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Phase 0 Trial of LB100, A Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma (NCT03027388)

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 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.
  • Drug: LB-100
    LB-100 will be infused over 2 hours via syringe pump in the OR. The dose established from a Phase I study will be 2.33 mg/m(2).
    Ages eligible for Study
    18 Years to 99 Years
    Genders eligible for Study
    All
    Accepts Healthy Volunteers
    No
    Background:

    - Glioblastoma is an incurable disease with expected survival of 12-14 months in spite of aggressive multimodality therapy consisting of craniotomy, irradiation, and chemotherapy. Therapeutic options for patients with recurrent glioblastoma 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 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 nearly complete phase I study of LB100 has established its safety and the recommended phase II dose (2.33 mg/m^2, equivalent to a plasma concentration of 5-6 uM).

    - 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 pharmacodynamic (PD) effect of LB100 by assaying phospho-protein expression in treated glioblastoma tumor tissue compared to untreated tumor samples for comparison.

    Eligibility:

    - Patients with histologically proven glioblastoma.

    - 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 0, open label, single institution study to determine the PK and PD profile of LB100.

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

    - PD effect from 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.

    - PD effect is defined as statistically significant elevation of phospho-proteins in treated tumor tissues compared to untreated glioblastoma 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 20 patients may be enrolled to obtain 13 evaluable subjects. Five patients will be initially treated. If one of five demonstrates a PD response significant at the .05 level, three additional subjects will be enrolled. PD effect will be declared to be significant if at least 2 of the 8 patients demonstrate a PD response. If we are able to detect LB100 in tumor tissue in the first 5 patients but do not observe PD effect, an additional 5 patients will be infused with LB100 10-12 hours before surgical resection to determine PD effect.

    1 locations

    United States (1)
    • National Institutes of Health Clinical Center
      not yet recruiting
      Bethesda, Maryland, United States, 20892
    Status:
    not yet recruiting
    Type:
    Interventional
    Phase:
    0
    Start:
    04 January, 2017
    Updated:
    18 October, 2017
    Participants:
    20
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