Prostate Cancer Intensive, Non-Cross Reactive Therapy (PRINT) for Castration Resistant Prostate Cancer (CRPC)

This phase II clinical trial will explore the efficacy of rapidly cycling non-cross reactive
treatment therapies in the treatment of patients with newly diagnosed mCRPC. The primary
hypothesis is that the best chance of eliminating or controlling disease is when the cancer
is treatment naïve, and has not yet developed therapeutic resistance. By finding an optimal
drug deployment strategy of already approved and available treatments for mCRPC, the
researchers believe providers can more effectively treat an intrinsically heterogeneous
disease, delay/prevent drug resistance, as well as minimize treatment toxicity.

All of the treatment agents selected have well-defined individual toxicity profiles from
large phase III trials, but there is limited clinical data about the toxicity profiles of
these drugs in combinations. While each agent is generally well tolerated, toxicities remain
a significant concern given the older age of the typical mCRPC patient, the comorbid
conditions common to this patient population, as well as those borne from previous chronic
androgen deprivation therapy.

Each drug in the proposed treatment regimen will be used at their FDA-approved dosing and
indication, with the exception of cabazitaxel, which will be used prior to disease
demonstration of docetaxel failure, and in combination with carboplatin. The proposed
sequencing is rationally designed, and based on each drug's distinct mechanisms of action as
well as their toxicity profiles.

The rapidly-cycling treatment regimen contains three, separate, consecutive treatment
modules, each lasting 3 months: 1. Abiraterone; 2. Cabazitaxel + Carboplatin; 3. Enzalutamide
+ Radium-223. Therapeutic agents are delivered as non-cross reactive combinations, in order
to achieve optimal therapeutic dosing at each cycle and decrease possibility of significant
adverse effects.

To the researcher knowledge, no study has evaluated the use of rapidly cycling, non-cross
reactive therapies for the treatment of mCRPC. The hypothesis is that the identification of
optimal combinations and sequencing of rapidly cycling non-cross reactive therapies can help
prevent or delay the development of therapeutic drug resistance, and can be safely tolerated.

Primary objective is to evaluate the time to disease progression after completion of all
modules of the rapidly-cycling, non-cross reactive regimen in patients with mCRPC. Secondary
objectives are to evaluate overall survival, prostate-specific antigen (PSA) response rate
with each treatment module, changes to alkaline phosphatase level, and assess safety of the
rapidly-cycling, non-cross reactive regimen. Additional exploratory objective are to evaluate
the correlation of a peripheral whole-blood RNA signature with clinical outcome measures
during and after treatment, and to evaluate changes to AR-V7 expression in CTCs with
different treatment modalities and clinical outcomes.

Inclusion Criteria:

- Histologically or cytologically confirmed adenocarcinoma of the prostate

- Metastatic castrate resistant prostate cancer, defined by progressive disease based on
either rising PSA, new bone metastases, or progression of measurable disease on
standard imaging, according to PCWG2 guidelines, despite androgen deprivation therapy

- Ongoing androgen deprivation therapy with a GnRH analogue, GnRH antagonist, or
bilateral orchiectomy

- ECOG performance status 0-1

- Serum testosterone level < 50 ng/dL

- Absolute neutrophil count > 1,500/μL, platelet count > 100,000/μL, and hemoglobin > 9
g/dL

- Creatinine < 2 mg/dL

- Total bilirubin < 1 times the upper limit of normal, alanine aminotransferase (ALT) or
aspartate aminotransferase (AST) ≤ 1.5 times the upper limit of normal

Exclusion Criteria:

- History of uncontrolled seizure disorder

- Clinically significant cardiovascular disease including:

1. Myocardial infarction or uncontrolled angina within 6 months

2. Congestive heart failure New York Heart Association (NYHA) class 3 or 4, or
patients with history of congestive heart failure NYHA class 3 or 4 in the past

3. Uncontrolled hypertension as indicated by a resting systolic blood pressure > 170
mmHg or diastolic blood pressure > 105 mmHg at the screening visit

- Have used or plan to use from 30 days prior to enrollment through the end of the study
medication known to lower the seizure threshold or prolong the QT interval

- Major surgery within 4 weeks of enrollment

- Radiation therapy within 4 weeks of enrollment

- Prior use of abiraterone acetate, enzalutamide, docetaxel, cabazitaxel, carboplatin,
or radium-223 for the treatment of castration-resistant disease

- Prior docetaxel use in the hormone-sensitive disease setting is allowed, but must be
completed ≥ 4 weeks prior to enrollment

- Prior sipuleucel-T use is allowed, but must be completed ≥ 4 weeks prior to enrollment

- Concurrent use of zoledronic acid or denosumab is allowed on study