The purpose of this study is to determine the safety and efficacy of a novel combination of agents, enzalutamide and everolimus, for the treatment of patients with metastatic castrate-resistant prostate cancer who have never received prior chemotherapy, or who have previously received docetaxel chemotherapy and have progressive disease.

This is a multi-center, open-label, Phase I study with an expansion cohort, in patients with metastatic Castrate-Resistant Prostate Cancer (CRPC) who are chemotherapy-naive or have previously received docetaxel chemotherapy and have progressive disease at the time of study entry. The dose escalation phase of this study will establish the optimum daily dose of everolimus that can be delivered along with a standard daily dose of enzalutamide to patients with metastatic CRPC. Eligible patients must have evaluable (elevated PSA) or measurable disease (per RECIST v1.1). Following completion of the dose escalation phase, an additional cohort of patients will be treated at the maximum tolerated dose (MTD) to give preliminary information regarding the efficacy of this combination.

Inclusion Criteria:

KEY POINTS:

1. Adenocarcinoma of the prostate confirmed histologically.

2. Metastatic disease confirmed by biopsy or imaging studies.

3. Castrate-resistant prostate cancer (i.e., progression of prostate cancer while receiving standard androgen ablation therapy, orchiectomy or luteinizing hormone-releasing hormone [LHRH] antagonist). Castrate levels of serum testosterone must be documented at progression in patients who have not had an orchiectomy.

4. Chemotherapy-naive or previously treated with docetaxel for metastatic prostate cancer.

5. ECOG of 0 to 2.

6. Patients must have progressive metastatic prostate cancer by at least 1 of the following criteria:

   • Progression of measurable lesions defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
   • Bone progression defined by 2 or more new lesions on bone scan.
   • PSA progression is determined by a minimum of two rising PSA levels with an interval of 1 week or greater between each determination. The screening PSA measurement (documenting progression) must be greater than or equal to 2 ng/mL.

7. Adequate hematologic, hepatic and renal function.

8. Adequate coagulation parameters and serum chemistries.

9. Ability to swallow and retain oral medication.

10. Life expectancy of 6 months or greater.

11. Ability to understand the nature of the study and give written informed consent.

Exclusion Criteria:

1. Treatment with more than 2 prior chemotherapy regimens.
2. Previous treatment with enzalutamide or other investigational androgen receptor inhibitors.
3. Previous treatment with PI3K/mTOR inhibitors.
4. Known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or its excipients.
5. Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study drug. For investigational drugs for which 5 half-lives is less than 21 days, a minimum of 10 days between termination of the investigational drug and administration of study drug is required.
6. Most recent chemotherapy ≤21 days from first dose of study treatment and/or patient did not recover from most recent chemotherapy side effects prior to study entry.
7. CNS metastases.