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Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03027388
Recruitment Status : Recruiting
First Posted : January 23, 2017
Last Update Posted : January 26, 2023
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )

Tracking Information
First Submitted Date  ICMJE January 18, 2017
First Posted Date  ICMJE January 23, 2017
Last Update Posted Date January 26, 2023
Actual Study Start Date  ICMJE January 9, 2019
Estimated Primary Completion Date August 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2021)
Drug Level in tumor tissue [ Time Frame: Post Surgery ]
To determine the pharmacokinetic properties of LB100 in glioblastoma tumor tissues
Original Primary Outcome Measures  ICMJE
 (submitted: January 20, 2017)
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. [ Time Frame: 8 hours following surgery ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2021)
  • 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 ]
    Intra-patient PD effect in PBMC and tumor tissue will be evaluated in all subjects for presence of correlation to identify potential predictive markers
  • Plasma concentration and calculated LB100 [ Time Frame: 8 hours post infusion ]
    determine the plasma concentration and calculated PK parameters of LB100 and LB100M (endothall).
  • Concentration of LG100 and its major metabolite LB100 in glioblastoma tumor tissue [ Time Frame: 8 hours post infusion ]
    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
  • Changes in phospho-protein expression in circulating PBMC [ Time Frame: 8 hours post infusion ]
    determine changes in phospho-protein expression in circulating PBMC
Original Secondary Outcome Measures  ICMJE
 (submitted: January 20, 2017)
  • To determine the concentration LB100 and its major metabolite, 7-oxabicyclo heptanes-2,3- dicarboxylic acid (LB100M) inglioblastoma tumor tissue when a known non-toxic dose of LB100 isdelivered intravenously over 2 hours. [ Time Frame: 8 hours following surgery ]
  • To determine the plasma concentration and calculated pharmacokinetic (PK) parameters of LB100 and LB100M (endothall) [ Time Frame: 8 hours following surgery ]
  • To determine changes in phosphoprotein expression in circulating PBMC. [ Time Frame: 8 hours following surgery ]
  • Intra-patient PD effect in PBMC and tumor tissue will be evaluated in all subjects for presence of correlation to identify potential predictive markers. [ Time Frame: 8 hours following surgery ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma
Official Title  ICMJE Phase II Trial of LB100, a Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma
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 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 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).
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE
  • Astrocytoma, Grades II, III and IV
  • Glioblastoma Multiforme
  • Giant Cell Glioblastoma
  • Glioma
  • Oligodendrogliomas
Intervention  ICMJE Drug: LB-100
LB-100 will be infused over 2 hours via IV infusion 2 to 4 hours before surgery. The dose established from a Phase I study will be 2.33 mg/m2.
Study Arms  ICMJE Experimental: 1/LB100
Treatment with LB100
Intervention: Drug: LB-100
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 16, 2020)
25
Original Estimated Enrollment  ICMJE
 (submitted: January 20, 2017)
20
Estimated Study Completion Date  ICMJE August 31, 2023
Estimated Primary Completion Date August 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Patients must have histologically confirmed glioblastoma/gliosarcoma, grades II-III astrocytoma and oligodendroglioma.
  • 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). These tests must be performed within 28 days prior to receiving drug. Eligibility level for hemoglobin may be reached by transfusion.
  • Patients must have a serum creatinine of <=1.7 mg/dL. If the serum creatinine is greater than 1.7 mg/dl, a 24-hour urine creatinine clearance will be obtained and if the result of this study is within normal limits*, the patient would be eligible to enroll onto study. This test must be performed within 28 days prior to registrationreceiving drug. (*Normal Creatinine Clearance Range: Male: 90 - 130 ml/min; Female: 80 - 125 ml/min)
  • Patients must be in adequate general medical health to safely tolerate a craniotomy.
  • 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.
  • Known 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 by the Neuro-Oncology Branch, Clinical Center. This study will be posted on NIH websites and on NIH Social media forums.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: NCI NOB Referral Group (866) 251-9686 ncinobreferrals@mail.nih.gov
Contact: Eric C Burton, M.D. (240) 760-6436 eric.burton@nih.gov
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03027388
Other Study ID Numbers  ICMJE 170037
17-C-0037
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: .BTRIS: All IPD recorded in the medical record will be shared with intramural investigators upon request.
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Time Frame: BTRIS: Clinical data available during the study and indefinitely.
Access Criteria: BTRIS: Clinical data will be made available via subscription to BTRIS and with the permission of the study PI.
Current Responsible Party National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
Original Responsible Party Same as current
Current Study Sponsor  ICMJE National Cancer Institute (NCI)
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Eric C Burton, M.D. National Cancer Institute (NCI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date October 3, 2022

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP