Study of TRC105 With Abiraterone and With Enzalutamide in Prostate Cancer Patients Progressing on Therapy

This is a Phase II, open-label study of TRC105 (anti-endoglin antibody) in combination with
abiraterone or enzalutamide in metastatic, castration-resistant prostate cancer patients who
are taking either abiraterone or enzalutamide and showing signs of biochemical progression
without radiographic progression. A patient who is progressing on AR-therapy will continue
the same AR-therapy on study with the addition of TRC105. The two arms will accrue in
parallel and independently.

There will be a 2-week washout of the active AR-targeted therapy prior to initiation of
combination therapy. Tumor response should be assessed at a frequency of 8 weeks by CT/MRI
chest, abdomen and pelvis as well as bone scan. Patients may continue on therapy until
radiographic progression by RECIST 1.1 or PCWG3 criteria.

Inclusion Criteria:

1. History of metastatic, castration-resistant prostate cancer with rising PSA on either
abiraterone or enzalutamide

- PSA rise will be defined as an increase in PSA of 0.2 ng/mL or higher on at least
2 separate occasions greater than 1 week apart while on either abiraterone or
enzalutamide

- If there is a drop in serum PSA after the first rise, and the patient has another
PSA rise which is greater than the first, the patient will still be considered
eligible.

2. ECOG 0-2

3. Resolution of adverse events results as described below.

- Laboratory abnormalities must meet values specified below in criteria #4

- If the patient's most recent line of therapy is treatment with abiraterone or
enzalutamide, then all adverse events must be resolved to Grade 2 or better

- If the most recent line of therapy is any other treatment for mCRPC then all
Adverse events must be resolved to grade 1 or better, with the exception of
fatigue, alopecia and neuropathy (which must resolve to CTCAE grade 2)

4. Adequate organ function defined by:

- AST and ALT < 2.5 x ULN

- Total serum bilirubin < 1.5 x ULN

- Platelets > 60,000

- Hgb > 8.5 g/dL

- Serum Cr <1.5 x ULN

- INR ≤ 1.2 unless the patient is receiving a direct Factor Xa inhibitor or a
direct thrombin inhibitor

5. Patients must be surgically sterile or must agree to use effective contraception
during the study and for 3 months following last dose of TRC105. The definition of
effective contraception will be based on the judgment of the Principal Investigator or
a designated associate. Abstinence from intercourse is an acceptable form of
contraception.

Exclusion Criteria:

1. Non-PSA producing prostate cancers- such as small cell prostate cancers or those
prostate cancers which exhibit radiographic progression without PSA rise

2. Inability to tolerate standard doses of abiraterone (1000 mg daily) or enzalutamide
(160 mg daily).

3. Other prior malignancy requiring active anticancer therapy

4. Prior exposure to TRC105 or any CD105 targeted antibody

5. Any major surgical procedure within 2 weeks of starting therapy

6. Uncontrolled chronic hypertension defined as sustained by systolic pressure (SBP) >150
mmHg or diastolic pressure (DBP) >90 despite optimal therapy.

7. Active bleeding or pathologic conditions that carries a high bleeding risk

8. Use of thrombolytics within 10 days prior to the first day of TRC105

9. Known hypersensitivity to Chinese hamster ovary products or other recombinant human,
chimeric, or humanized antibodies

10. A known diagnosis of Osler-Weber-Rendu syndrome

11. Ascites or pericardial or pleural effusion requiring external drainage procedures

12. History of untreated brain involvement with cancer, spinal cord compression, or
carcinomatous meningitis, or new evidence of brain or leptomeningeal disease. Patients
with radiated or resected lesions are permitted, provided the lesions are fully
treated and inactive, patients are asymptomatic, and no steroids have been
administered for at least 28 days. Imaging for CNS disease will not be required for
screening unless there is a history of a neurological finding such as new onset
weakness or numbness that cannot be explained by other medical history.

13. Acute cardiovascular event within the past 6 months. An acute cardiovascular event
will be defined as a myocardial infraction, NYHA Class II or worse congestive heart
failure, cerebrovascular accident, transient ischemic attack, arterial embolism,
pulmonary embolism, percutaneous transluminal coronary angioplasty (PTCA), or CABG.
Deep venous thrombosis within 6 months, unless the patient is anti-coagulated without
the use of warfarin for at least 2 weeks. In this situation, low molecular weight
heparin is preferred.