A Study of Aplidin ( Plitidepsin) in Subjects With Advanced Prostate Cancer

This is a study to test the safety and efficacy of an investigational chemotherapy agent in patients with advanced prostate cancer. Subjects who meet all entry criteria and have signed the informed consent will be enrolled in the study. Participants will be required to attend regular clinic visits to receive study medication and have their status monitored. A detailed explanation can be provided by the investigator conducting the study.

Prostate cancer is the most common non-cutaneous cancer diagnosed in men in the United States. The majority of deaths occur in men with androgen-independent prostate cancer \[AIPC\]. Although 80% of men with advanced cancer will initially respond to androgen ablation with disease regression or stabilization, their malignancies become resistant to such therapy.

Eligibility Criteria:
Inclusion Criteria:

1. Written informed consent before starting any study-specific procedure. If any patient is unable to give consent, it may be obtained from the patient's legal representative if in accordance with local laws and regulations.
2. Men with castrate metastatic adenocarcinoma of the prostate, with the following characteristics:

   * Confirmed pathological diagnosis.
   * Metastatic disease (radiologically documented).
   * All patients with chemical castration must have a serum testosterone level below 50 ng/ml. There is no need to document a serum testosterone in patients having a prior surgical castration2.
   * Baseline PSA \> 5 ng/ml (according to the recommendations from the Prostate-Specific Antigen Working Group2).
   * Androgen-independent progressive disease, as defined by detectable, rising PSA in two consecutive measurements at least one week apart:

     * If PSA responded to a prior therapy, progression occurs when the PSA is 50% above the nadir level.
     * If PSA did not respond to a prior therapy, progression occurs when the PSA increases by 25% or more above pretreatment levels.
     * In both cases, the increase in absolute value PSA level must be at least 5 ng/ml, and must be confirmed by a second measurement a minimum of 1 week later.
   * Patients must have received prior docetaxel-based chemotherapy.
3. Recovery from any toxicity derived from previous treatments. The presence of alopecia and NCI-CTC grade \< 2 sensitive peripheral neuropathy is allowed.
4. Age \> 18 years.
5. Performance status (ECOG) \< 2.
6. Life expectancy \> 3 months.
7. Adequate renal, hepatic, and bone marrow function (assessed \< 14 days before inclusion in the study):

   * Neutrophil count ³ 1.5 x 109/L.
   * Platelet count ³ 100 x 109/L. Hemoglobin \> 9 g/dl.
   * Creatinine clearance ³ 40 ml/min (calculated from the Cockcroft and Gault formula), see Appendix 3.
   * Serum bilirubin \* 1.5 mg/dl.
   * AST, ALT \< 2.5 x ULN (\< 5 x ULN in case of liver metastasis).
   * Albumin \> 25 g/L.
8. Left ventricular ejection fraction within normal limits

Exclusion Criteria:

1. Prior therapy with Aplidin®.
2. Concomitant therapy with any anti-tumor agent, including glucocorticoids at a daily dose greater than 10 mg prednisone or equivalent, except when they were indicated for symptom control, provided that disease progression was documented while on steroids.
3. Small cell carcinoma of the prostate.
4. More than two previous lines of systemic therapy for patient's castrate metastatic disease, considering biological agents or chemotherapy as systemic therapy.
5. Patients with progressive measurable disease but without increased PSA value (according to the consensus recommendations) will not be considered eligible.
6. Wash-out periods less than:

   * 6 weeks after the last dose of a nitroso-urea or high dose chemotherapy
   * 4 weeks after the last dose of other chemotherapies or biological agents
   * 6 weeks after the end of treatment with extensive external beam radiation (more than 25% of bone marrow distribution) or radionuclide therapy.
   * 4 weeks after the end of treatment with palliative radiation involving less than 25% of bone marrow reserves.
   * 4 weeks for major prior surgery
   * 30 days after receiving any other investigational product
7. Men of reproductive potential who are not using effective contraceptive methods, considering complete abstinence from intercourse throughout the treatment with the study drug and for at least 6 months after completion or premature discontinuation from the study as an effective contraceptive method, to be sure that the patient's female partner does not become pregnant.
8. History of another neoplastic disease. The exceptions are:

   8.1 Non-melanoma skin cancer. 8.2 Any other cancer curatively treated with no evidence of disease for at least 10 years.
9. Known symptomatic cerebral or leptomeningeal involvement.
10. Other relevant diseases or adverse clinical conditions:

    * History or presence of unstable angina, myocardial infarction, valvular heart disease or congestive heart failure.
    * Previous mediastinal radiotherapy.
    * Uncontrolled arterial hypertension despite optimal medical therapy.
    * Previous treatment with doxorubicin at cumulative doses in excess of 400 mg/m².
    * Symptomatic arrhythmia or any arrhythmia requiring treatment.
    * Abnormal ECG as detailed below:

      * QT interval prolongation:
      * QTc\> 480 msec.
      * Left ventricular hypertrophy :
      * Sokolow Index: (R V5 or V6) + S V1)\> 3.5mv.
      * Left bundle-branch block:
      * Complete: QRS\> 0.12 sec. No Q wave is seen in leads V5 and V6. A notched R wave is seen in left leads and a notched S wave in right side leads.
      * Right bundle-branch block:
      * Complete: QRS\> 0.12 sec. Secondary R (R') wave in leads V1-V2. Slurred S wave in leads D1 ,avL, V5 and V6.
      * Second-degree atrioventricular (av) block:
      * Mobitz I AV block, or Wenckebach block: Progressive prolongation of the PR interval causing progressive R-R interval shortening until a P wave fails to conduct the ventricle. The RR interval containing the blocked P wave is shorter than the sum of the twPP interval.
      * Mobitz II AV block is characterized by sudden unexpected blocked P waves without variation or prolongation of the PR interval. It can be 2:1, 3:1, 4:1 etc.
      * Third-degree atrioventricular block:
      * P waves and QRS complexes without mutual relationship. P wave rate is greater than that of QRS complexes.
      * Ischemia, injury and infarction:
      * Subendocardial ischemia. - Symmetrical T waves of increased amplitude.
      * Subepicardial ischemia. - Inverted symmetrical T waves.
      * Subendocardial injury. - ST segment depression (horizontal or descending).
      * Subepicardial injury. - ST segment elevation with upper convexity.
      * Infarction or necrosis. - Q wave voltage greater than 25% of R wave voltage.
      * Duration of Q wave is 0.04 sec or more
    * History of significant neurological or psychiatric disorders.
    * Active infection; infection by HIV, HBV or HCV. HIV, HBV or HCV testing are not required unless infection is clinically suspected.
    * Myopathy or any clinical situation that causes significant and persistent elevation of CK (\> 2.5 ULN in two different determinations performed with one week apart).
    * Significant non-neoplastic liver disease (e.g., cirrhosis, active chronic hepatitis).
    * Limitation of the patient's ability to comply with the treatment or follow-up protocol.
    * Uncontrolled endocrine diseases (e.g. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
11. Known hypersensitivity to Aplidin®, mannitol, cremophor EL, or ethanol.