Safety Study of Autologous Dendritic Cells Injected Into the Prostate After Cryoablation for Advanced Prostate Cancer (CRITICAL)

The purpose of this study is to determine if the intra-tumoral injection of a subject's own dendritic cells after cryotherapy of the prostate is a safe and effective treatment for advanced prostate cancer.

In theory, the injected dendritic cells will internalize antigens from the tumor cells which have been damaged by cryotherapy and activate the subject's immune system against that specific tumor.

Subjects will also receive a low dose chemotherapy designed to lower the number of T-regulatory cells which have been shown to lower or stop some immune system responses.

Hypothesis 1: Dendritic cell injection into cryotreated prostate cancer is non-toxic;

Hypothesis 2: Dendritic cell injection into cryotreated prostate cancer is medically beneficial to the subject.

Inclusion Criteria

• Men ≥ 18 years of age and any race.
• Signed Informed Consent document obtained prior to the initiation of screening procedures.
• Histologically documented primary adenocarcinoma of the prostate. A specimen of the primary tumor must be submitted to the Central Pathology Laboratory for confirmation of prostatic adenocarcinoma and determination of Gleason Sum grading.

• Prior history of:

  1. Androgen Deprivation Therapy; or
  2. Organ-preserving therapy (i.e., non-prostatectomy) for primary prostate cancer (e.g., radiation therapy).
• In case of recurrence, subject must have evidence of prostate cancer by a positive biopsy revealing adenocarcinoma within the past 6 months of screening and confirmed by the Central Pathology Laboratory.

• TxNxM1a and/or TxNxM1b disease limited to three total metastatic sites as evidenced by lymph node metastases and /or bone metastases at time of screening.

  1. TxNxM1a : Lymph node metastases histologically proven and confirmed by Central Pathology Laboratory;

  2. TxNxM1a: Lymph node metastases not histologically proven, given that the following are satisfied in the temporal order listed:

     1. Computed tomography (CT) or Magnetic Resonance Imaging (MRI) for positive lymph nodes negative at original diagnosis of prostate cancer;
     2. Definitive local treatment undertaken;
     3. Evidence of local treatment failure on the basis of rising serum PSA;
     4. Prostatic biopsy positive for carcinoma;
     5. Subsequent CT or MRI reveals lymph node(s) of 2 cm diameter or greater
  3. TxNxM1b: Bone metastases demonstrated by radionuclide bone scan, CT, or MRI.

• Androgen-independent prostate cancer as defined by:

  1. Three consecutive rises of at least 10% each in serum PSA, in which all serum PSA measurements are separated by at least one week and results are obtained within 60 days of study screening; OR
  2. Three rises that involve an increase of 50% over the nadir serum PSA, in which all serum PSA measurements are separated by at least one week and results are obtained within 60 days of study screening;
  3. A castrate level of testosterone (<50 ng/dl) obtained within 60 days of study screening.
• Life expectancy of greater than or equal to 12 months.

• Adequate hematological function as defined by:

  1. Total WBC > 4,500/mm3
  2. Total lymphocyte count > 500/mm3
  3. Hemoglobin > 12.0 g/dl
  4. Neutrophils > 1,500/mm3
  5. Platelets > 150,000/mm3
• Adequate renal function with creatinine < 2.0 mg/dl.

• Adequate liver function as defined by:

  1. AST and ALT < 2 times the upper limit of normal;
  2. Serum bilirubin < 2.0 mg/dl;
  3. Alkaline Phosphatase < 2.0 upper limit of normal.
• Assessment of superficial veins as adequate for the performance of leukapheresis.
• No active major medical or psychological problems that could be complicated by study participation.

Exclusion Criteria

• The presence of lung, liver or brain metastases, malignant pleural effusions or malignant ascites.

• Moderate or severe symptomatic metastatic disease. Subjects who meet either of the following criteria must be excluded:

  1. A requirement for treatment with opioid analgesics for any reason within 21 days prior to study screening;
  2. Average weekly pain score of 4 or more as reported on the 11-point Pain Intensity - Numerical Rating Scale (Appendix III) over the two weeks prior to study enrollment.
• Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2 accessed at study screening visit.
• Chemotherapy treatment at any time prior to study screening.
• Radiation therapy for metastatic disease, including intravenous radioactive strontium therapy.
• Initiation or discontinuation of bisphosphonate therapy within 28 days prior to study screening. Subjects taking bisphosphonate medication must not have their dosing regimen altered until objective disease progression is independently confirmed.

• Treatment with any of the following medications or interventions within 28 days of study screening:

  1. Systemic corticosteroids (use of inhaled, intranasal and topical steroids is acceptable);
  2. External beam radiation therapy or surgery;
  3. PC-SPES (or PC-SPEC) or Saw Palmetto extract;
  4. Megestrol acetate (Megace®), diethyl stilbesterol (DES), or cyproterone acetate;
  5. Ketoconazole;
  6. High dose calcitriol (i.e., > 7.0 μg/week);
  7. Any other systemic therapy for prostate cancer.
• Treatment with any investigational vaccine within 2 years of enrollment to this study.
• Treatment with any other investigational product within 28 days of study screening.
• Pathologic long-bone fractures, imminent pathologic long-bone fracture (cortical erosion on radiography > 50%) or spinal cord compression.
• Impending untreated spinal cord compression or urinary outlet obstruction.
• Paget's Disease of bone.

• History of stage III or greater cancer, excluding prostate cancer:

  1. Basal or squamous cell skin cancers must have been adequately treated and the subject must be disease-free at the time of study screening visit;
  2. Subjects with a history of stage I or II cancer must have been adequately treated and be disease-free for ≥ 3 years at the time of study screening
• Requirement for systemic immunosuppressive therapy for any reason
• Prior or currently active autoimmune disease requiring management with systemic immunosuppression. Such conditions include inflammatory bowel disease, systemic vasculitis, scleroderma, psoriasis, multiple sclerosis, hemolytic anemia, immune-related thrombocytopenia, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, sarcoidosis, or other rheumatological disease.
• Any infection requiring parenteral antibiotic therapy or causing fever (body temperature > 100.5°F or 38.1°C) within 1 week prior to study screening.
• Known allergy, intolerance, or medical contraindication to receiving the contrast dye required for the protocol-specified CT imaging
• History of asthma, anaphylaxis, or other known serious adverse reactions to vaccines.
• Any medical intervention or other condition which, in the opinion of the Physician-Investigator could compromise adherence with study requirements or otherwise compromise study subject safety and the study's objectives.

• Prostate Institute of America
• Community Memorial Hospital
• HemaCare Corporation