Tamoxifen and Bortezomib to Treat Recurrent Brain Tumors

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00108069
• Collaborator: (none)
• Enrollment: 43
• Location: 1
• Arms: 2
• Duration (Months): 95
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Glioma	Drug: Tamoxifen citrate; Drug: Bortezomib	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 43 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial of Tamoxifen and Bortezomib in Patients With Recurrent High-Grade Gliomas
• Study Start Date: Apr 1, 2005
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: GBM (Glioblastoma multiforme)	Drug: Tamoxifen citrate; oral dose 120 mg twice a day, every day; Other Names: Nolvadex ; Drug: Bortezomib; intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle; Other Names: Velcade
Experimental: AG (Anaplastic glioma)	Drug: Tamoxifen citrate; oral dose 120 mg twice a day, every day; Other Names: Nolvadex ; Drug: Bortezomib; intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle; Other Names: Velcade

Outcome Measures

Primary Outcome Measures

1. 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

1. 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.

2. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Katherine Warren, M.D., National Cancer Institute (NCI)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• 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.
• Bigner SH, Bjerkvig R, Laerum OD. DNA content and chromosomal composition of malignant human gliomas. Neurol Clin. 1985 Nov;3(4):769-84. Review.
• Moss AR. Occupational exposure and brain tumors. J Toxicol Environ Health. 1985;16(5):703-11.

• Responsible Party: Katherine E. Warren, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC)
• ClinicalTrials.gov Identifier: NCT00108069
• Other Study ID Numbers: 050137; 05-C-0137; NCT00112762
• First Posted: Apr 13, 2005
• Last Update Posted: Nov 5, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Katherine E. Warren, M.D., Principal Investigator, National Institutes of Health Clinical Center (CC): Brain; Tumor; Malignant; Therapy; Progression; Chemotherapy; Antiangiogenesis; Radiation; Malignant Brain Tumor; Malignant Glioma; Glioma
• Additional relevant MeSH terms: Glioma; Tamoxifen; Bortezomib

Study Results

Participant Flow

Arm/Group Title	GBM (Glioblastoma Multiforme)	AG (Anaplastic Glioma)
Arm/Group Description	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day
Period Title: Overall Study
STARTED	30	13
COMPLETED	0	0
NOT COMPLETED	30	13

Baseline Characteristics

Arm/Group Title	GBM (Glioblastoma Multiforme)	AG (Anaplastic Glioma)	Total
Arm/Group Description	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day	Total of all reporting groups
Overall Participants	30	12	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	29 96.7%	12 100%	41 97.6%
>=65 years	1 3.3%	0 0%	1 2.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	46 (12)	42 (10)	44 (11)
Sex: Female, Male (Count of Participants)
Female	7 23.3%	3 25%	10 23.8%
Male	23 76.7%	9 75%	32 76.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 8.3%	1 2.4%
Not Hispanic or Latino	29 96.7%	11 91.7%	40 95.2%
Unknown or Not Reported	1 3.3%	0 0%	1 2.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 3.3%	0 0%	1 2.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	28 93.3%	10 83.3%	38 90.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 3.3%	2 16.7%	3 7.1%
Region of Enrollment (participants) [Number]
United States	30 100%	12 100%	42 100%

Outcome Measures

1. Primary Outcome

Title	Response, Defined as Stable Disease or Objective (Partial or Complete) Response.
Description	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.
Time Frame	Patients were followed for an average of six weeks for assessment of response

Outcome Measure Data

Analysis Population Description

Two patients were not able to complete follow-up neuroimaging to assess response due to clinical progression of disease.

Arm/Group Title	GBM (Glioblastoma Multiforme)	AG (Anaplastic Glioma)
Arm/Group Description	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day
Measure Participants	28	12
Complete response	0 0%	0 0%
Partial response	0 0%	0 0%
Stable disease	1 3.3%	0 0%
Progressive disease	27 90%	12 100%

2. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
Time Frame	7.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	GBM (Glioblastoma Multiforme)	AG (Anaplastic Glioma)
Arm/Group Description	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day
Measure Participants	30	12
Number [Participants]	30 100%	12 100%

3. Secondary Outcome

Title	Adverse Event Grades
Description	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.
Time Frame	7.5 years

Outcome Measure Data

Analysis Population Description

Neither cohort completed planned accrual and are small in number separately. Additionally, the underlying histological grade would not affect toxicity. Therefore, these cohorts may be combined. The Table describes count of patients whose highest grade adverse event for any CTC (common terminology criteria) term was related to study drugs.

Arm/Group Title	Grade 1	Grade 2	Grade 3	Grade 4	Grade 5	Total
Arm/Group Description	Mild adverse event	Moderate adverse event	Severe adverse event	Life-threatening or disabling adverse event	Death related to adverse event	Total number of participants.
Measure Participants	42	42	42	42	42	42
thrombocytopenia	19 63.3%	3 25%	1 2.4%	1 NaN	0 NaN	24 NaN
lymphopenia	4 13.3%	4 33.3%	4 9.5%	0 NaN	0 NaN	12 NaN
hypophosphatemia	0 0%	6 50%	3 7.1%	0 NaN	0 NaN	9 NaN
ALT/sGPT	6 20%	1 8.3%	0 0%	0 NaN	0 NaN	7 NaN
anemia (Decreased Hgb)	6 20%	0 0%	0 0%	0 NaN	0 NaN	6 NaN
hyponatremia	4 13.3%	0 0%	1 2.4%	0 NaN	0 NaN	5 NaN
headache	0 0%	2 16.7%	1 2.4%	0 NaN	0 NaN	3 NaN
leukopenia	1 3.3%	2 16.7%	0 0%	0 NaN	0 NaN	3 NaN
AST/sGOT	2 6.7%	0 0%	0 0%	0 NaN	0 NaN	2 NaN
dyspnea	1 3.3%	0 0%	1 2.4%	0 NaN	0 NaN	2 NaN
fatigue	2 6.7%	0 0%	0 0%	0 NaN	0 NaN	2 NaN
fever	1 3.3%	1 8.3%	0 0%	0 NaN	0 NaN	2 NaN
hyperkalemia	2 6.7%	0 0%	0 0%	0 NaN	0 NaN	2 NaN
cough	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
depression (mood alteration)	0 0%	1 8.3%	0 0%	0 NaN	0 NaN	1 NaN
diarrhea	0 0%	1 8.3%	0 0%	0 NaN	0 NaN	1 NaN
dizziness	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
venous thrombosis	0 0%	0 0%	1 2.4%	0 NaN	0 NaN	1 NaN
edema	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
hyperbilirubinemia	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
hypermagnesemia	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
hypocalcemia	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
hypokalemia	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
hypotension	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
elevated creatinine	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
infection with unknown ANC	0 0%	0 0%	1 2.4%	0 NaN	0 NaN	1 NaN
neutropenia	0 0%	1 8.3%	0 0%	0 NaN	0 NaN	1 NaN
pain	0 0%	1 8.3%	0 0%	0 NaN	0 NaN	1 NaN
rash	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
hemorrhage (rectal)	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN
somnolence	0 0%	0 0%	1 2.4%	0 NaN	0 NaN	1 NaN
urinary frequency	1 3.3%	0 0%	0 0%	0 NaN	0 NaN	1 NaN

Adverse Events

Arm/Group Title	GBM (Glioblastoma Multiforme)		AG (Anaplastic Glioma)
Arm/Group Description	Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day		Bortezomib : intravenous (IV) injection 1.3 mg/m^2 days 3, 6, 10, 13, 24, 27,31,34 on every 6 week cycle Tamoxifen citrate : oral dose 120 mg twice a day, every day
All Cause Mortality
	GBM (Glioblastoma Multiforme)		AG (Anaplastic Glioma)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	GBM (Glioblastoma Multiforme)		AG (Anaplastic Glioma)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/30 (36.7%)		3/12 (25%)
Blood and lymphatic system disorders
Platelets	1/30 (3.3%)	2	0/12 (0%)	0
Gastrointestinal disorders
Speech impairment (e.g., dysphagia or aphasia)	1/30 (3.3%)	1	0/12 (0%)	0
Diarrhea	0/30 (0%)	0	1/12 (8.3%)	1
General disorders
Death not associated with CTCAE term: Death NOS	1/30 (3.3%)	1	1/12 (8.3%)	1
Death not associated with CTCAE term: Disease progression NOS	4/30 (13.3%)	4	0/12 (0%)	0
Fatigue (asthenia, lethargy, malaise)	1/30 (3.3%)	1	0/12 (0%)	0
Fever (in the absence of neutropenia, where neutropenia is defined as ANC<1.0 x 10e9/L)	0/30 (0%)	0	1/12 (8.3%)	1
Infections and infestations
Infection - Other (Specify, infection w/unknown ANC)	1/30 (3.3%)	1	0/12 (0%)	0
Infection	0/30 (0%)	0	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Muscle weakness, genralized or specific area (not due to neuropathy): Right-sided	0/30 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
Neuropathy: motor	1/30 (3.3%)	1	0/12 (0%)	0
Pain: head/headache	2/30 (6.7%)	2	0/12 (0%)	0
Seizure	4/30 (13.3%)	4	1/12 (8.3%)	2
Somnolence/depressed level of consciousness	1/30 (3.3%)	2	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	0/30 (0%)	0	1/12 (8.3%)	1
Vascular disorders
Vascular - Other (Specify-deep vein thrombosis)	1/30 (3.3%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	GBM (Glioblastoma Multiforme)		AG (Anaplastic Glioma)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/30 (86.7%)		10/12 (83.3%)
Blood and lymphatic system disorders
Blood/Bone Marrow - Other (Specify, elevated white blood count;)	2/30 (6.7%)	2	0/12 (0%)	0
Edema: limb	2/30 (6.7%)	2	0/12 (0%)	0
Hemoglobin	4/30 (13.3%)	6	0/12 (0%)	0
Leukocytes (total WBC)	2/30 (6.7%)	3	2/12 (16.7%)	2
Lymphatics - Other (Specify)	1/30 (3.3%)	1	0/12 (0%)	0
Lymphopenia	10/30 (33.3%)	14	0/12 (0%)	0
Neutrophils/granulocytes (ANC/AGC)	1/30 (3.3%)	1	0/12 (0%)	0
Platelets	13/30 (43.3%)	21	4/12 (33.3%)	5
Cardiac disorders
Hypotension	1/30 (3.3%)	2	1/12 (8.3%)	1
Eye disorders
Nystagmus	1/30 (3.3%)	1	0/12 (0%)	0
Ocular/Visual - Other (Specify, horizontal diplopia)	1/30 (3.3%)	1	0/12 (0%)	0
Vision-flashing lights/floaters	1/30 (3.3%)	1	0/12 (0%)	0
Vision-blurred vision	0/30 (0%)	0	1/12 (8.3%)	1
Gastrointestinal disorders
Anorexia	1/30 (3.3%)	1	0/12 (0%)	0
Constipation	1/30 (3.3%)	1	0/12 (0%)	0
Nausea	1/30 (3.3%)	1	1/12 (8.3%)	1
Hemorrhage: GI: Rectum	0/30 (0%)	0	1/12 (8.3%)	1
General disorders
Death not associated with CTCAE term: Disease progression NOS	1/30 (3.3%)	1	0/12 (0%)	0
Fatigue (asthenia, lethargy, malaise)	4/30 (13.3%)	4	1/12 (8.3%)	1
Fever (in the absence of neutropenia, where neutropenia is defined as ANC<1.0 x 10e9/L)	1/30 (3.3%)	1	1/12 (8.3%)	1
Pain - Other (Specify, L side - hip and rib)	1/30 (3.3%)	1	0/12 (0%)	0
Weight gain	1/30 (3.3%)	1	0/12 (0%)	0
Constitutional symptoms - Other (Specify, fatigue)	0/30 (0%)	0	1/12 (8.3%)	1
Infections and infestations
Infection	0/30 (0%)	0	1/12 (8.3%)	1
Metabolism and nutrition disorders
ALT, SGPT (serum glutamic pyruvic transaminase)	7/30 (23.3%)	7	3/12 (25%)	3
Albumin, serum-low (hypoalbuminemia)	4/30 (13.3%)	4	1/12 (8.3%)	1
Calcium, serum-low (hypocalcemia)	2/30 (6.7%)	2	1/12 (8.3%)	2
Magnesium, serum-high (hypermagnesemia)	1/30 (3.3%)	1	1/12 (8.3%)	1
Phosphate, serum-low (hypophosphatemia)	6/30 (20%)	6	3/12 (25%)	4
Potassium, serum-high (hyperkalemia)	1/30 (3.3%)	1	0/12 (0%)	0
Sodium, serum-low (hyponatremia)	4/30 (13.3%)	5	0/12 (0%)	0
Bicarbonate, serum-low	0/30 (0%)	0	1/12 (8.3%)	1
Bilirubin (hyperbilirubinemia)	0/30 (0%)	0	1/12 (8.3%)	1
Calcium, serum-high (hypercalcemia)	0/30 (0%)	0	1/12 (8.3%)	1
Creatinine	0/30 (0%)	0	1/12 (8.3%)	1
Glucose, serum-high (hyperglycemia)	0/30 (0%)	0	1/12 (8.3%)	1
AST, SGOT (serum glutamic oxaloacetic transaminase)	0/30 (0%)	0	1/12 (8.3%)	1
Sodium, serum-high (hypernatremia)	0/30 (0%)	0	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Extremity - lower (gait-walking)	1/30 (3.3%)	2	0/12 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy): Extremity-lower	1/30 (3.3%)	1	0/12 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy): Facial	2/30 (6.7%)	2	0/12 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy): Left-sided	7/30 (23.3%)	7	0/12 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy): Right-sided	2/30 (6.7%)	2	0/12 (0%)	0
Muscle weakness, generalized or specific area (not due to neuropathy): Whole-body/generalized	1/30 (3.3%)	2	1/12 (8.3%)	1
Pain: Back	1/30 (3.3%)	1	1/12 (8.3%)	1
Osteoporosis	0/30 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
Ataxia	1/30 (3.3%)	1	0/12 (0%)	0
Cognitive disturbance	2/30 (6.7%)	2	0/12 (0%)	0
Confusion	1/30 (3.3%)	1	1/12 (8.3%)	1
Dizziness	1/30 (3.3%)	1	1/12 (8.3%)	1
Memory impairment	1/30 (3.3%)	1	0/12 (0%)	0
Mood alteration: depression	2/30 (6.7%)	2	0/12 (0%)	0
Neuropathy: motor	3/30 (10%)	5	1/12 (8.3%)	1
Neuropathy: sensory	1/30 (3.3%)	2	0/12 (0%)	0
Pain: head/headache	3/30 (10%)	4	0/12 (0%)	0
Seizure	4/30 (13.3%)	5	1/12 (8.3%)	1
Somnolence/depressed level of consciousness	1/30 (3.3%)	1	1/12 (8.3%)	1
Speech impairment (e.g., dysphagia or aphasia)	7/30 (23.3%)	7	1/12 (8.3%)	1
Renal and urinary disorders
Urinary frequency/urgency	0/30 (0%)	0	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Dyspnea (shortness of breath)	1/30 (3.3%)	1	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.