinical indication.

Objective:

-To determine the pharmacokinetic (PK) properties of LB100 in glioma tumor tissues.

Eligibility:

* Patients with histologically proven glioblastoma and grades II-III astrocytomas and oligodendrogliomas.

* A clear clinical indication for another surgical resection must be present.

* Subjects must be greater than or equal to 18 years old.

* Karnofsky performance status of greater than or equal to 60%.

* Patients must have adequate organ function.

Design:

* This is a two stage Phase II, open label, single institution study to determine the PK and pharmacodynamic (PD) profile of LB100.

* The dose (established from a Phase I study) will be 2.33 mg/m\^2 delivered intravenously over 2 hours.

* PK and PD effect of LB100 treated tissues will only be evaluated with pathologic confirmation of recurrent tumor. Resected material demonstrating chemoradiation treatment effect or inflammatory response will not be included in the analysis.

* PK will be determined by quantitating LB100 in tumor tissues removed at various time points.

* The primary endpoint is PK response, defined as a binary variable indicating the presence/absence of LB100 in tumor tissues.

* PD effect is defined as statistically significant elevation of phospho-proteins in treated tumor tissues compared to untreated glioma specimens. Untreated inter-patient baseline variance and standard deviation (SD) will be calculated. Post-treatment PD effect difference greater than 2.5 times the baseline SD is statistically significant at the .05 significance level. Due to relatively small sample size, t-distribution is to be used to calculate the cutoff defining the PD response.

* Up to 25 patients may be enrolled to obtain 8 evaluable subjects. A two-stage design will be used. Five patients will be initially treated. If at least one of five demonstrates PK activity, 3 additional subjects will be enrolled. PK effect will be declared to be significant if at least 2 of the 8 patients demonstrate a PK response (presence of LB100 in tumor tissue).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
1/LB100 Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma	LB-100	Treatment with LB100

Primary Outcome Measures

Name	Time	Method
Number of Participants With the Presence of Drug in the Tumor Tissue	an average of 5.5 hours after drug administration	Participants tumor tissue was examined to determine the presence of drug in the tumor tissue.

Secondary Outcome Measures

Name	Time	Method
Plasma Concentration and Calculated LB100	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Blood samples for the determination of plasma levels of LB-100 will be obtained from each participant. Plasma concentrations of LB100 will be determined at each time point. LC-MS-MS assay that can measure LB-100 in human plasma. Assay range is 2.0 -1000 ng/mL. A higher value is better because it would have made it more likely drug could penetrate the blood brain barrier at therapeutic levels.
Maximum Observed Plasma Concentration of LB100 (Cmax)	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	The maximum observed analyte concentration in serum was reported.
Concentration of LB100	average of 5.5 hours after infusion	Concentration of LB100 in glioma tumor tissue when a known non-toxic dose of LB100 is delivered intravenously. Glioma tissue sampling to detect and quantify LB100 will be performed by assaying phospho-protein expression in glioma tissue resected prior to and after infusion of LB100. These are values for the LB100 in the tumor which was done at one timepoint.
Changes in Phospho-protein Expression in Circulating Peripheral Blood Mononuclear Cells (PBMC)	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Changes in phospho-protein expression in circulating PBMC. Pharmacodynamic (PD) response is defined as statistically significant elevation of phospho-protein expression in treated tumor tissues compared to untreated glioma specimens. Post-treatment PD effect (as measured by increase in tumor tissue phospho-protein expression) difference greater than 2.5 times the baseline standard deviation (SD) is statistically significant at the .05 significance level.
Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	AUC is a measure of the serum concentration of LMB100 over time. It is used to characterize drug absorption.
Plasma Half-Life of Drug LB100	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.
Time to Maximum Observed Plasma Concentration of LMB100 (Tmax)	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Time to maximum observed plasma concentration of LMB100 (Tmax).
Total Clearance (CL) of LMB100	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	The CL is a quantitative measure of the rate at which a drug substance is removed from the body.
Volume of Distribution (Vd) of LMB100	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
Brain Concentration	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Drug amount in brain as a percent of drug in plasma.
Brain Penetration	Pre-dose; End of infusion (2 hours post-start); 30 minutes post LB100 infusion completion; 1 hour post LB-100 infusion completion; 2 hours post LB100 infusion completion; 4 hours post LB100 infusion completion; 8 hours post LB100 infusion completion	Concentration of drug in brain tumor tissue. Brain penetration is measured as "drug amount in a brain as a percent of drug in plasma.