Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors

Phase 2

Completed

Conditions: Glioma

Interventions: Drug: Tamoxifen citrate
Drug: Bortezomib

Registration Number: NCT00108069

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This study will determine whether the drugs tamoxifen and bortezomib can delay tumor growth in patients with recurrent glioma (malignant brain tumor). Tamoxifen may work by interfering with the internal signaling needed for the cancer to grow. Bortezomib may also interfere with tumor growth processes. Laboratory studies show that low doses of bortezomib significantly enhance glioma cell death when used with tamoxifen.

Patients 18 years of age and older with glioma whose tumor does not respond to standard medical treatment and who are not taking enzyme-inducing anti-seizure medications such as Dilantin, phenobarbitol, or Tegretol, may be eligible for this study. Candidates are screened with a physical examination, blood tests, and magnetic resonance imaging (MRI) or computed tomography (CT). MRI and CT scans produce images of the brain that can show if the brain tumor is growing (see below).

Participants receive treatment in 6-week cycles for up to 1 year. (The treatment duration may be extended in some patients who continue to tolerate the drug and show no signs of tumor growth after 1 year.) During each cycle, patients take six tamoxifen tablets twice a day every day and receive bortezomib by infusion into a vein on days 3, 6, 10, 13, 24, 27, 31 and 34. Treatment may continue as long as the tumor does not grow and the patient does not develop unacceptable side effects. In addition to drug treatment, patients undergo the following tests and procedures:

* Periodic routine blood tests.

* MRI or CT scan of the head before starting each new cycle. MRI uses a magnetic field and radio waves to produce images of body tissues and organs. CT uses x-rays to provide 3-dimensional views of the part of the body being studied. For both procedures, the patient lies on a table that slides into the cylindrical scanner.

* Blood test to measure levels of bortezomib. Blood is drawn before the bortezomib infusion on days 3 and 24, and 4 hours after the infusion on day 24 of the first treatment cycle only.

* Dynamic MRI with spectroscopy or positron emission tomography (PET). Patients may be asked to undergo one of these tests, which help distinguish live tumor from dying tumor. The experience of dynamic MRI with spectroscopy is the same as standard MRI and is done at the same time as the standard procedure (see above). PET uses a radioactive substance to show cellular activity in specific tissues of the body. The patient is given an injection of a sugar solution in which a radioactive isotope has been attached to the sugar molecule. A special camera detects the radiation emitted by the radioisotope, and the resulting images show how much glucose is being used in various parts of the body. Because rapidly growing cells, such as tumors, take up and use more glucose than normal cells do, this test can be used to show active tumors.

* Drug diary. Patients maintain a calendar to record when they take their study drugs and what side effects they develop.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 43

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
GBM (Glioblastoma multiforme)	Tamoxifen citrate	-
GBM (Glioblastoma multiforme)	Bortezomib	-
AG (Anaplastic glioma)	Tamoxifen citrate	-
AG (Anaplastic glioma)	Bortezomib	-

Primary Outcome Measures

Name	Time	Method
Response, Defined as Stable Disease or Objective (Partial or Complete) Response.	Patients were followed for an average of six weeks for assessment of response	Complete response (CR) is complete disappearance of all measurable and evaluable disease. No new lesions. No evidence of non-evaluable disease. All measurable, evaluable and non-evaluable lesions and site must be assessed using the same techniques as baseline. Patients who respond must be on the same or decreasing doses of dexamethasone. Partial response (PR) is greater than or equal to a 50% decrease compared to baseline in the sum of products of perpendicular diameters of all measurable disease. No new lesions. All measurable and evaluable lesions and sites must be assessed using same techniques as baseline. Responders must be on the same decreasing doses of dexamethasone. Stable disease (SD) does not qualify for CR, PR, or progression (e.g., a 25% increase in the sum of products of all measurable lesions). The designation of stable/no response requires a minimum of 6 weeks duration. All measurable and evaluable sites must be assessed using the same techniques as baseline.

Secondary Outcome Measures

Name	Time	Method
Adverse Event Grades	7.5 years	The combined serious and non-serious adverse event Table describes count of patients whose highest grade adverse event for any CTC (common terminology criteria) term was related to study drugs for the GBM (Glioblastoma multiforme) and AG (Anaplastic glioma) cohorts.
Number of Participants With Adverse Events	7.5 years	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.