Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

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 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 glioblastoma tumor tissues.

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 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 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 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).

- 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 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.