Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors

NCT00108069 | Completed Phase 2 Results

• 2 other identifiers: 05013705-C-0137
• Study Type: interventional
• Target: 43
• Locations: 1 country
• Sites: 1

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.

Conditions

Glioma

Keywords

Brain; Tumor; Malignant; Therapy; Progression; Chemotherapy; Antiangiogenesis; Radiation; Malignant Brain Tumor; Malignant Glioma; Glioma

Outcome Measures

Primary Outcomes (1)

• Response, Defined as Stable Disease or Objective (Partial or Complete) 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.

  Patients were followed for an average of six weeks for assessment of response

Secondary Outcomes (2)

• Number of Participants With Adverse Events

  7.5 years

• Adverse Event Grades

  7.5 years

Study Arms (2)

GBM (Glioblastoma multiforme)

EXPERIMENTAL

Drug: Tamoxifen citrate; Drug: Bortezomib

AG (Anaplastic glioma)

EXPERIMENTAL

Drug: Tamoxifen citrate; Drug: Bortezomib

Interventions

Tamoxifen citrate DRUG

oral dose 120 mg twice a day, every day

Also known as: Nolvadex

AG (Anaplastic glioma); GBM (Glioblastoma multiforme)

Bortezomib DRUG

intravenous (IV) injection 1.3 mg/m\^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle

Also known as: Velcade

AG (Anaplastic glioma); GBM (Glioblastoma multiforme)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:
• They have recovered from the effects of surgery.
• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Barker D, Wright E, Nguyen K, Cannon L, Fain P, Goldgar D, Bishop DT, Carey J, Baty B, Kivlin J, et al. Gene for von Recklinghausen neurofibromatosis is in the pericentromeric region of chromosome 17. Science. 1987 May 29;236(4805):1100-2. doi: 10.1126/science.3107130.

  PMID: 3107130 BACKGROUND

• Bigner SH, Bjerkvig R, Laerum OD. DNA content and chromosomal composition of malignant human gliomas. Neurol Clin. 1985 Nov;3(4):769-84.

  PMID: 3001489 BACKGROUND

• Moss AR. Occupational exposure and brain tumors. J Toxicol Environ Health. 1985;16(5):703-11. doi: 10.1080/15287398509530780.

  PMID: 4093991 BACKGROUND

• Odia Y, Kreisl TN, Aregawi D, Innis EK, Fine HA. A phase II trial of tamoxifen and bortezomib in patients with recurrent malignant gliomas. J Neurooncol. 2015 Oct;125(1):191-5. doi: 10.1007/s11060-015-1894-y. Epub 2015 Aug 19.

  PMID: 26285768 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Glioma; Neoplasms; Disease Progression; Brain Neoplasms

Interventions

Tamoxifen; Bortezomib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Stilbenes; Benzylidene Compounds; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Boronic Acids; Acids, Noncarboxylic; Acids; Inorganic Chemicals; Boron Compounds; Pyrazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Kathy Warren, M.D.
• Organization: National Cancer Institute

warrenk@box-w.nih.gov

301-435-4683

Study Officials

• Katherine Warren, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 12, 2005
• First Posted: April 13, 2005
• Study Start: April 1, 2005
• Primary Completion: March 1, 2013
• Study Completion: March 1, 2013
• Last Updated: November 5, 2015
• Results First Posted: June 12, 2014

Record last verified: 2015-10

Locations

US (1)