Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer

The primary objective of this study is to assess the safety and toxicity of a fractionated
docetaxel schedule in combination with standard Ra-223.

Secondary Objectives include: assessment of progression-free survival, time to treatment
failure, overall survival, ability of subjects to complete 6 cycles of the combination
therapy, assessment of Prostate Specific Antigen (PSA) kinetics and objective responses
(measurable disease), assessment of quality of life and assessment of bone bio-marker
outcomes.

The study features a 4-week lead-in period with docetaxel monotherapy to assess for docetaxel
intolerance. The lead-in period is then followed by combination therapy with Ra-223 every 4
weeks for 6 cycles in a traditional Phase I dose-escalation design.

A provision has been made to include prophylactic granulocyte colony stimulating factor
(G-CSF) cohorts after the lead-in period if neutropenia is the dose limiting toxicity at
either dose level.

The investigators hypothesize that the fractionated dosing of docetaxel will significantly
mitigate the hematologic toxicity, preserve antineoplastic activity and allow for maintenance
of the 4-weekly Ra-223 schedule.

Inclusion Criteria:

1. Histologically or cytologically confirmed adenocarcinoma of the prostate

2. Documented metastatic castration resistant disease with PSA progression, radiographic
progression, or both, despite medical or surgical castration

3. Two or more bone metastases detected on skeletal scintigraphy

4. No more than one prior second generation androgen receptor inhibitor

5. Eligible for docetaxel chemotherapy

6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

7. Adequate organ function:

1. Hemoglobin > 10 g/dL

2. Absolute Neutrophil Count > 1,500 K/mL

3. Platelet count > 150,000 x 10^9/L

4. Total bilirubin < 1.5x upper limit of normal range, excluding Gilbert syndrome

5. Serum aspartate aminotransferase (AST) < 1.5 x upper limit of normal range

6. Serum alanine aminotransferase (ALT) < 1.5 x upper limit of normal range

7. Calculated creatinine clearance > 30mL/min

8. Age ≥ 18 years

9. Ongoing castration (androgen deprivation therapy or prior orchiectomy)

10. Male subjects with female sexual partners of childbearing potential must agree to use
at least one highly effective methods of birth control.

11. Ability to understand and willingness to sign an informed consent form prior to
initiation of any study procedures.

Exclusion Criteria:

1. Prior radionuclide therapy for CRPC

2. Prior docetaxel for CRPC. (Permitted if given for castration sensitive disease > 6
months prior).

3. Antiandrogen therapy within 4 weeks of enrollment. However, patients with primary
failure of secondary anti-androgen therapy OR symptomatic progression, objective
progression and/or biochemical evidence of rising PSA less than 4 weeks after
discontinuation of anti-androgen therapy will not have anti-androgen withdrawal
responses and will not be excluded.

4. Preexisting peripheral neuropathy grade 2 or higher.

5. Other serious medical condition as judged by the investigator.

6. Active second malignancy that requires therapy.

7. Known brain or leptomeningeal metastases

8. Concurrent enrollment in any other investigational anticancer therapy

9. Treatment with any myelosuppressive agent within 30 days of enrollment

10. Presence of bulky visceral metastases, defined as any of the following:

1. ≥ 4 lung lesions (at least 1cm each in size in the longest diameter) or pulmonary
lymphangitic metastasis

2. Liver metastases with sum of lesion diameters totaling ≥ 5cm

11. Evidence of neuroendocrine or small cell differentiation on prior biopsy

12. History of severe hypersensitivity reactions to docetaxel or to drugs formulated with
polysorbate 80