Toxicity & Pharmacokinetics of 2 & 3-weekly Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC)

This pilot study is designed to investigate the toxicity and PK of 2-weekly and 3-weekly
docetaxel in mHSPC. Furthermore, a mechanism-based population PK/ pharmacodynamics (PD) model
will be developed to provide a better understanding of the complex relationships between the
drug exposure and toxicity profiles of docetaxel in mHSPC. In addition, selected
pro-inflammatory and macrophage-associated cytokines will be collected to assess the
potential role of these cytokines as the early markers of docetaxel resistance in patients
with mHSPC. (Cytokines: macrophage inhibitory cytokine 1 (MIC1), interleukin (IL)-1ra, IL-1β,
IL-4, IL-6, IL-12, and IFNγ). Serological response, defined as a prostate-specific antigen
(PSA) level of <0.2 ng/mL at 12 months, and progression-free survival at 12 months are
selected as the secondary clinical endpoints of the study.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed prostate cancer with
EXTENSIVE metastatic disease and have been on androgen deprivation therapy for <90
days. Hormonal therapy must not have commenced more than 90 days prior to study.

Definition of extensive disease: Metastases involving at least one lesion in any bony
structures beyond the vertebral column and pelvic bone or any involvement with
viscera. In the absence of visceral lesion, there must be four or more bone lesions.
Patients with disease limited to vertebral column and/or pelvis alone with or without
lymph node or lymph node only disease involvement are not eligible for this trial.

2. Age ≥18 years.

3. ECOG performance status ≤2 (Karnofsky ≥60%).

4. Patients must have normal organ and marrow function as defined below within four weeks
prior to the study:

- Absolute neutrophil count ≥1,500/mcL

- Platelets ≥100,000/mcL

- Total bilirubin less than ULN

- AST(SGOT)/ALT(SGPT) ≤1.5 × institutional upper limit of normal

- Alkaline phosphate ≤2.5 x ULN

- Creatinine clearance ≥ 30 mL/min calculated using the Cockcroft-Gault formula:
Creatinine clearance for male (mL/min) = (140-age)*(body weight in kg)/(72 x
serum creatinine in mg/dl)

5. If a patient has had major surgery, the patient must be longer than four weeks post
surgery and must have recovered from all toxicity prior to beginning protocol study.

6. Peripheral neuropathy with Grade ≤1

7. Patients may be enrolled if they have had prior palliative radiation therapy. However,
this has to have been commenced within 30 days of starting androgen deprivation.

8. Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

1. Patients who are receiving any other investigational agents.

2. Patients with known brain metastases are excluded from this clinical trial because of
their poor prognosis and because they often develop progressive neurologic dysfunction
that would confound the evaluation of neurologic and other adverse events.

3. History of hypersensitivity to docetaxel or polysorbate 80.

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social dysfunction that could impair the ability of
the patients to participate in the study or interfere with interpretation of study
results.

5. Docetaxel is a CYP3A4 substrate and caution should be taken with its use and any drugs
known to interact with it. Because the lists of these agents are constantly changing,
it is important to regularly consult a frequently updated list such as
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as
the Physicians' Desk Reference for this information. As part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal
product. Appendix B contains a list of known drugs that are contraindicated or have
major interactions with docetaxel.

6. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for PK interactions with docetaxel. In addition, these patients are at
increased risk of lethal infections when treated with marrow-suppressive therapy.
Appropriate studies will be undertaken in patients receiving combination
antiretroviral therapy when indicated.

7. Patients with prior docetaxel chemotherapy.