A Phase I/II Study of TRC105 in Metastatic Castrate Resistant Prostate Cancer (CRPC)

Background:

- Inhibition of angiogenesis has demonstrable antitumor efficacy against castrate-resistant
prostate cancer (CRPC). TRC105 is a human/murine chimeric immunoglobulin heavy constant gamma
1 (IgG1) kappa monoclonal antibody that binds to human CD105 (endoglin), thus inhibiting
angiogenesis and tumor growth. Data from an ongoing phase I clinical trial suggest that
TRC105 is well tolerated with evidence of clinical efficacy in patients with metastatic CRPC.

Primary Objectives:

- Define the maximum tolerable dose (MTD) of TRC105 given every one to two weeks.

Secondary Objectives:

- Define the dose-limiting toxicities and toxicity profile of TRC105 given every one to
two weeks

- Evaluate time to disease progression, overall response rate and overall survival.

- Describe the prostate specific antigen (PSA) response rate to therapy with TRC105

- Characterize the pharmacokinetics of TRC105

- Demonstrate a biologic effect of TRC105 in the patient and, when possible, on the tumor
via laboratory evaluation of the molecular markers of angiogenesis before and after drug
administration respectively

Eligibility:

- Progressive, castrate-resistant, metastatic adenocarcinoma of the prostate

- Eastern Cooperative Oncology Group (ECOG) less than or equal to 2

Design:

- An initial single-arm, phase I dose escalation study open to all patients with progressive
metastatic CRPC. The study will evaluate patients in five cohorts of escalating dose levels.
A maximum of 30 patients will be needed to complete the phase I evaluation.

- INCLUSION CRITERIA:

1. Patients must have histopathological confirmation of prostate cancer by the
Laboratory of Pathology of the National Cancer Institute (NCI), Pathology
Department of the National Naval Medical Center or Pathology Department of Walter
Reed Army Medical Center prior to entering this study. Patients whose pathology
specimens are no longer available may be enrolled in the trial if the patient has
a clinical course consistent with prostate cancer and available documentation
from an outside pathology laboratory of the diagnosis. In cases where original
tissue blocks or archival biopsy material is available, efforts will be made to
contact referring physicians and outside pathology departments to have the
material forwarded to the research team for use in correlative studies.

2. Patients must have metastatic progressive castrate-resistant prostate cancer
defined as progressive disease (see below) despite surgical castration or ongoing
use of gonadotropin-releasing hormone agonists with confirmed castrate levels of
testosterone.

Criteria of progression for trial eligibility are defined from the Prostate Cancer Clinical
Trials Working Group-2. Clinically progressive prostate cancer must be evidenced and
documented by any of the following parameters:

1. Two consecutively rising prostate specific antigen (PSA) values at a minimum of 1-week
intervals (2.0 ng/mL is the minimum starting value for PSA)

2. Appearance of one or more new lesion on bone scans

3. Progressive measurable disease by Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1

Patients on flutamide for at least 6 months must have disease progression at least 4
weeks after withdrawal. Patients on bicalutamide or nilutamide for at least 6 months
must have progression at least 6 weeks after withdrawal.

All patients enrolled will be required to have measurable or non-measurable disease on
imaging studies.

4. Age greater than or equal to 18 years.

5. Life expectancy of greater than 3 months.

6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.

7. Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than or equal to 1,500/mcL

- Platelets greater than or equal to 100,000/mcL

- Total bilirubin less than or equal to 1.5 times upper normal limits or less than
3 mg/dl in subjects with Gilbert's Syndrome

- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) less than or
equal to 2.5 times upper limit of normal

- Creatinine less than or equal to 1.5 times upper normal limits OR creatinine
clearance greater than or equal to 40 mL/min/1.73 m^2 for patients with
creatinine levels above institutional normal, as calculated by the Cockcroft
Gault formula.

8. Patients must have recovered from any acute toxicity related to prior therapy,
including surgery. Toxicity should be less than or equal to grade 1 or returned
to baseline.

9. All patients who have not undergone bilateral surgical castration must
continue suppression of testosterone production by appropriate usage of
gonadotropin releasing hormone (GnRH) agonists or antagonists.

10. Patients must not have other invasive malignancies (within the past 2 years
with the exception of non-melanoma skin cancers or non-invasive bladder cancer).

11. Enrolled patients must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry, the duration
of study participation and 3 months after the end of the treatment.

12. Patient must be able to understand and willing to sign a written informed
consent document.

13. Patients on a stable dose of steroids of 10 mg/day or less can continue on
steroids if they are on peptic ulcer disease prophylaxis with an H2-blocker or
proton pump inhibitor.

EXCLUSION CRITERIA:

1. Patients who have had chemotherapy, large field radiotherapy, or major surgery
must wait 3 weeks prior to entering the study.

2. Patients may not be receiving any agents not approved by the Food and Drug
Administration (FDA) within the past 4 weeks.

3. Patients with known brain metastases will be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive
neurologic dysfunction that would confound the evaluation of neurologic and other
adverse events.

4. Proteinuria, as demonstrated by a 24 hour protein of (Bullet) 2000 mg. Urine
protein will be screened by urine protein-creatinine ratio (UPC). For UPC ratio >
1.0, a 24-hour urine protein will need to be obtained and the level should be <
2000 mg for patient enrollment.

5. Uncontrolled intercurrent illness including, but not limited to, hypertension
(systolic blood pressure (BP) > 160, diastolic BP > 100), ongoing or active
systemic infection, symptomatic congestive heart failure, unstable angina
pectoris, cardiac arrhythmia or psychiatric illness/social situations that would
limit compliance with study requirements.

6. Thrombolytic or treatment-dose anticoagulant use within 10 days prior to first
dose with TRC105.

7. Hemorrhage within 30 days of dosing.

8. History of peptic ulcer disease or gastritis within 6 months of TRC105
administration, unless patient has received adequate treatment for peptic ulcer
disease and has evidence of complete resolution documented by
esophagogastroduodenoscopy (EGD).

9. Corrected QT interval (QTc) > 500 msec.

10. Known human immunodeficiency virus (HIV)-positive patients are excluded.

11. History of hypersensitivity reaction to human or mouse antibody products.

12. Patients with a history of familial bleeding disorders.

13. Patients with a history of hereditary hemorrhagic telangiectasia
(Osler-Weber-Rendu syndrome).

14. Use of non-steroidal anti-inflammatory drugs (NSAIDs) beginning 14 days prior to
the first TRC105 dose, with the exception of aspirin when clinically indicated.