Please select the eligibility criteria that correspond to the clinical trial below.
Title: Atrasentan and Zometa for Men With Androgen Independent Prostate Cancer Metastatic to Bone: A Randomized Pilot Study
Brief Summary: The main purpose of this study is to look at the effects (good or bad) that Atrasentan given alone and Atrasentan given with Zometa has on levels of bone formation and bone destruction in men with prostate cancer that has spread to the bones.


Options:
A: Inclusion Criteria:

* Patients at least 18 years of age with histologically confirmed solid tumor carcinomas (except lung) or multiple myeloma
* Radiographic evidence of 1 or more bone lesions or lytic lesion in myeloma
* Currently receiving IV bisphosphonates
* Urinary N-Telopeptide (uNTx) greater than 50 nM BCE/mM creatinine
* Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2

Exclusion Criteria:

* More than 2 prior skeletal related events (SRE)
* Known brain metastases
* Prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
* Active dental or jaw conditions which requires oral surgery
* Non-healed dental/oral surgery
* Prior administration of AMG 162
* Evidence of impending fracture in weight bearing bones
* Pregnancy or breastfeeding. Subjects must be surgically sterile, postmenopausal, or must agree to use effective contraception during the study.
B: Inclusion Criteria:

* Histologically confirmed adenocarcinoma of the prostate
* History of bilateral orchiectomy or current treatment with a GnRH agonist or antagonist
* Radiographically documented bone metastases
* Disease progression according to criteria from the PSA Working Group

Exclusion Criteria:

* Prior treatment with Atrasentan or Zometa within one year
* Serum creatinine \> 2.0mg/dL
* Documented cardiovascular disability status of New York Heart Association Class 2
* Treatment with chemotherapy, radiation, steroids, estrogens, or PC-SPES within 6 weeks
* Treatment with bisphosphonates or radiopharmaceuticals within 12 weeks
* History of Paget's disease, hyperthyroidism, hyperparathyroidism, Cushing's syndrome, hyperprolactinemia or other disorder associated with metabolic bone disease.
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: 1. Histologic Documentation: Histologic documentation of prostate adenocarcinoma. Patients with small cell, neuroendocrine, or transitional cell carcinomas are not eligible.
2. Staging: At least one bone metastasis by radiographic imaging (bone scan, magnetic resonance imaging, computed tomography, or plain radiographs). Indeterminate lesions should be confirmed by a second imaging method. Imaging to document bone metastases is to be completed either within 12 weeks before registration or within 12 weeks before initiating androgen deprivation therapy for bone metastases.
3. Hormone Therapy

   * While on this study, patients must receive androgen deprivation therapy (ADT) for treatment of prostate cancer. Androgen deprivation therapy may have begun prior to enrollment on this study; however patients must have initiated ADT ≤ 6 months prior to enrollment.
   * Androgen deprivation therapy is defined as bilateral orchiectomy or gonadotropin- releasing hormone (GnRH) agonist with or without an antiandrogen.
   * Patients treated with intermittent androgen deprivation therapy are not eligible except for patients concurrently enrolled in SWOG-9346/INT-0162/CALGB 9594, Phase III Study of Intermittent Androgen Deprivation in Patients with Stage D2 Prostate Cancer.
4. Prior Treatment:

   * Hormone therapy at any point prior to 6 months before enrollment is prohibited. This includes any of the following treatments:

     * orchiectomy,
     * GnRH agonist (e. g., leuprolide, goserelin, triptorelin),
     * estrogen therapy,
     * antiandrogen (e. g., bicalutamide, flutamide, nilutamide), or
     * any other therapy known to lower testosterone level or inhibit testosterone effect.
   * Prior neoadjuvant and/or adjuvant hormone therapy is allowed provided that the duration of hormone therapy was six months or less and the hormone therapy was discontinued more than 6 months prior to study entry.
   * No prior treatment with a bisphosphonate
   * No prior treatment with denosumab
   * No prior treatment with radiopharmaceuticals
   * ≥ 4 weeks since completion of prior radiation therapy with at least one bone metastasis present that has NOT been radiated.
5. ECOG (CTC) performance status 0-2
6. Age: ≥ 18 years
7. Required Initial Laboratory Data:

   * Calculated Creatinine Clearance ≥ 30 mL/min
   * Corrected serum calcium ≥ 8.0 mg/dL (2.00 mmol/L) and \<11.6 mg/dL (2.90 mmol/L)

Answer: B