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

A Phase I Trial of Fractionated Docetaxel and Radium 223 in Metastatic Castration-Resistant Prostate Cancer (CRPC)

The objective of this study is to determine the maximum safe dose of Ra-223 in combination with fractionated (split doses) docetaxel when given to subjects and to determine the best administering dose. The study will look at side effects that may happen while taking the combination treatment. A total of approximately 18 subjects will take part in the dose escalation part of the study and an additional 25 subjects will participate in the expansion cohort. This study will be conducted across four centers in the United States.

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. Eligible for docetaxel chemotherapy

5. ECOG Performance Status 0-2

6. 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 AST ≤ 1.5 x upper limit of normal range
   6. Serum ALT ≤ 1.5 x upper limit of normal range

7. Estimated glomerular filtration rate (GFR) > 30mL/min

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

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

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

11. Age ≥ 18 years

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