<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/NCT01698281</url>
  </required_header>
  <id_info>
    <org_study_id>AEZS-108-049</org_study_id>
    <nct_id>NCT01698281</nct_id>
  </id_info>
  <brief_title>Phase 2 Trial of AEZS-108 in Chemotherapy Refractory in Triple Negative Breast Cancer</brief_title>
  <official_title>A Randomized Phase 2 Trial of AEZS-108 in Chemotherapy Refractory Triple Negative, LHRH-positive Metastatic Breast Cancer.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AEterna Zentaris</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AEterna Zentaris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a therapeutic exploratory Phase 2 study evaluating AEZS-108 compared to standard&#xD;
      single agent cytotoxic chemotherapy (SSCC) as measured by the median time of progression-free&#xD;
      survival (PFS) in patients with chemotherapy refractory triple negative (ER/PR/HER2-negative)&#xD;
      LHRH-R positive metastatic breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study will be conducted as an open-label randomized two-arm multicenter Phase II study.&#xD;
      Patients will be randomized in a 1:1 ratio into one of the two treatment arms within each&#xD;
      stratum: AEZS-108 (267 mg/m2 every 21 calendar days) (Arm A) OR SSCC (Arm B) at discretion of&#xD;
      treating oncologist cycled every 21 calendar days.&#xD;
&#xD;
      Stratified randomization will be used with number of prior lines of therapies (1-2 versus&#xD;
      &gt;2). Tumor assessment will be repeated every 2 cycles. At the time of disease progression,&#xD;
      Arm B patients may be crossed over to AEZS-108 as long as none of the exclusion criteria for&#xD;
      study entry apply. Particularly, LVEF ≥50% is required, and patients failing on liposomal&#xD;
      doxorubicin cannot be crossed over to AEZS-108.&#xD;
&#xD;
      Analysis of the main study endpoint, PFS, will follow a group sequential design with one&#xD;
      interim and one final analysis utilizing the O'Brien-Fleming stopping boundaries procedure.&#xD;
      The study will be terminated for futility if the lower bound is crossed and for superiority&#xD;
      if the upper bound is crossed. The sponsor may also terminate the study for futility based on&#xD;
      other considerations such as safety.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Poor recruitment&#xD;
  </why_stopped>
  <start_date>December 2012</start_date>
  <completion_date type="Actual">October 2014</completion_date>
  <primary_completion_date type="Actual">August 2014</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Efficacy of AEZS-108 compared to SSCC as measured by the median time of progression-free survival (PFS).</measure>
    <time_frame>Up to two years</time_frame>
    <description>PFS is defined as the time elapsed from randomization to the date of documented progression or death, whichever comes first. For surviving patients without progression who begin alternative treatment, PFS will be censored at the last date of documented progression-free status prior to starting alternative treatment. Similarly, losses to follow up will be censored at the last date of documented progression-free status.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy of AEZS-108: overall response</measure>
    <time_frame>Up to two years</time_frame>
    <description>Overall response per RECIST 1.1 (i.e. complete response (CR) + partial response (PR).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy of AEZS-108: clinical benefit</measure>
    <time_frame>up to 2 years</time_frame>
    <description>Overall clinical benefit = complete response (CR) + partial response (PR) + stable disease (SD)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy of AEZS-108: duration of response</measure>
    <time_frame>up to 2 years</time_frame>
    <description>The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy of AEZS-108: time to progression (TTP)</measure>
    <time_frame>up to 2 years</time_frame>
    <description>TTP is defined as the time elapsed from randomization to the earliest date of documented disease progression. For surviving patients without progression of breast cancer who begin alternative treatment, TTP will be censored at the last date of documented progression-free status prior to starting alternative treatment. This is expected to be negligible and, if the actual data suggest otherwise, competing risk methods will be used instead of Kaplan-Meier estimates. Similarly, losses to follow up will be censored at the last date of documented progression free status.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Efficacy of AEZS-108: overall survival</measure>
    <time_frame>up to 2 years</time_frame>
    <description>Overall survival (OS) is defined as the elapsed time from start of therapy to death from any cause. For surviving patients, follow-up will be censored at the date of last contact.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity of AEZS-108 in this patient population</measure>
    <time_frame>up to 2 years</time_frame>
    <description>All patients will be evaluable for toxicity from the time of their first treatment with the study drug.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Breast Cancer</condition>
  <arm_group>
    <arm_group_label>Arm A: AEZS-108</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention: AEZS-108 (267 mg/m^2, 2-hour IV infusion every Day 1 of a 21-day (3-week) cycle). Recommended prophylactic anti-emetic for AEZS-108: 8 mg dexamethasone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B: Standard (SCCC)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>commercially available standard single agent cytotoxic chemotherapy (SSCC): - doses below the recommended package insert at the discretion of treating oncologist;&#xD;
- on a 21-day cycle (although weekly administration is allowed; note: pegylated liposomal doxorubicin will be administered on a 28-day cycle).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AEZS-108</intervention_name>
    <description>AEZS-108 (267 mg/m2, 2-hour IV infusion every Day 1 of a 21-day (3-week) cycle. Allowed delay of re-treatment: up to 2 weeks.&#xD;
Dose reduction: to 210 mg/m2 and 160 mg/m2, if dose limiting toxicity.</description>
    <arm_group_label>Arm A: AEZS-108</arm_group_label>
    <other_name>Zoptarelin doxorubicin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>SCCC</intervention_name>
    <description>commercially available SSCC (doses below the recommended package insert at the discretion of treating oncologist), on a 21-day cycle (although weekly administration is allowed; note: pegylated liposomal doxorubicin will be administered on a 28-day cycle).&#xD;
Drugs considered acceptable as SSCC: paclitaxel; nab-paclitaxel; eribulin; pegylated liposomal doxorubicin (PLD); vinorelbine; gemcitabine; capecitabine.&#xD;
Related to PLD: Per notification from EMA (dated 22-Nov-2011) &quot;no new patients should be started on treatment with Caelyx until further notice.&quot; Accordingly, this drug may be selected as SSCC treatment option only after such written notice is available.</description>
    <arm_group_label>Arm B: Standard (SCCC)</arm_group_label>
    <other_name>Standard single agent cytotoxic chemotherapy</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>Recommended prophylactic anti-emetic for AEZS-108: 8 mg dexamethasone.</description>
    <arm_group_label>Arm A: AEZS-108</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Women ≥ 18 years of age&#xD;
&#xD;
          2. Histologically documented breast cancer (either primary or metastatic site) that is&#xD;
             (i) ER-negative (0), (ii) PR-negative (0), and (iii) HER2-negative, defined by IHC&#xD;
             (immunohistochemistry; IHC 0/1, non-overexpressing) or FISH (fluorescence in situ&#xD;
             hybridization; FISH negative) or CISH (chromogen in situ hybridization; CISH&#xD;
             negative).&#xD;
&#xD;
          3. Expression of LHRH receptor confirmed by IHC on archival (or current biopsy of breast&#xD;
             tumor or metastatic site) breast cancer tissue&#xD;
&#xD;
          4. Progressive disease after failure of 1 to 3 prior chemotherapy regimens for recurrent&#xD;
             or metastatic (Stage IV) disease (prior adjuvant/neoadjuvant therapy is allowed)&#xD;
&#xD;
          5. Measurable disease by RECIST 1.1 criteria; at least one target lesion that has not&#xD;
             been previously irradiated.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Eastern Cooperative Oncology Group (ECOG) performance status &gt; 2&#xD;
&#xD;
          2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia or recent myocardial infarction (within 6 months of enrollment)&#xD;
&#xD;
          3. Leptomeningeal disease or brain metastases requiring steroids or other therapeutic&#xD;
             intervention&#xD;
&#xD;
          4. Left ventricular ejection fraction (LVEF) &lt; 50 %, determined by echocardiogram or MUGA&#xD;
             scan&#xD;
&#xD;
          5. Compromised organ or marrow function as evidenced by any of the following:&#xD;
&#xD;
               -  thrombocyte count: &lt; 100x109/L&#xD;
&#xD;
               -  absolute neutrophil count (ANC): &lt; 1.5x109/L&#xD;
&#xD;
               -  hemoglobin: &lt; 6.0 mmol/L (&lt; 9 g/100 mL)&#xD;
&#xD;
               -  AS(A)T, AL(A)T: &gt; 2.5 times upper limit of normal range (ULN) (&gt; 5x ULN if&#xD;
                  clearly related to liver metastases)&#xD;
&#xD;
               -  bilirubin: &gt; 1.5 mg/dL&#xD;
&#xD;
               -  creatinine: &gt; 1.5 mg/dL or creatinine clearance &lt; 40 mL/min.&#xD;
&#xD;
          6. Systemic anticancer therapy or radiotherapy within 21 calendar days of the first dose&#xD;
             of study drug*)&#xD;
&#xD;
             * also excluded are patients with anticipated ongoing concomitant anticancer therapy&#xD;
             during the study&#xD;
&#xD;
          7. Prior exposure to anthracyclines or anthracenediones for the treatment of metastatic&#xD;
             breast cancer including liposomal doxorubicin (Doxil), doxorubicin, daunorubicin, or&#xD;
             mitoxantrone&#xD;
&#xD;
          8. Prior adjuvant anthracyclines with a cumulative anthracycline dose ≥ 300 mg/m2&#xD;
&#xD;
          9. Ongoing therapeutic anticoagulation&#xD;
&#xD;
         10. Patients who are not surgically sterile or post-menopausal must agree to use for the&#xD;
             duration of the study reliable methods of birth control defined as:&#xD;
&#xD;
               -  complete abstinence&#xD;
&#xD;
               -  any intrauterine device (IUD) with published data showing that the lowest&#xD;
                  expected failure rate is &lt; 1 % per year, or&#xD;
&#xD;
               -  any other methods with published data showing that the lowest expected failure&#xD;
                  rate is less than 1 % per year&#xD;
&#xD;
         11. Investigational therapy within 30 calendar days of the first scheduled day of protocol&#xD;
             treatment (investigational therapy is defined as treatment for which there is&#xD;
             currently no regulatory authority approved indication).&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alberto J. Montero, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Miami</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Miami</name>
      <address>
        <city>Miami</city>
        <state>Florida</state>
        <zip>33136</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitäts-Frauenklinik</name>
      <address>
        <city>Göttingen</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinik für Frauenheilkunde und Geburtshilfe</name>
      <address>
        <city>Regensburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2013</verification_date>
  <study_first_submitted>September 21, 2012</study_first_submitted>
  <study_first_submitted_qc>September 27, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2012</study_first_posted>
  <disposition_first_submitted>February 7, 2018</disposition_first_submitted>
  <disposition_first_submitted_qc>February 7, 2018</disposition_first_submitted_qc>
  <disposition_first_posted type="Actual">February 9, 2018</disposition_first_posted>
  <last_update_submitted>February 20, 2018</last_update_submitted>
  <last_update_submitted_qc>February 20, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 22, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Doxorubicin</mesh_term>
  </intervention_browse>
  <!-- Results have not yet been posted, but a results disposition has been submitted           -->
</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/NCT01698281
org study id: AEZS-108-049
nct id: NCT01698281
lead sponsor: 
has dmc: No
This is a therapeutic exploratory Phase 2 study evaluating AEZS-108 compared to standard
      single agent cytotoxic chemotherapy (SSCC) as measured by the median time of progression-free
      survival (PFS) in patients with chemotherapy refractory triple negative (ER/PR/HER2-negative)
      LHRH-R positive metastatic breast cancer.
The study will be conducted as an open-label randomized two-arm multicenter Phase II study.
      Patients will be randomized in a 1:1 ratio into one of the two treatment arms within each
      stratum: AEZS-108 (267 mg/m2 every 21 calendar days) (Arm A) OR SSCC (Arm B) at discretion of
      treating oncologist cycled every 21 calendar days.

      Stratified randomization will be used with number of prior lines of therapies (1-2 versus
      >2). Tumor assessment will be repeated every 2 cycles. At the time of disease progression,
      Arm B patients may be crossed over to AEZS-108 as long as none of the exclusion criteria for
      study entry apply. Particularly, LVEF ≥50% is required, and patients failing on liposomal
      doxorubicin cannot be crossed over to AEZS-108.

      Analysis of the main study endpoint, PFS, will follow a group sequential design with one
      interim and one final analysis utilizing the O'Brien-Fleming stopping boundaries procedure.
      The study will be terminated for futility if the lower bound is crossed and for superiority
      if the upper bound is crossed. The sponsor may also terminate the study for futility based on
      other considerations such as safety.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy of AEZS-108 compared to SSCC as measured by the median time of progression-free survival (PFS).
time frame: Up to two years
description: PFS is defined as the time elapsed from randomization to the date of documented progression or death, whichever comes first. For surviving patients without progression who begin alternative treatment, PFS will be censored at the last date of documented progression-free status prior to starting alternative treatment. Similarly, losses to follow up will be censored at the last date of documented progression-free status.
measure: Efficacy of AEZS-108: overall response
time frame: Up to two years
description: Overall response per RECIST 1.1 (i.e. complete response (CR) + partial response (PR).
measure: Efficacy of AEZS-108: clinical benefit
time frame: up to 2 years
description: Overall clinical benefit = complete response (CR) + partial response (PR) + stable disease (SD)
measure: Efficacy of AEZS-108: duration of response
time frame: up to 2 years
description: The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The duration of overall CR is measured from the time measurement criteria are first met for CR until the first date that progressive disease is objectively documented.
measure: Efficacy of AEZS-108: time to progression (TTP)
time frame: up to 2 years
description: TTP is defined as the time elapsed from randomization to the earliest date of documented disease progression. For surviving patients without progression of breast cancer who begin alternative treatment, TTP will be censored at the last date of documented progression-free status prior to starting alternative treatment. This is expected to be negligible and, if the actual data suggest otherwise, competing risk methods will be used instead of Kaplan-Meier estimates. Similarly, losses to follow up will be censored at the last date of documented progression free status.
measure: Efficacy of AEZS-108: overall survival
time frame: up to 2 years
description: Overall survival (OS) is defined as the elapsed time from start of therapy to death from any cause. For surviving patients, follow-up will be censored at the date of last contact.
measure: Toxicity of AEZS-108 in this patient population
time frame: up to 2 years
description: All patients will be evaluable for toxicity from the time of their first treatment with the study drug.
arm group label: Arm A: AEZS-108
arm group type: Experimental
description: Intervention: AEZS-108 (267 mg/m^2, 2-hour IV infusion every Day 1 of a 21-day (3-week) cycle). Recommended prophylactic anti-emetic for AEZS-108: 8 mg dexamethasone
arm group label: Arm B: Standard (SCCC)
arm group type: Active Comparator
description: commercially available standard single agent cytotoxic chemotherapy (SSCC): - doses below the recommended package insert at the discretion of treating oncologist;
- on a 21-day cycle (although weekly administration is allowed; note: pegylated liposomal doxorubicin will be administered on a 28-day cycle).
intervention type: Drug
intervention name: AEZS-108
description: AEZS-108 (267 mg/m2, 2-hour IV infusion every Day 1 of a 21-day (3-week) cycle. Allowed delay of re-treatment: up to 2 weeks.
Dose reduction: to 210 mg/m2 and 160 mg/m2, if dose limiting toxicity.
arm group label: Arm A: AEZS-108
other name: Zoptarelin doxorubicin
intervention type: Drug
intervention name: SCCC
description: commercially available SSCC (doses below the recommended package insert at the discretion of treating oncologist), on a 21-day cycle (although weekly administration is allowed; note: pegylated liposomal doxorubicin will be administered on a 28-day cycle).
Drugs considered acceptable as SSCC: paclitaxel; nab-paclitaxel; eribulin; pegylated liposomal doxorubicin (PLD); vinorelbine; gemcitabine; capecitabine.
Related to PLD: Per notification from EMA (dated 22-Nov-2011) "no new patients should be started on treatment with Caelyx until further notice." Accordingly, this drug may be selected as SSCC treatment option only after such written notice is available.
arm group label: Arm B: Standard (SCCC)
other name: Standard single agent cytotoxic chemotherapy
intervention type: Drug
intervention name: Dexamethasone
description: Recommended prophylactic anti-emetic for AEZS-108: 8 mg dexamethasone.
arm group label: Arm A: AEZS-108
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alberto J. Montero, MD
role: Principal Investigator
affiliation: University of Miami
facility: 
facility: 
facility: 
country: Germany
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Dexamethasone
mesh term: Doxorubicin