AMG 386 and Abiraterone for Advanced Prostate Cancer

Background:

- Inhibition of angiogenesis, either as a stand-alone approach or in combination with
chemotherapy, has demonstrable antitumor efficacy against castration-resistant prostate
cancer (CRPC) and there are several antiangiogenic agents that are now in clinical
trials in this population of patients.

- AMG 386 is a novel peptide-Fc fusion protein. The molecule is a non-glycosylated
homodimer engineered by fusing an Immunoglobulin gamma-1 heavy chain constant region,
partial (IgG1 Fc) domain to 4 copies of an anti-angiopoietin 2 (Ang2) peptide. AMG 386
sequesters Ang1 and Ang2, thereby preventing their interaction with Tie2 and inhibiting
tumor endothelial cell (EC) proliferation and tumor growth.

- Abiraterone acetate is a small molecule that irreversibly inhibits Cytochrome P450 17A1
(CYP17), a rate-limiting enzyme in androgen biosynthesis, to block residual androgen
synthesis in the adrenal gland and tumor cells.

- Previous studies have demonstrated that in vivo alterations of testosterone levels
regulate the expression of vascular endothelial growth factor (VEGF), fibroblast growth
factor (FGF), and angiopoietin family members. Dual targeting of the androgen and
angiogenic axis represents a novel approach as a potential targeted therapy for patients
with metastatic castration-resistant prostate cancer (CRPC).

Objectives:

-To estimate the treatment effect as measured by progression free survival (PFS) in patients
treated with AMG 386 plus abiraterone/prednisone relative to abiraterone/prednisone alone.

Eligibility:

-Patients with progressive, metastatic CRPC with radiographic evidence of progression after
primary therapy (surgery or radiotherapy) and adequate androgen deprivation therapy.

Design:

- This is an open-label, randomized, phase II multicenter trial with a two-part design and
a planned accrual of 88 patients.

- An initial run-in phase of AMG 386 will be conducted with 15mg/kg weekly escalating to
30mg/kg weekly to establish the MTD. The decision on declaration of a safe and tolerable
dose during this run-in phase will lead to the second part of the study consisting of a
randomized comparison of abiraterone/prednisone plus AMG 386 (at the established maximum
tolerated dose (MTD)) vs. abiraterone/prednisone alone.

- AMG 386 will be administered intravenously every week, on days 1, 8, 15 and 22 of each
28-day cycle. Abiraterone acetate will be self-administered once daily by mouth and
prednisone will be self-administered by mouth either twice per day at 5 mg per dose or
once per day at 10 mg per dose as the patient prefers.

- INCLUSION CRITERIA:

- Must have metastatic, progressive, castrate-resistant prostate cancer (CRPC) with
radiographic evidence of disease that has continued to progress radiographically or
biochemically (rising prostatic specific antigen (PSA) levels on successive
measurements) despite adequate androgen-deprivation therapy. If patients had been on
flutamide, disease progression is documented 4 weeks or more after withdrawal. For
patients on bicalutamide or nilutamide disease progression is documented 6 or more
weeks after withdrawal. Flutamide, nilutamide and bicalutamide disease progression
requirements only apply to patients who have been on these drugs for at least the
prior 6 months.

- Histopathological confirmation of prostate cancer by the Laboratory of Pathology of
the National Cancer Institute (NCI) or Walter Reed National Military Medical Center
prior to entering this study. Patients enrolled at participating sites may have
histopathological confirmation at the enrolling center prior to entering the study.
Patients whose pathology specimens are no longer available may be enrolled if the
patient has a clinical course that is consistent with prostate cancer and available
documentation from an outside pathology laboratory of the diagnosis. All efforts
should be made to have the material forwarded to the research team for use in
correlative studies in cases where original tissue blocks or archival biopsy material
is available.

- Patients must have metastatic disease, defined as at least one lesion on bone scan or
at least one lesion that can be accurately measured in at least one dimension (longest
diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >20
mm with conventional techniques or as >10 mm with spiral computed tomography (CT)
scan, magnetic resonance imaging (MRI), or calipers by clinical exam.

- Patients participating in the study must have Metastatic Castration-Resistant Prostate
Cancer (mCRPC).

- Patients who have received docetaxel plus androgen deprivation therapy (ADT) for
metastatic castrate sensitive prostate cancer are eligible for the study. (Patients
may enroll as long as they did not have progressive disease while on docetaxel and are
6 months removed from treatment, with all treatment related toxicities resolving to at
least grade 1.)

- Patients may not have had more than 7 days of treatment with ketoconazole by mouth in
the past 6 months.

- Males greater than or equal to 18 years of age. Because no dosing or adverse event
data are currently available on the use AMG 386 in combination with abiraterone in
patients <18 years of age, children are excluded from this study, but will be eligible
for future pediatric trials.

- Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
for run-in phase; ECOG less than or equal to 1 for randomized phase.

- Life expectancy of > 3 months for the run in phase and > 6 months for the randomized
phase.

- Adequate bone marrow, hepatic, and renal function with:

- Leukocytes greater than or equal to 3000/mu L

- Absolute neutrophil count (ANC) greater than or equal to 1500/mu L

- Platelets greater than or equal to 100000/mu L

- Total bilirubin less than or equal to 1.5 times institutional upper limits of
normal

- Aspartate aminotransferase (AST) serum glutamic oxaloacetic
transaminase(SGOT)/alanine aminotransferase (ALT) serum glutamic pyruvic
transaminase(SGPT) less than or equal to 2.5 times institutional upper limits of
normal

- Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT)
less than or equal to 1.5 times upper limits of normal (ULN) per institutional
laboratory range and international normalized ratio (INR) less than or equal to 5

- Creatinine less than or equal to 1.5 times institutional upper limits of normal

OR

- Creatinine clearance of >40 mL/min per 24 h urine collection or calculated according
to the Cockcroft-Gault formula

---Creatinine clearance (CrCl) (mL/min) = (((140-age) times actual body weight
(kg))/(72 x serum creatinine (mg/dL)))*(x 0.85 for females)

- Urinary protein less than or equal to 30 mg/dL in urinalysis or less than or equal
to1+ on dipstick, unless quantitative protein is <1000 mg in a 24h urine sample

- Generally well-controlled blood pressure with systolic blood pressure less than
or equal to 140 mmHg AND diastolic blood pressure less than or equal to 90 mmHg
prior to enrollment. The use of antihypertensive medications to control
hypertension is permitted.

- Must have recovered from any acute toxicity related to prior therapy, including
surgery. Toxicity should be less than or equal to grade 1 Common Terminology
Criteria in Adverse Events (CTCAE) version 4 or has returned to baseline.
Alopecia >grade 1 is permitted.

- The effects of AMG 386 on the developing human fetus are unknown. For this reason
and because inhibitors of angiogenesis as well as other therapeutic agents used
in this trial are known to be teratogenic, 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 her partner is participating in this study, she should inform her treating

physician immediately. Men treated or enrolled on this protocol must agree to use adequate
contraception prior to the study, for the duration of study participation, and 6 months
after completion of AMG 386 administration.

-Must have the ability to understand and the willingness to sign a written informed consent
document.

EXCLUSION CRITERIA:

- Patients who have had chemotherapy for metastatic castration-resistant prostate
cancer.

- History or presence of known central nervous system metastases.

- History of venous or arterial thromboembolism within 12 months prior to
enrollment/randomization.

- History of clinically significant bleeding within 6 months of
enrollment/randomization.

- Currently or previously treated with AMG 386, or other molecules that primarily
inhibit the angiopoietins or Tie2 receptor.

- Clinically significant cardiovascular disease within 12 months prior to
enrollment/randomization, including myocardial infarction, unstable angina, grade 2 or
greater peripheral vascular disease, cerebrovascular accident, transient ischemic
attack, congestive heart failure, or arrhythmias not controlled by outpatient
medication or placement of percutaneous transluminal coronary angioplasty/stent.

- Major surgery within 28 days prior to enrollment or still recovering from prior
surgery.

- Minor surgical procedures, placement of tunneled central venous access device within 3
days prior to randomization/enrollment.

- Treatment within 30 days prior to enrollment with the following: cyclosporine,
tacrolimus, sirolimus, mycophenolate mofetil, methotrexate, azathioprine, rapamycin,
and targeted immune modulators such as abatacept (CTLA-4-Ig), adalimumab,

alefacept, anakinra, belatacept (LEA29Y), efalizumab, etanercept, infliximab, or rituximab.

- Patients who have had large field radiotherapy must wait 2 weeks prior to entering the
study.

- Non-healing wound, ulcer (including gastrointestinal), or fracture.

- Contraindication to steroid use or history of allergic reactions attributable to the
study compounds.

- History of allergic reactions to bacterially-produced proteins.

- Previously diagnosed with another malignancy, within the past two years with the
exception of non-melanoma skin cancers or non-invasive bladder cancer.

- Patients who have not yet completed at least 28 days (30 days for prior monoclonal
antibody therapy) since receiving other investigational drugs.

- Inability to absorb abiraterone after oral administration (i.e., previous major
gastrointestinal surgery or gastrointestinal disease resulting in malabsorption).

- Use of ketoconazole, itraconazole, ritonavir, cyclosporine, carbamazepine, phenytoin,
phenobarbital within 2 weeks prior to and while on study therapy.

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
the study agents. In addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive

therapy. Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.

- Uncontrolled intercurrent illness or infections, unstable angina pectoris, cardiac
arrythmias, renal dysfunction, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Have had treatment with docetaxel for the treatment of metastatic castrate-sensitive
prostate cancer within 6 months before the first dose of study enrollment.

- Have had progression of prostate cancer on prior docetaxel treatment for castrate
sensitive disease.