Study of Docetaxel +153 Sm-EDTMP in Patients With Hormone-Refractory Prostate Cancer
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 1

Summary: 
      The primary objective of the study is to determine a recommended phase II dose (RP2D).

      The secondary objective of the study are:

        1. To evaluate preliminary incidence and duration of clinical benefits as determined by
           improvements of pain, PSA decline and bone scan changes.

        2. To evaluate the toxicity profile of the escalating doses of Docetaxel in combination
           with Samarium 153 in patients with advanced, hormone refractory prostate cancer
           metastatic to the bone.
    

Detailed description: 
      Prostate cancer remains the leading cancer diagnosed in men in the USA. It is estimated that
      232,090 new cases will be diagnosed in 2003, which account for about 30% of all cancer cases
      diagnosed in men.(1) Prostate cancer is still the second leading cause of cancer death in men
      (after lung cancer) in the US with estimated 28,900 men dying of prostate cancer in 2003.
      Although 79% of men will present with early stage disease (i.e., local or regional) at the
      time of diagnosis, a substantial number of men will present with metastatic disease. (2)
      Unfortunately many of the patients who present with local disease and are treated with local
      therapy will eventually experience disease recurrence. Initial treatment for patients with
      prostate cancer in advanced stages has been through androgen deprivation. Approximately 85%
      of men will have an objective response to hormonal therapy initially but eventually these
      patients will develop progressive and eventually fatal disease. Treatment options for
      patients with HRPC include systemic cytotoxic chemotherapy and /or palliation of symptoms
      (especially pain) (3). Single agent and combination chemotherapy regimens have been
      associated objective response rates ranging from 40-70% in patients with HRPC (4). No
      survival advantage has been shown with any treatment in phase III studies. More effective
      systemic therapies are needed if we are to have an impact on the morbidity and mortality
      caused by the disease. (5)

      A newer bone targeted approach is the combination of radioisotopes with chemotherapy. In
      addition to its inherent systemic benefits chemotherapeutic agents can also act as
      radiosensitizers when combined with radiopharmaceutical. Preliminary clinical experience with
      the combination of radiopharmaceuticals and systemic chemotherapy indicate that this approach
      is feasible tolerable and potentially effective. In a randomized phase II trial metastatic
      HRPC patients were treated with chemotherapy: Ketoconazole and Doxorubicin alternating with
      Vinblastine and Estramustine (KAVE regimen). Seventy-two patients who were stable or
      responded after 2-3 cycles were randomized to receive a consolidation treatment with
      additional 6 weekly doxorubicin treatments with a single dose of 89Sr or weekly doxorubicin
      alone. Patients receiving the combined consolidation treatment had a significantly longer
      time to progression and survival (27.7 vs.16.8 months. P=0.0014).(20)

      Docetaxel clearly represents the most active single agent for the treatment of metastatic
      prostate cancer. The radiosensitizing properties of Docetaxel are well documented in
      preclinical and clinical experiments. The most likely underlying mechanism is a G2M block in
      the cell cycle induced by docetaxel and this will result in cycling cells at the most
      radiosensitive phase of the cell cycle.

      Besides a palliative role, current clinical and preclinical data suggest that a bone targeted
      approach may represent a potentially useful component of the overall therapeutic approach for
      metastatic prostate cancer. Randomized, double-blind, placebo controlled trials suggest that
      bisphosphonates and endothelin A antagonists may delay the progression of prostate cancer in
      bone. These clinical observations of relatively large trials have provided impetus for the
      design of large definitive studies to evaluate the role of various bone targeted approaches
      for the treatment of prostate cancer.

      The currently proposed trial represents a preliminary evaluation of the safety of the
      docetaxel +153 Sm combination. This study may also provide important preliminary efficacy
      information with this combination.

      The combination regimen was designed to explore clinically the possible interactions between
      docetaxel and samarium-153-EDTMP. The block in the G2/M phase following the administration of
      docetaxel results in the accumulation of cells in the most radiosensitive phase of the cell
      cycle. Pre-clinical data suggest that this is likely to occur 24-48hrs post administration of
      docetaxel. This is followed 24 hours later by the administration of the radiopharmaceutical
      which has a short physical half life of 46.3 hours. The bone uptake of the complexed sm153-
      EDTMP molecule will be effectively taken up at the bone metastatic site within this time
      interval. To target cells repopulating the cell cycle following the initial block+ cell kill
      in the mitotic phase, we planned a Q3 week x 2 administration of docetaxel on Day 1 and Day
      22. Following a 8 week of rest (weeks 5 -12), treatment is repeated for a maximum of 2 cycles
      or until the development of dose-limiting toxicity or disease progression.

      Samarium is given in 12 week intervals. Docetaxel is a radiosensitizer that has shown
      activity in prostate cancer given to patients on both Q3 week and Q week schedules.

      Based on a personal communication from Dr. Theodore DeWeese's (Johns Hopkins Hospital
      Radiation Oncologist) preclinical data suggests that 24 hours after a dose of docetaxel,
      there is a maximum G2M arrest. This represents the rationale for the bolus dose of docetaxel
      for the combined schedule.
    

Intervention name(s): Docetaxel; Docetaxel; Docetaxel; Docetaxel
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Docetaxel 50mg/m2 IV on day 1 and day 22; Docetaxel 75mg/m2 IV on day 1 and day 22; Docetaxel 75mg/m2 IV on day 1 and day 22; Docetaxel 75 mg/m2 IV on day 1, 22 and day 43
Other intervention name(s): Samarium 153-EDTMP 1.0 mCi/kg IV on day 2; Samarium 153-EDTMP 1.0 mCi/kg IV on day 2; Samarium 153-EDTMP 1.0 mCi/kg IV on day 2; Samarium 153-EDTMP 1.0 mCi/kg IV on day 2
Intervention MeSH terms: Docetaxel; Samarium Sm-153 lexidronam
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Prostate Cancer