<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04424654</url>
  </required_header>
  <id_info>
    <org_study_id>HSL-1820</org_study_id>
    <nct_id>NCT04424654</nct_id>
  </id_info>
  <brief_title>Biomarker Analysis of Castration-resistant Prostate Cancer Undergoing Bipolar Androgen Therapy</brief_title>
  <acronym>PSMA-BAT</acronym>
  <official_title>Prospective Biomarker Analysis of Patients With Metastatic Castration-resistant Prostate Cancer (mCRPC) Undergoing Bipolar Androgen Therapy (BAT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospital Sirio-Libanes</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Hospital Moinhos de Vento</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hospital Sirio-Libanes</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is an open label phase II, single-arm, biomarker multi-institutional pilot study. Men&#xD;
      with progressive metastatic castration-resistant prostate cancer (mCRPC) who have been&#xD;
      treated with androgen deprivation therapy (ADT) and at least one prior second generation&#xD;
      AR-targeted therapy (either abiraterone or enzalutamide) will be enrolled in this study. All&#xD;
      patients will receive treatment with testosterone cypionate 400 mg, intramuscular, every 28&#xD;
      days for a maximum of 3 cycles or limiting toxicity, if it occurs before the end of the&#xD;
      scheduled therapy. After 3 cycles of BAT (12 weeks), patients may continue receiving this&#xD;
      therapy off study at the discretion of the treating physician, if clinical/radiographic&#xD;
      benefit.&#xD;
&#xD;
      During the study period, patients will have plasma collected for cell-free tumor DNA analysis&#xD;
      and CTC ARV7 status and also will perform 68Gallium-PSMA PET at baseline and then every 6&#xD;
      weeks.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 22, 2020</start_date>
  <completion_date type="Actual">July 1, 2022</completion_date>
  <primary_completion_date type="Actual">May 1, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Ga68-PSMA uptake and response to Bipolar Androgen Therapy (BAT)</measure>
    <time_frame>12 weeks</time_frame>
    <description>To evaluate the correlation between baseline Galium68-PSMA/PET maximal standard uptake value (SUVmax) and response to bipolar androgen therapy based on Prostate Cancer Working Group 3 (PCWG3).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>PSMA SUV kinetics during BAT</measure>
    <time_frame>12 weeks</time_frame>
    <description>To describe the median Galium68-PSMA/PET SUVmax value variation after bipolar androgen therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ARV7 status and response to BAT</measure>
    <time_frame>12 weeks</time_frame>
    <description>To evaluate the correlation between the AR-V7 status and response to bipolar androgen therapy based on Prostate Cancer Working Group 3 (PCWG3).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AR mutational status and response to BAT</measure>
    <time_frame>12 weeks</time_frame>
    <description>To evaluate the correlation between the presence of AR mutations and response to bipolar androgen therapy based on Prostate Cancer Working Group 3 (PCWG3).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ARV7 status kinetics during BAT</measure>
    <time_frame>12 weeks</time_frame>
    <description>To describe the ARV7 conversion rate from positive to negative after bipolar androgen therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>cfDNA kinetics during BAT</measure>
    <time_frame>12 weeks</time_frame>
    <description>To describe the median cfDNA value variation after bipolar androgen therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life of patients receiving BAT (BPI-SF)</measure>
    <time_frame>12 weeks</time_frame>
    <description>To evaluate quality of life using the BPI-SF questionnaire before and after BAT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life of patients receiving BAT (EQ-5D-3L)</measure>
    <time_frame>12 weeks</time_frame>
    <description>To evaluate quality of life using the EQ-5D-3L questionnaire before and after BAT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life of patients receiving BAT (FACT-P)</measure>
    <time_frame>12 weeks</time_frame>
    <description>To evaluate quality of life using the FACT-P questionnaire before and after BAT.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Prostate Cancer</condition>
  <arm_group>
    <arm_group_label>Bipolar Androgen Therapy (BAT)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Testosterone cypionate 400 mg IM every 28 days for 3 cycles</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Testosterone cypionate</intervention_name>
    <description>Testosterone cypionate 400 mg IM</description>
    <arm_group_label>Bipolar Androgen Therapy (BAT)</arm_group_label>
    <other_name>Testosterone</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Willing and able to provide signed informed consent.&#xD;
&#xD;
          -  Males aged 18 years of age and above.&#xD;
&#xD;
          -  Histological or cytologic proof of adenocarcinoma of the prostate.&#xD;
&#xD;
          -  Known castration-resistant disease, defined according to PCWG3 criteria as: castrate&#xD;
             serum testosterone level ≤ 50 ng/dL (≤ 1.7 nmol/L). Subjects who have failed initial&#xD;
             hormonal therapy, either by orchiectomy or by using a GnRH agonist in combination with&#xD;
             an anti-androgen, must first progress through anti-androgen withdrawal prior to being&#xD;
             eligible. The minimum timeframe to document failure of anti-androgen withdrawal will&#xD;
             be 4 weeks.&#xD;
&#xD;
          -  Disease progression: serum PSA progression defined as 2 consecutive increases in PSA&#xD;
             over a previous reference value within 6 months, each measurement at least 1 week&#xD;
             apart, or documented bone lesions by the appearance of ≥ 2 new lesions by bone&#xD;
             scintigraphy or dimensionally measurable soft tissue metastatic lesion assessed by CT&#xD;
             or MRI.&#xD;
&#xD;
          -  Absolute PSA ≥ 1.0 ng/mL at screening.&#xD;
&#xD;
          -  Must have PSA and/or radiographic progression on AT LEAST ONE novel AR- targeted&#xD;
             therapy (abiraterone acetate, enzalutamide, apalutamide or darolutamide). One prior&#xD;
             chemotherapy agent for mCRPC will be allowed but is not required for inclusion.&#xD;
&#xD;
          -  Prior treatment with abiraterone, enzalutamide, apalutamide, darolutamide,&#xD;
             bicalutamide, and/or ketoconazole is allowed. There is no limit on the maximum number&#xD;
             or types of prior hormonal therapies received.&#xD;
&#xD;
          -  Must be maintained on a GnRH analogue or have undergone orchiectomy.&#xD;
&#xD;
          -  Radiographic evidence of metastatic disease by CT scan and/or bone scan, performed&#xD;
             within the prior 6 months&#xD;
&#xD;
          -  Karnofsky Performance Status (KPS): ≥ 80% within 14 days before start of study&#xD;
             treatment (ECOG &lt; 2)&#xD;
&#xD;
          -  Asymptomatic or minimally symptomatic mCRPC according to Brief Pain Inventory - Short&#xD;
             Form (BPI-SF) performed during screening: asymptomatic is defined as BPI-SF item #3&#xD;
             score of 0 to 1; minimally symptomatic is defined as BPI-SF item #3 score of 2 to 4.&#xD;
&#xD;
          -  Archived tumor tissue obtained prior to enrollment from a metastatic tumor lesion or&#xD;
             from a primary tumor lesion (formalin fixed paraffin-embedded [FFPE] block or&#xD;
             unstained tumor tissue sections). Tumor sample may be from core biopsy, punch biopsy,&#xD;
             excisional biopsy, or surgical specimen).&#xD;
&#xD;
          -  Participants must have adequate organ and bone marrow function measured within 28 days&#xD;
             prior to administration of study treatment as defined below:&#xD;
&#xD;
               -  Hemoglobin ≥ 9.0 g/dL with no blood transfusion in the past 28 days&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.0 x 109/L&#xD;
&#xD;
               -  Platelet count ≥ 100 x 109/L&#xD;
&#xD;
               -  Total bilirubin within institutional upper limit of normal (ULN) (In patients&#xD;
                  with Gilbert's syndrome, total bilirubin &lt; 1.5x institutional ULN will be&#xD;
                  acceptable)&#xD;
&#xD;
               -  Aspartate aminotransferase (AST) (Serum Glutamic Oxaloacetic Transaminase (SGOT))&#xD;
                  / Alanine aminotransferase (ALT) (Serum Glutamic Pyruvate Transaminase (SGPT))&#xD;
                  within institutional upper limit of normal&#xD;
&#xD;
               -  Participants must have Creatinine Clearance estimated using the Modified&#xD;
                  Cockcroft-Gault equation of ≥ 40 mL/min: Estimated Creatinine Clearance =&#xD;
                  (140-age [years]) x weight (kg) serum creatinine (mg/dL) x 72&#xD;
&#xD;
          -  Participants must have a life expectancy ≥ 6 months.&#xD;
&#xD;
          -  Male participants and their partners, who are sexually active and of childbearing&#xD;
             potential, must agree to the use of two highly effective forms of contraception in&#xD;
             combination, throughout the period of taking study treatment and for 6 months after&#xD;
             the last dose of BAT, to prevent pregnancy in a partner.&#xD;
&#xD;
          -  No evidence (within 5 years) of prior malignancies (except successfully treated basal&#xD;
             cell or squamous cell carcinoma of the skin).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  External-beam radiotherapy within the last 4 weeks prior to start of study treatment.&#xD;
&#xD;
          -  Prior oral anti-androgen (e.g. bicalutamide, nilutamide, enzalutamide, apalutamide,&#xD;
             darolutamide), or androgen synthesis inhibitor (e.g. abiraterone, orteronel) within&#xD;
             the past 4 weeks is not permitted. 5-alpha reductase inhibitor therapies are not&#xD;
             allowed as well.&#xD;
&#xD;
          -  Prior treatment with chemotherapy for the treatment of metastatic hormone- sensitive&#xD;
             prostate cancer is allowed if the last dose of chemotherapy was ≥ 6 months prior to&#xD;
             enrollment. In addition, one prior chemotherapy agent for mCRPC will be allowed after&#xD;
             a minimum wash-out period of 4 weeks prior to enrollment.&#xD;
&#xD;
          -  Patients who have received prior treatment with bipolar androgen therapy (e.g.&#xD;
             testosterone, BAT).&#xD;
&#xD;
          -  Pain due to metastatic prostate cancer requiring opioid therapy.&#xD;
&#xD;
          -  Patients with an intact prostate AND urinary obstructive symptoms are excluded (which&#xD;
             includes patients with urinary symptoms from benign prostatic hyperplasia (BPH).&#xD;
&#xD;
          -  Patients receiving anticoagulation therapy are not eligible for study.&#xD;
&#xD;
          -  Patients with prior history of an arteriovenous thromboembolic event that occurred&#xD;
             within the last 12 months are excluded.&#xD;
&#xD;
          -  Participation in another clinical study with an investigational product during the&#xD;
             last 4 weeks.&#xD;
&#xD;
          -  Evidence of disease in sites or extent that, in the opinion of the investigator, would&#xD;
             put the patient at risk from therapy with testosterone (e.g. femoral metastases with&#xD;
             concern over fracture risk, severe and extensive spinal metastases with concern over&#xD;
             spinal cord compression, extensive liver metastases).&#xD;
&#xD;
          -  Concurrent use of other anticancer agents or treatments, with the following&#xD;
             exceptions:&#xD;
&#xD;
          -  Ongoing treatment with LHRH agonists or antagonists, denosumab or bisphosphonate (e.g.&#xD;
             zoledronic acid) is allowed. Ongoing treatment should be kept at a stable schedule;&#xD;
             however, if medically required, a change of dose, compound, or both is allowed.&#xD;
&#xD;
          -  Any treatment modalities involving major surgery within 4 weeks prior to the start of&#xD;
             study treatment.&#xD;
&#xD;
          -  Symptomatic nodal disease, i.e. scrotal, penile or leg edema (CTCAE ≥ Grade 3).&#xD;
&#xD;
          -  Patients are excluded if they have active, known brain metastases or leptomeningeal&#xD;
             metastases.&#xD;
&#xD;
          -  Patients should be excluded if they have an active, known or suspected autoimmune&#xD;
             disease (e.g. inflammatory bowel disease, rheumatoid arthritis, autoimmune hepatitis,&#xD;
             lupus, celiac disease). Subjects are permitted to enroll if they have vitiligo, type I&#xD;
             diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring&#xD;
             hormone replacement, psoriasis not requiring systemic treatment, or conditions not&#xD;
             expected to recur in the absence of an external trigger.&#xD;
&#xD;
          -  Patients should be excluded if they have a condition requiring systemic treatment with&#xD;
             either corticosteroids (&gt; 10 mg/day prednisone equivalents) or other immunosuppressive&#xD;
             medications within 14 days of study drug administration. Inhaled or topical steroids&#xD;
             and adrenal replacement doses &gt; 10 mg/day prednisone equivalents are permitted in the&#xD;
             absence of active autoimmune disease.&#xD;
&#xD;
          -  Permitted therapies include topical, ocular, intra-articular, intranasal, and&#xD;
             inhalational corticosteroids (with minimal systemic absorption). Physiologic&#xD;
             replacement doses of systemic corticosteroids are permitted, even if &gt; 10 mg/day&#xD;
             prednisone equivalents. A brief course of corticosteroids for prophylaxis (e.g.&#xD;
             contrast dye allergy) or for treatment of non-autoimmune conditions (e.g. delayed-&#xD;
             type hypersensitivity reaction caused by contact allergen) is permitted.&#xD;
&#xD;
          -  History of allergy to study drug components.&#xD;
&#xD;
          -  Other primary tumor (other than CRPC) including hematological malignancy present&#xD;
             within the last 5 years (except non-melanoma skin cancer, low-grade superficial&#xD;
             bladder cancer, or cancers that can be cured with local treatment alone).&#xD;
&#xD;
          -  Has imminent or established spinal cord compression based on clinical findings and/or&#xD;
             MRI.&#xD;
&#xD;
          -  Any other serious illness or medical condition that would, in the opinion of the&#xD;
             investigator, make this protocol unreasonably hazardous, including, but not limited&#xD;
             to:&#xD;
&#xD;
               -  Any uncontrolled major infection.&#xD;
&#xD;
               -  Cardiac failure NYHA (New York Heart Association) III or IV.&#xD;
&#xD;
          -  Persistent toxicities (CTCAE &gt; Grade 2) caused by previous cancer therapy, excluding&#xD;
             alopecia.&#xD;
&#xD;
          -  Poor medical risk due to a serious, uncontrolled medical disorder, non-malignant&#xD;
             systemic disease, or active, uncontrolled infection. Examples include, but are not&#xD;
             limited to, uncontrolled ventricular arrhythmia, recent (within 12 months) myocardial&#xD;
             infarction, uncontrolled major seizure disorder, extensive interstitial bilateral lung&#xD;
             disease, or any psychiatric disorder that prohibits obtaining informed consent.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Hospital Moinhos de Vento</name>
      <address>
        <city>Porto Alegre</city>
        <state>Rio Grande Do Sul</state>
        <zip>90035-000</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Sirio-Libanes</name>
      <address>
        <city>São Paulo</city>
        <zip>01308050</zip>
        <country>Brazil</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Brazil</country>
  </location_countries>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>June 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>August 1, 2022</last_update_submitted>
  <last_update_submitted_qc>August 1, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Castration-resistant prostate cancer</keyword>
  <keyword>Bipolar androgen therapy</keyword>
  <keyword>PSMA-PET</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prostatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methyltestosterone</mesh_term>
    <mesh_term>Testosterone</mesh_term>
    <mesh_term>Testosterone undecanoate</mesh_term>
    <mesh_term>Testosterone enanthate</mesh_term>
    <mesh_term>Testosterone 17 beta-cypionate</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04424654
org study id: HSL-1820
nct id: NCT04424654
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is an open label phase II, single-arm, biomarker multi-institutional pilot study. Men
      with progressive metastatic castration-resistant prostate cancer (mCRPC) who have been
      treated with androgen deprivation therapy (ADT) and at least one prior second generation
      AR-targeted therapy (either abiraterone or enzalutamide) will be enrolled in this study. All
      patients will receive treatment with testosterone cypionate 400 mg, intramuscular, every 28
      days for a maximum of 3 cycles or limiting toxicity, if it occurs before the end of the
      scheduled therapy. After 3 cycles of BAT (12 weeks), patients may continue receiving this
      therapy off study at the discretion of the treating physician, if clinical/radiographic
      benefit.

      During the study period, patients will have plasma collected for cell-free tumor DNA analysis
      and CTC ARV7 status and also will perform 68Gallium-PSMA PET at baseline and then every 6
      weeks.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Ga68-PSMA uptake and response to Bipolar Androgen Therapy (BAT)
time frame: 12 weeks
description: To evaluate the correlation between baseline Galium68-PSMA/PET maximal standard uptake value (SUVmax) and response to bipolar androgen therapy based on Prostate Cancer Working Group 3 (PCWG3).
measure: PSMA SUV kinetics during BAT
time frame: 12 weeks
description: To describe the median Galium68-PSMA/PET SUVmax value variation after bipolar androgen therapy
measure: ARV7 status and response to BAT
time frame: 12 weeks
description: To evaluate the correlation between the AR-V7 status and response to bipolar androgen therapy based on Prostate Cancer Working Group 3 (PCWG3).
measure: AR mutational status and response to BAT
time frame: 12 weeks
description: To evaluate the correlation between the presence of AR mutations and response to bipolar androgen therapy based on Prostate Cancer Working Group 3 (PCWG3).
measure: ARV7 status kinetics during BAT
time frame: 12 weeks
description: To describe the ARV7 conversion rate from positive to negative after bipolar androgen therapy.
measure: cfDNA kinetics during BAT
time frame: 12 weeks
description: To describe the median cfDNA value variation after bipolar androgen therapy
measure: Quality of life of patients receiving BAT (BPI-SF)
time frame: 12 weeks
description: To evaluate quality of life using the BPI-SF questionnaire before and after BAT.
measure: Quality of life of patients receiving BAT (EQ-5D-3L)
time frame: 12 weeks
description: To evaluate quality of life using the EQ-5D-3L questionnaire before and after BAT.
measure: Quality of life of patients receiving BAT (FACT-P)
time frame: 12 weeks
description: To evaluate quality of life using the FACT-P questionnaire before and after BAT.
arm group label: Bipolar Androgen Therapy (BAT)
arm group type: Experimental
description: Testosterone cypionate 400 mg IM every 28 days for 3 cycles
intervention type: Drug
intervention name: Testosterone cypionate
description: Testosterone cypionate 400 mg IM
arm group label: Bipolar Androgen Therapy (BAT)
other name: Testosterone
criteria: 
gender: Male
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
facility: 
country: Brazil
responsible party type: Sponsor
mesh term: Prostatic Neoplasms
mesh term: Methyltestosterone
mesh term: Testosterone
mesh term: Testosterone undecanoate
mesh term: Testosterone enanthate
mesh term: Testosterone 17 beta-cypionate