Phase 2 Trial of Carfilzomib for Metastatic Castration-resistant Prostate Cancer Following Treatment

First-line chemotherapy for metastatic castration-resistant prostate cancer (CRPC) combined
with androgen inhibitors modestly extends overall survival. Carfilzomib is anticipated to
enhance progression-free survival (PFS) as well as reduce pain and toxicities.

Proteasome inhibitors are promising agents used in the therapy of prostate cancer.
Carfilzomib is a more potent and irreversible proteasome inhibitor than the frequently used
proteasome inhibitor, Bortezomib. In Phase I trials Carfilzomib demonstrated substantial
antitumor activity while exhibiting tolerable side effects.

Carfilzomib has been approved by the FDA for patients with multiple myeloma. The drug,
however, is not approved for the use with CRPC patients. This trial will evaluate the
tolerance and effectiveness of Carfilzomib in men with metastatic progressive CRPC following
chemotherapy and androgen inhibitors.

Inclusion Criteria:

- Histologically proven adenocarcinoma of the prostate

- Metastatic disease

- Progressive disease (PSA, radiologic, symptomatic) following abiraterone acetate
and/or Enzalutamide (prior sipuleucel-T and chemotherapy are allowed); PSA progression
is defined as baseline increase followed by any PSA increase ≥1 week apart.

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Patients, even if surgically sterilized (i.e., status post-vasectomy) must agree to
one of the following: practice effective barrier contraception during the entire study
treatment period and through a minimum of 30 days after the last dose of study drug,
or completely abstain from heterosexual intercourse if female partner of childbearing
age.

- An elevated PSA level of >2ng/mL for patients progressing by PSA criteria is required
(last confirmatory sample must be >2ng/mL)

- Currently on androgen ablation hormone therapy (a luteinizing hormone- releasing
hormone (LHRH) agonist/antagonist or orchiectomy) with testosterone level <50ng/dL)

- Has an Eastern Cooperative Oncology Group (ECOG) Performance status of 0 - 2

- Left ventricular ejection fraction (LVEF) ≥40% on 2-D transthoracic echocardiogram
(ECHO); Multi-gated Acquisition Scan (MUGA) is acceptable if ECHO is not available.

- ≥19 years of age

- Resolution of all acute toxic effects of prior chemotherapy or surgical procedures to
NCI CTCAE Version 4.03 Grade <1, in the opinion of the treating physician.

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patient has a platelet count of <100,000/mm3, or absolute neutrophil count of
<1500/mm3 or Hemoglobin <8.0gm/dL

- Patient has a calculated or measured creatinine clearance of <30 milliliters
(mL)/minute

- Patient has total bilirubin >2 x upper limit of normal (ULN), or aspartate
aminotransferase (AST), alanine aminotransferase (ALT) >3.5 x ULN

- Patient has ≥ Grade 2 peripheral neuropathy within 14 days before enrollment

- Myocardial infarction within 6 months prior to enrollment or has New York Heart
Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe
uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute
ischemia or active conduction system abnormalities. Before study entry, any ECG
abnormality at screening has to be documented by the investigator as not medically
relevant.

- Participation in clinical trials with other investigational agents not included in
this trial, within 14 days of the start of this trial and throughout the duration of
this trial.

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- Diagnosed or treated for another malignancy within 3 years of enrollment, with the
exception of: a) adequately treated basal cell carcinoma, squamous cell skin cancer,
or thyroid cancer; b) carcinoma in situ of the breast; c) cancer considered cured by
surgical resection or unlikely to impact survival during the duration of the study,
such as localized transitional cell carcinoma of the bladder or benign tumors of the
adrenal or pancreas.

- Known HIV, hepatitis B and hepatitis C infection

- Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to
randomization

- Prior treatment with bortezomib

- Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize
Carfilzomib)

- Has received prior radiation to >50% of the bone marrow

- Has had significant bleeding/thrombosis in previous 4 weeks

- Has received treatment with radiation therapy, surgery, chemotherapy, or an
investigational agent within 4 weeks prior to registration, (6 weeks for radiation
therapy, radionuclides, nitrosoureas, or Mitomycin C) or who have not recovered from
adverse events due to agents administered more than 4 weeks earlier

- Has evidence of uncontrolled Central Nervous System (CNS) involvement (previous
radiation and off steroids is acceptable)

- Patients may not be receiving any other investigational agents

- Has a serious uncontrolled intercurrent medical or psychiatric illness, including
serious infection

- Is unable to comply with study requirements

- 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.