Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors

Background:

Tamoxifen (TAM), a member of the selective estrogen receptor modulator (SERM) family, is
widely used in the treatment of estrogen receptor (ER) expressing breast cancer. It has
previously been shown that high-dose TAM has cytotoxic activity against glioma cells, but
whether this effect is drug-specific or represents a general property of SERMs was unknown.
We have now demonstrated that suppression of nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-kB) activation markedly enhances SERM-induced apoptosis, suggesting a
role for NF-kB in protecting glioma cells from SERM-induced cytotoxicity.

Bortezomib is a potent inhibitor of the 26S proteosome and causes significant
anti-proliferative and cytotoxic effects in a number of cell lines through its protean
effects on a variety of cellular signaling pathways, including its ability to potently
inhibit the NF-kB pathway. We have recently demonstrated that bortezomib has significant
anti-glioma activity in vitro and a ongoing clinical trial has demonstrated some possible
activity in patients with recurrent gliomas. We have now also generated preclinical data
demonstrating that bortezomib in combination with Tamoxifen has synergistic cytotoxic
effects on glioma cells.

Thus, given the minimal to modest activity of both drugs in patients with recurrent gliomas,
given their spectrum of non-overlapping toxicities, and given the marked synergistic glioma
cell killing of the combination of drugs in our preclinical screens, we are now proposing a
phase II trial of bortezomib in combination with Tamoxifen in patients with recurrent
gliomas not taking enzyme inducing anti-epileptic drugs (EIAEDs).

Objectives:

The primary statistical endpoint will be response (defined as either stable disease or
objective response as is standard in neuro-oncology clinical trials) after 6 weeks of
treatment.

Eligibility:

Patients with histologically proven high-grade gliomas or patients with a clinical and
radiographic diagnosis of brainstem glioma will be eligible for this protocol.

Design:

The phase II study will be stratified by the type of high grade glioma (anaplastic glioma
(AA) or glioblastoma (GBM)) and a two-stage min-max design with a maximum of 41 patients in
the GBM stratum and 36 patients in the AA stratum.

- INCLUSION CRITERIA:

Patients with histologically proven high-grade gliomas or patients with a clinical and
radiographic diagnosis of brainstem glioma will be eligible for this protocol. High-grade
gliomas include glioblastoma multiforme (GBM; stratum 1) and its variants such as
gliosarcoma and anaplastic gliomas (AG; stratum 2), such as anaplastic astrocytoma (AA),
anaplastic oligodendroglioma (AO), anaplastic mixed oligoastrocytoma (AMO), or malignant
astrocytoma/glioma NOS (not otherwise specified).

Patients must have unequivocal evidence for tumor progression by magnetic resonance
imaging (MRI) or computerized tomography (CT) scan. This scan should be performed within
14 days prior to registration and on a steroid dosage that has been stable for at least 5
days. If the steroid dose is increased between the date of imaging and registration a new
baseline MR/CT is required. The same type of scan, i.e., MRI or CT must be used throughout
the period of protocol treatment for tumor measurement.

Patients having undergone recent resection of recurrent or progressive tumor will be
eligible as long as all of the following conditions apply:

1. They have recovered from the effects of surgery.

2. Residual disease following resection of recurrent tumor is mandated for eligibility
into the study. To best assess the extent of residual disease post-operatively, a CT/
MRI should be done:

- no later than 96 hours in the immediate post-operative period or

- at least 4 weeks post-operatively, and

- within 14 days of registration, and

- on a steroid dosage that has been stable for at least 5 days.

If the 96 hour scan is more than 21 days before registration, the scan needs to be
repeated. If the steroid dose is increased between the date of imaging and
registration, a new baseline MRI/CT is required on a stable steroid dosage for at
least 5 days.

Patients must have failed prior radiation therapy and must have an interval of
greater than or equal to 4 weeks from the completion of radiation therapy to study
entry.

Ability of subjects or Legally Authorized Representative (LAR) to understand and the
willingness to sign a written informed consent document.

Patients must be greater than or equal to 18 years old, and with a life expectancy
greater than 8 weeks.

Patients must have a Karnofsky performance status of greater than or equal to 60.

Patients must have recovered from the toxic effects of prior therapy: 2 weeks from
any investigational agent, 4 weeks from prior cytotoxic therapy, two weeks from
vincristine, 6 weeks from nitrosoureas, 3 weeks from procarbazine administration, and
1 week for non-cytotoxic agents, e.g., interferon, thalidomide, cis-retinoic acid,
etc. (radiosensitizer does not count). Any questions related to the definition of
non-cytotoxic agents should be directed to the Study Chair.

Patients must have adequate bone marrow function (white blood cell (WBC) greater than
or equal to 3,000/microl, absolute neutrophil count (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 (serum glutamic
oxaloacetic transaminase (SGOT) and bilirubin less than 2 times ULN), and adequate
renal function (creatinine less than 1.5 mg/dL and/or creatinine clearance greater
than or equal to 60 cc/min) before starting therapy. These tests must be performed
within 14 days prior to registration. Eligibility level for hemoglobin may be reached
by transfusion.

Patients must not have any significant medical illnesses that in the investigator's
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patients' ability to tolerate this therapy.

This study was designed to include women and minorities, but was not designed to
measure differences of intervention effects. Males and females will be recruited with
no preference to gender. No exclusion to this study will be based on race. Minorities
will actively be recruited to participate.

Patients must practice adequate contraception.

EXCLUSION CRITERIA:

Patients who, in the view of the treating physician, have significant active cardiac
(documented coronary artery disease, congestive heart failure, arrhythmia requiring
medication), hepatic (hepatocellular and/or cholestatic dysfunction as documented by
liver biopsy, liver ultrasound, or abnormal liver function blood tests, renal (as
documented by renal biopsy, ultrasound, CT/MRI scans or reflected in the blood tests
or psychiatric diseases (requiring hospitalization or is of significant severity to
impair the patients ability to cooperate with the study instructions).

No concurrent use of other standard chemotherapeutics or investigative agents.

Patients known to have an active malignancy other than their glioma (except
non-melanoma skin cancer or carcinoma in-situ of the cervix).

Patients who have an active infection requiring intravenous (IV) antibiotics.

Patients who are pregnant or breast feeding.

Patients who have any disease that will obscure toxicity or dangerously alter drug
metabolism.

Patients who have had clear tumor progression while being treated with tamoxifen
and/or patients treated with tamoxifen within the past year.

Patients who are taking EIAEDs (enzyme inducing anti-epileptic drugs) are not
eligible.

Patients who have had documented tumor progression while taking tamoxifen and/or any
treatment with tamoxifen within 6 months of registration.

Salicylates ARE permitted.

Patients with grade 2 or greater peripheral neuropathy.

Invasive procedures defined as follows:

- Major surgical procedures, open biopsy or significant traumatic injury within 28
days prior to Day ! therapy

- Anticipation of need for major surgical procedures during the course of the
study

- Core biopsy within 7 days prior to D1 therapy