Clinical Trials /

Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

NCT03027388

Description:

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.

Related Conditions:
  • Astrocytoma
  • Glioblastoma
  • Gliosarcoma
  • Oligodendroglioma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma
  • Official Title: Phase II Trial of LBlOO, a Protein Phosphatase 2A Inhibitor, in Recurrent Gliomas

Clinical Trial IDs

  • ORG STUDY ID: 170037
  • SECONDARY ID: 17-C-0037
  • NCT ID: NCT03027388

Conditions

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

Interventions

DrugSynonymsArms
LB-1001/LB100

Purpose

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.

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 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 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 20 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).
    

Trial Arms

NameTypeDescriptionInterventions
1/LB100ExperimentalTreatment with LB100
  • LB-100

Eligibility Criteria

        -  INCLUSION CRITERIA:

          -  Patients must have histologically confirmed glioblastoma/gliosarcoma, grades II-III
             astrocytoma and oligodendroglioma confirmed by the Laboratory of Pathology, NCI.

          -  Patients must have recurrent disease for which there is a clinical indication for
             resection.

          -  Age greater than or equal to18 years.

          -  Karnofsky greater than or equal to 60%.

          -  Patients must have adequate bone marrow function (WBC greater than or equal to
             3,000/uL ANC greater than or equal to 1,500/mm^3, platelet count of greater than or
             equal to 100,000/mm^3, and hemoglobin greater than or equal to 10 gm/dL), adequate
             liver function (SGOT and bilirubin < 2 times ULN), adequate renal function (creatinine
             ,< ULN) before participation in the study. These tests must be performed within 14
             days prior to registration. Eligibility level for hemoglobin may be reached by
             transfusion.

          -  Patients must be in adequate general medical health to safely tolerate a craniotomy.

          -  Tumor tissue blocks or at least 20 unstained slides from a prior diagnosis will be
             requested. H&E to confirm diagnosis must be available. The 20 unstained slides is
             preferred, but not required.

          -  At the time of registration, all subjects must be removed greater than or equal to 28
             days from any investigational agents.

          -  The effects of LB100 on the developing human fetus are unknown. For this reason, women
             of child-bearing potential and men must agree to use adequate contraception (hormonal
             or barrier method of birth control; abstinence) prior to study entry and for the
             duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

          -  Ability of subject to understand and the willingness to sign a written informed
             consent document indicating that they are aware of the investigational nature of this
             study, and that this is not a therapeutic clinical trial.

        EXCLUSION CRITERIA:

          -  Patients who are receiving any other investigational agents.

          -  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.

          -  Patients unwilling to undergo craniotomy.

          -  Pregnant women are excluded from this study because the safety of PP2A inhibition on a
             developing fetus has not been established. Because there is an unknown but potential
             risk for adverse events in nursing infants secondary to treatment of the mother with
             LB100, breastfeeding should be discontinued if the mother is treated with LB100.

          -  Patients may not have had prior chemotherapy or biologic therapy in the 4 weeks prior
             to study entry. For patients who have been treated with targeted therapy, 5 half-lives
             of that therapy (or 28 days, whichever is shorter) must have passed prior to
             enrollment in the study.

          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of
             the potential for pharmacokinetic interactions with LB100. Appropriate studies will be
             undertaken in patients receiving combination antiretroviral therapy when indicated.

          -  Patients who are receiving strong CYP450 inducers or inhibitors are ineligible

          -  Recruitment Strategies

        Patients with recurrent disease will be identified at the Outpatient Clinic of the
        Neuro-Oncology Branch, Clinical Center.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Drug Level in tumor tissue
Time Frame:Post Surgery
Safety Issue:
Description:To determine the pharmacokinetic properties of LB100 in Gliomas tumor tissues

Secondary Outcome Measures

Measure:Plasma concentration and calculated LB100
Time Frame:8 hours post infusion
Safety Issue:
Description:determine the plasma concentration and calculated PK parameters of LB100 and LB100M (endothall).
Measure:Concentration of LG100 and its major metabolite LB100 in glioblastoma tumor tissue
Time Frame:8 hours post infusion
Safety Issue:
Description:determine the concentration LB100 and its major metabolite, 7-oxabicyclo [2.2.1] heptanes-2,3- dicarboxylic acid (LB100M) in glioma tumor tissue when a known non-toxic dose of LB100 is delivered intravenously over 2 hours
Measure:Relationship between drug concentration at the site of action and the resulting effect and the presence of correlation to identify predictive markers.
Time Frame:8 hours post infusion
Safety Issue:
Description:Intra-patient PD effect in PBMC and tumor tissue will be evaluated in all subjects for presence of correlation to identify potential predictive markers
Measure:Changes in phospho-protein expression in circulating PBMC
Time Frame:8 hours post infusion
Safety Issue:
Description:determine changes in phospho- protein expression in circulating PBMC

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

  • Brain Tumor
  • Blood Brain Barrier
  • Pharmacokinetics
  • Pharmacodynamics

Last Updated

December 5, 2019