Anti-Endoglin Monoclonal Antibody TRC105 in Treating Patients With Recurrent Glioblastoma

PRIMARY OBJECTIVES:

I. To determine the radiographic response rate for patients with recurrent GBM treated with
TRC105 (anti-endoglin monoclonal antibody TRC105).

II. To establish data regarding the anti-tumor activity of TRC105 in patients with GBM, as
determined by progression free survival.

SECONDARY OBJECTIVES:

I. To obtain information regarding the safety of TRC105 in patients with recurrent GBM.

II. To evaluate the health-related quality of life (HRQL) in patients while on treatment
with TRC105.

III. To examine the effect of TRC105 on vascular permeability as measured by percent change
from baseline in Ktrans of dynamic contrast enhanced (DCE)-magnetic resonance imaging (MRI).

IV. To examine the effect of TRC105 on vascular perfusion as measured by percent change from
baseline in cerebral blood volume (CBV), cerebral blood flow (CBF), and mean transit time
(MTT) of dynamic susceptibility contrast (DSC)-MRI.

V. To examine the effect of TRC105 on water diffusion as measured by percent change from
baseline in apparent diffusion coefficient (ADC) and fractional anisotropy (FA) of diffusion
MRI.

VI. To examine the effect of TRC105 on tumor metabolism as measured by percent change from
baseline in fludeoxyglucose F 18 (FDG) uptake of positron emission tomography (PET) scan.

VII. To obtain preliminary data regarding how changes in serial FDG-PET scans and
physiological MRI correlate with radiographic response rates and with progression-free
survival in patients treated with TRC105.

OUTLINE:

Patients receive anti-endoglin monoclonal antibody TRC105 intravenously (IV) over 1-4 hours
on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 12 courses in the
absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 12 weeks.

Inclusion Criteria:

- Patients must have histologically confirmed glioblastoma or gliosarcoma

- Patients must have evidence for tumor progression by MRI or CT scan; this scan should
be performed within 14 days prior to registration and on a fixed dose of steroids 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, ie, MRI or CT
must be used throughout the period of protocol treatment for tumor measurement

- Patients must have progressed after radiation therapy and must have an interval of
greater than or equal to 8 weeks from the completion of radiation therapy to study
entry

- Patients must have recovered from the toxic effects of prior therapy: 4 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, tamoxifen, thalidomide,
cis-retinoic acid, etc.; any questions related to the definition of non-cytotoxic
agents should be directed to the study chair; all toxicities from prior therapies
should be resolved to National Cancer Institute (NCI) Common Toxicity Criteria for
Adverse Events (CTCAE) =< grade 1 (except for toxicities such as alopecia or
vitiligo)

- Karnofsky performance status >= 60%

- Life expectancy of greater than 12 weeks

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin =< 1.5 x upper limit of normal (ULN) institutional upper limit of
normal

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Prothrombin time (PT) =< 1.5 x institutional upper limit of normal

- Partial thromboplastin time (PTT) =< 1.5 x institutional upper limit of normal

- Creatinine =< 1.5 x ULN within normal institutional limits or creatinine clearance >=
60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Hemoglobin of >= 9g/dL without transfusion support in the past 28 days

- 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

- 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

- They should have residual disease following resection of recurrent tumor

- 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 and

- 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 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

- 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; men treated or enrolled on this protocol
must also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of TRC105 administration

- Patients must have the ability to understand and the willingness to sign a written
informed consent document

- A baseline 12 lead electrocardiogram (ECG) to be performed within 2 weeks of trial
entry with corrected QT (QTc) < 460 msec

Exclusion Criteria:

- Patients who are receiving any other investigational agents and/or who have received
an investigational agent in the prior 28 days

- Patients may not have had prior therapy with vascular endothelial growth factor
(VEGF) receptor inhibitors

- Patients with a history of peptic ulcer disease or erosive gastritis within the past
6 months, unless treated for the condition and complete resolution has been
documented by esophagogastroduodenoscopy (EGD)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TRC105

- 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

- Exclude patients who have had angina, myocardial infarction (MI), symptomatic
congestive heart failure (CHF), cerebrovascular accident (CVA), transient
ischemic attack (TIA), arterial embolism, pulmonary embolism, deep vein
thrombosis (DVT), percutaneous transluminal coronary angioplasty (PTCA) or
coronary artery bypass grafting (CABG) within the last 6 months

- Exclude patients with cardiac arrhythmias >= grade 2 in the last 28 days

- Exclude patients with chronic hypertension, systolic blood pressure (BP) > 140
and/or diastolic BP > 90 despite optimal treatment

- Exclude human immunodeficiency virus (HIV)+ patients who have cluster of
differentiation (CD)4 counts which are below the lower limit of normal for the
institution

- Patients known to have a malignancy (other than their glioblastoma) that has required
treatment in the last 12 months and/or is expected to require treatment in the next
12 months (except non-melanoma skin cancer or carcinoma in-situ in the cervix)

- Patients are not allowed to receive concurrent anti-coagulation, and may not have
received thrombolytic or anticoagulant agents (except heparin or alteplase to
maintain IV catheters) within 10 days prior to drug administration

- Serious or non-healing wound, ulcer or bone fracture

- Evidence of bleeding diathesis or coagulopathy

- Patients with a history of hereditary hemorrhagic telangiectasia (HHT)

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with TRC105

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess
within 6 months