Phase I Trial of PACE for Metastatic Prostate Cancer

Multiple agents have been shown to improve survival in patients with mCRPC by up to five
months. The combination of prednisone, abiraterone, cabazitaxel and enzalutamide may be
anticipated to be feasible therapy with minimal or no adverse drug interactions. This is a
phase I trial to study the feasibility of the proposed therapy.

Patients will undergo a combination of oral daily drug intake at varying doses over a period
of three weeks. Monitoring including blood collection for laboratory testing will be done on
Day 1 of each three-week cycle with additional monitoring during the first cycle. Imaging and
correlative studies will be done every 12 weeks. Therapy will continue until disease
progression or severe toxicities.

Inclusion Criteria:

1. Age ≥18 years

2. Histologically proven adenocarcinoma of the prostate with metastatic disease.

3. Progressive disease following androgen deprivation therapy; Prostate Specific Antigen
(PSA) progression defined as baseline increase followed by any PSA increase greater
than or equal to 1 week apart.

4. Most recent PSA ≥2 ng/ml

5. Testosterone < 50 ng/dL

6. Anti-androgen withdrawal of first generation AR inhibitors (bicalutamide, nilutamide)
is required for 6 weeks if previous duration of stability on them was ≥3 months.

7. ECOG performance status 0-1.

8. Adequate organ function as defined below:

ANC 1,500/µl; Hemoglobin 10 g/dL; Platelet count 100,000/µL; Creatinine clearance ≥45
ml/min; Potassium >3.5 mmol/L (or within institutional normal range) Bilirubin ≤ ULN
(unless documented Gilbert's disease); SGOT (AST) 1.5 x ULN; SGPT (ALT) 1.5 x ULN

9. Subject agrees to use a double barrier method of contraception during the course of
study therapy and for at least 3 months after completion of therapy. A double barrier
method involves the use of a condom in combination one of the following: sponge,
diaphragm, cervical ring with spermicidal gel or foam. Subjects who have had a
vasectomy ≥6 months prior to trial therapy and those with female sexual partners who
are 55 years old and post-menopausal for 2 years or sterile (by tubectomy,
hysterectomy, bilateral oophorectomy) need to agree to use at least a condom.

10. Ability to sign a written informed consent form.

11. Subject is willing to stop herbal supplements.

Exclusion Criteria:

1. Prior docetaxel for castration-resistant disease (prior docetaxel for
castration-sensitive disease is allowed but not required).

2. Prior enzalutamide, abiraterone, cabazitaxel.

3. History of severe hypersensitivity reaction (≥grade 3) to docetaxel.

4. History of severe hypersensitivity reaction (≥grade 3) to polysorbate 80 containing
drugs.

5. Concomitant vaccination with yellow fever vaccine.

6. Prior investigational androgen synthesis or androgen receptor antagonists.

7. Prior hypersensitivity reaction to capsule components of enzalutamide including
labrasol, butylated hydroxyanisole and butylated hydroxytoluene

8. Other non-chemotherapeutic investigational agents within 14 days (prior chemotherapy
needs a ≥4 week washout).

9. Concurrent or planned treatment with strong inhibitors or strong inducers of
cytochrome P450 3A4/5 (a one week wash-out period is necessary for patients who are
already on these treatments).

10. Prior isotope therapy with Strontium-89, Samarium or radium-223.

11. Patients with a history of central nervous system metastases (brain, meninges, spinal
cord).

12. Imminent risk of pathologic fracture or cord compression.

13. History of seizures, underlying brain injury with loss of consciousness, transient
ischemic attack within 12 months, cerebrovascular accident, and brain arteriovenous
malformations.

14. Uncontrolled severe intercurrent illness or medical conditions including, but not
limited to, ongoing or active infection, symptomatic congestive heart failure (New
York Heart Association Class III and IV heart failure), unstable angina pectoris,
uncontrolled diabetes mellitus, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements or concurrent
medications that alter cardiac conduction.

15. Patients with a "currently active" second malignancy other than non- melanoma skin or
superficial urothelial cancers are not eligible. Patients are not considered to have a
"currently active" malignancy if they have completed therapy and are now considered
without evidence of disease for 3 years.