Patient case: 84-year-old male with glioblastoma; genetic feature: CDK6

Clinical trial: Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

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 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:
  -  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.

Eligibility: -  INCLUSION CRITERIA:
  -  Patients must have histologically confirmed glioblastoma/gliosarcoma 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 the initial diagnosis must be available.
  -  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.

Relevance to patient case: not relevant