Please select the eligibility criteria that correspond to the clinical trial below.
Title: A Randomized, Double Blind, Placebo Controlled Phase 3 Trial of Immunotherapy With Autologous Antigen Presenting Cells Loading With PA2024 (Provenge(R), APC8015) in Men With Metastatic Androgen Independent Prostatic Adenocarcinoma
Brief Summary: Provenge is an investigational product designed to activate a man's own antigen presenting cells, a type of immune cell, so that they can detect prostate cancer cells and initiate an immune response against them.

Having completed Phase 1 and Phase 2 clinical trials, Provenge is now at the Phase 3 level. One important Phase 3 trial of Provenge has been completed; the current trial is also a Phase 3 study.

If you decide to participate and are eligible, you will be enrolled in the study and randomly assigned to receive either active product or placebo. There are two chances in three that you will receive Provenge. After receiving treatment, you will be monitored at regular intervals until the study endpoints are met. At the end of the trial, men who received placebo will have the opportunity to be treated with active product in another study.


Options:
A: To qualify for this trial, you must have ALL of the following:

* Histologically documented adenocarcinoma of the prostate
* Cancer that has progressed while on adequate hormone therapy. This state of the disease is androgen independent prostate cancer (AIPC).
* Cancer that has spread outside the prostate (metastatic) to lymph nodes or bone. Please note that if your cancer has spread to organs (e.g., liver, lung, brain), you are not eligible for the study.
* The absence of or minimal current cancer-related pain

Please note that there are additional eligibility criteria. The study center will determine if you meet all of the criteria.

Study personnel will explain the trial in detail and answer any questions you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, study personnel will explain the reasons.
B: Inclusion Criteria:

Fit for the treatments and estimates life expectancy of 10 years Registration with eligible primary care practice

Exclusion Criteria:

Unable to give written informed consent. Concomitant or past malignancy.
C: Inclusion Criteria Participants must fulfil all the criteria in one of the following three categories. Additionally, all patients must fulfil the criteria in Section 4.

1. High-Risk Newly-Diagnosed Non-Metastatic Node-Negative (N0/Nx) Disease

   Both:

   • At least two of: T category T3/4, PSA≥40ng/ml or Gleason sum score 8-10

   • Intention to treat with radical radiotherapy (unless there is a contra-indication)

   OR
2. Newly-Diagnosed Metastatic Or Node-Positive Disease

   At least one of:
   * Stage Tany N+ M0
   * Stage Tany Nany M+

   OR
3. Previously Radically Treated, Now Relapsing (Prior Radical Surgery And/or Radiotherapy)

   At least one of:

   • PSA ≥4ng/ml and rising with doubling time less than 6 months

   • PSA ≥20ng/ml

   • N+

   • M+

   AND
4. General Inclusion Criteria Required For All Participants

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1. Histologically confirmed prostate adenocarcinoma
2. Intention to treat with long-term androgen deprivation therapy
3. Fit for all protocol treatment and follow up, WHO performance status 0-2
4. Have completed the appropriate investigations prior to randomisation
5. Adequate haematological function: neutrophil count ≥1.5x109/l and platelets ≥100x109/l
6. Adequate renal function, defined as GFR ≥30ml/min/1.73m2
7. Written informed consent
8. Willing and expected to comply with follow up schedule
9. Using effective contraceptive method if applicable

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1. Medical contraindications to the trial medications are given in Section 6
2. For WHO performance status definitions see Appendix A

5. General Exclusion Criteria

Patients must not fulfil any of the criteria below:

1. Prior systemic therapy for locally-advanced or metastatic prostate cancer (1) (except as listed in the protocol section 4.3)
2. Prior exposure to hormone therapy for a duration of \> 12 months, or prior exposure completing \< 12 months before randomisation (see section 4.3.1 for permitted prior exposure details)
3. Metastatic brain disease or leptomeningeal disease
4. Abnormal liver functions consisting of any of the following:

   • Serum bilirubin ≥1.5 x ULN (except for patients with Gilbert's disease, for whom the upper limit of serum bilirubin is 51.3μmol/l or 3mg/dl)

   • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2.5 x ULN - site must indicate at randomisation whether one or both tests are performed at site. Where both results are available both must confirm eligibility.
5. Any other previous or current malignant disease which, in the judgement of the responsible clinician, is likely to interfere with STAMPEDE treatment or assessment
6. Any surgical wound (e.g. TURP) which in the judgement of the responsible clinician may interfere with or be exacerbated by protocol treatment
7. Participant with significant cardiovascular disease, including:

   • Severe/unstable angina

   • Myocardial infarction less than 6 months prior to randomisation

   • Arterial thrombotic events less than 6 months prior to randomisation

   • Clinically significant cardiac failure requiring treatment, defined as New York Heart Association (NYHA) class II or above (1)

   • Cerebrovascular disease (e.g. stroke or transient ischaemic episode) less than 6 months prior to randomisation
   * Any other significant cardiovascular disease that in the investigator's opinion means the participant is unfit for any of the study treatments.

     1. Excluding participants receiving docetaxel as part of SOC
     2. NYHA classifications can be found in Appendix A

6. Comparison-specific eligibility criteria

In addition to the general inclusion and exclusion criteria, the following comparison-specific eligibility criteria apply.

For Randomisation to the "Metformin Comparison"

Please note from protocol v20 only patients willing to participate in the metabolic sub study should be randomised to the metformin comparison. The sub study will be conducted in a limited number of sites, see section 4.7.4 for further information.

In addition to the general inclusion and general exclusion criteria the following comparison-specific inclusion criteria must be met to be eligible for randomisation to the "metformin comparison":

• HbA1c \<48mmol/mol (equivalent to \<6.5%) (1)

• Adequate renal function, defined as GFR ≥45ml/min/1.73m (except for Switzerland (2))

• No history of lactic acidosis or pre-disposing conditions

* Not current or previous treatment with metformin
* No contra-indications to metformin
* No current or previous medication for treatment of diabetes
* Willingness to join the metabolic sub study

The method used to determine glomerular filtration rate may vary according to local practice.

Equations that either estimate glomerular filtration rate (eGFR) or creatinine clearance (CrCl) may be used and the same threshold value applies. Where possible, HbA1c should be performed prior to commencing SOC docetaxel to reduce the likelihood of corticosteroid-related hyperglycaemia impacting on eligibility. All participants with abnormal baseline HbA1c (i.e. 6.5% or higher) should be informed and referred to their GP for further management.

(2) Except Switzerland, please refer to SAKK appendix for local guidance

For Randomisation To The "Transdermal Oestradiol Comparison"

In addition to the general inclusion and exclusion criteria, participants fulfilling all of the following are eligible for the "transdermal oestradiol comparison":

• ≤8 weeks of anti-androgen (AR-antagonists) use

• Maximum of 1 dose of monthly or 4-weekly LHRH agonist/antagonist

• No prior LHRH agonist injection with a stated duration of effect greater than 1 month

• ≤12 weeks since first dose of any hormone therapy

• Not had a bilateral orchidectomy

• No use of cyproterone acetate (36) prior to randomisation

• No known porphyria

* No known history of deep vein thrombosis or pulmonary embolism confirmed radiologically
* No known thrombophilic disorder (e.g. Protein C, Protein S, antithrombin deficiency)
* Not yet started SOC abiraterone, enzalutamide or apalutamide
D: Randomized, Double Blind Treatment Period:

Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small cell features
* Ongoing androgen deprivation therapy with a GnRH analogue or bilateral orchiectomy
* Progressive disease despite androgen deprivation therapy as defined by rising PSA levels or progressive soft tissue or bony disease
* No prior treatment with cytotoxic chemotherapy
* Asymptomatic or mildly symptomatic from prostate cancer

Exclusion Criteria:

* Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment
* Known or suspected brain metastasis or active leptomeningeal disease
* History of another malignancy within the previous 5 years other than curatively treated non-melanomatous skin cancer

Open-Label Treatment Period:

The following inclusion criteria apply to patients receiving enzalutamide or placebo during double-blind treatment.

Eligible patients must meet all inclusion criteria.

* Received randomized double-blind treatment in PREVAIL;
* Open-label day 1 visit is within 6 months after this amendment is approved and becomes effective at the study site;
* Is willing to maintain androgen deprivation therapy with a gonadotropin-releasing hormone (GnRH) agonist/antagonist or has had a bilateral orchiectomy;

The exclusion criteria apply only to patients starting new treatment with enzalutamide after receiving placebo as randomized treatment. Each patient must not meet any of the following criteria:

* Has taken commercially available enzalutamide (Xtandi);
* Severe concurrent disease, infection, or co-morbidity that, in the judgment of the Investigator, would make the patient inappropriate for enrollment
* Known or suspected brain metastasis or active leptomeningeal disease

Answer: A