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

A Prospective Open-label, Randomized, Two-arm Pilot Study to Investigate the Toxicity and Pharmacokinetics of 2-Weekly and 3-Weekly Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer.

This study is designed to investigate the toxicity and pharmacokinetics (PK) of 2-weekly and 3-weekly docetaxel in metastatic hormone-sensitive prostate cancer (mHSPC). Also, a mechanism-based population pharmacokinetics/pharmacodynamics (PK/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.

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.