<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/NCT03013504</url>
  </required_header>
  <id_info>
    <org_study_id>TROIKA</org_study_id>
    <nct_id>NCT03013504</nct_id>
  </id_info>
  <brief_title>A Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of HD201 to Herceptin® in HER2+ Early Breast Cancer Patients</brief_title>
  <acronym>TROIKA</acronym>
  <official_title>A Randomised, Double-blind, Parallel Group, Equivalence, Multicentre Phase III Trial to Compare the Efficacy, Safety and Pharmacokinetics of HD201 to Herceptin® in Patients With HER2+ Early Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Prestige Biopharma Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Prestige Biopharma Limited</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the TROIKA study, the proposed biosimilar HD201 will be compared to its reference product&#xD;
      Herceptin®. The aim of the study is to demonstrate equivalence of HD201 and Herceptin® in&#xD;
      terms of efficacy, safety and pharmacokinetics.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a randomised, double-blind, parallel group, equivalence, multicentre Phase III study.&#xD;
      500 patients with HER2+ early breast cancer (EBC) will be randomised (1:1) to receive either&#xD;
      HD201 in combination with chemotherapy (n=250) or Herceptin® in combination with chemotherapy&#xD;
      (n=250).&#xD;
&#xD;
      HD201 or Herceptin® will be administered every 3 weeks for 8 cycles(24 weeks). After&#xD;
      administration of the final neoadjuvant study drug dose, surgery will be done within 3-8&#xD;
      weeks followed by an adjuvant treatment period for 10 cycles.&#xD;
&#xD;
      Patients completing the 18 cycles of treatment and those discontinuing the study will attend&#xD;
      an End of Treatment (EOT) visit 4 weeks (+/- 2 days), after last administration of study&#xD;
      medication, followed by a follow-up period of 2 years.&#xD;
&#xD;
      Patients will attend study visits every 3 weeks. At each visit, patients will undergo a&#xD;
      complete physical examination, vital signs, weight, performance status, clinical laboratory&#xD;
      tests and adverse events (AEs), concomitant medication will be recorded. After the EOT visit&#xD;
      patients will be followed every 6 months for an additional 24 months or until death,&#xD;
      whichever occurs first, to collect data on cardiac safety and disease status.&#xD;
&#xD;
      Cardiac safety will be assessed by echocardiography or multigated acquisition (MUGA) scan to&#xD;
      evaluate the left ventricular ejection fraction (LVEF) (at screening, before cycle 5, before&#xD;
      surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the completion of&#xD;
      trastuzumab (more frequent if necessary)) and by means of a 12-lead ECG (at screening, before&#xD;
      cycle 5, before surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the&#xD;
      completion of trastuzumab).&#xD;
&#xD;
      The primary efficacy endpoint, total pathological complete response (tpCR) will be assessed&#xD;
      at the time of surgery after neoadjuvant treatment completion after 24 weeks. tpCR will be&#xD;
      assessed both by local and by central reading.&#xD;
&#xD;
      Sampling for pharmacokinetics (PK) analysis (determination of Ctrough values) will be&#xD;
      performed in all patients before cycle 5 and cycle 8.&#xD;
&#xD;
      An Independent Data Monitoring Committee will be implemented that reviews accumulating data&#xD;
      of the clinical trial with respect to any potential safety issues, study progress and&#xD;
      critical efficacy endpoints. The members will be selected on the basis of relevant experience&#xD;
      and understanding of clinical research and the issues specific to the therapeutic area, as&#xD;
      well as previous data monitoring committee experience.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">February 19, 2018</start_date>
  <completion_date type="Actual">January 13, 2022</completion_date>
  <primary_completion_date type="Actual">April 19, 2019</primary_completion_date>
  <phase>Phase 3</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>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>total pathological complete response rate (tpCR)</measure>
    <time_frame>After 24 weeks (end of cycle 8)</time_frame>
    <description>To compare the total pathological complete response rate (tpCR) in patients treated with HD201 plus chemotherapy to that in patients treated with Herceptin® plus chemotherapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>total breast pathological complete response rate (bpCR)</measure>
    <time_frame>After 24 weeks (end of cycle 8)</time_frame>
    <description>To compare total breast pathological complete response rate (bpCR) between the two arms at the time of surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response rate (ORR)</measure>
    <time_frame>After 24 weeks (end of cycle 8)</time_frame>
    <description>ORR defined as proportion of patients whose best overall response is either complete response (CR) or partial response (PR) at the time of surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>From date of randomisation until death from any cause or two years after End of Treatment, whichever comes first</time_frame>
    <description>OS defined as the time from Day 1 of therapy until death from any cause</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free Survival (EFS)</measure>
    <time_frame>From date of randomisation until death from any cause or two years after End of Treatment, whichever comes first</time_frame>
    <description>EFS defined as the time from Day 1 of therapy (day of first infusion of medication on study) until progression of disease or death from any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)</measure>
    <time_frame>From baseline through study completion until 18 months or until death, whichever came first</time_frame>
    <description>Safety and tolerability will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events and CTC v4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cardiac dysfunction</measure>
    <time_frame>Within 28 days before start of treatment, before cycle 5,12 and 16 (1 cycle is 3 weeks), before surgery (after 24 weeks), at end of treatment (4 weeks from last administration of drug medication) and one year after completion of trastuzumab therapy.</time_frame>
    <description>Cardiac dysfunction will be monitored by 12-Lead ECG and measurement of the LVEF by echocardiography or MUGA scan</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunogenecity</measure>
    <time_frame>At baseline (within 28 days before start of treatment), before surgery (after 24 weeks), at end of treatment (4 weeks from last administration of drug medication) and one year after completion of trastuzumab therapy.</time_frame>
    <description>Incidence of human trastuzumab antibodies</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance (Pharmacokinetic)</measure>
    <time_frame>Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks)</time_frame>
    <description>Sampling will be performed in all patients to compare the PK through values of HD201 and Herceptin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the curve (AUC, Pharmacokinetic)</measure>
    <time_frame>Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks)</time_frame>
    <description>Sampling will be performed in all patients to compare the PK through values of HD201 and Herceptin.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma half life (Pharmacokinetic)</measure>
    <time_frame>Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks)</time_frame>
    <description>Sampling will be performed in all patients to compare the PK through values of HD201 and Herceptin.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">503</enrollment>
  <condition>HER2 Positive Breast Cancer</condition>
  <arm_group>
    <arm_group_label>HD201 in combination with docetaxel</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2-8), followed by surgery, then adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, and subsequent 6mg/kg (if therapy is missed by &gt;1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.&#xD;
Neoadjuvant chemotherapy:&#xD;
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Herceptin® in combination with docetaxel</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2 -8) for cycles 2-8, followed by surgery, and subsequent adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, then 6mg/kg (if therapy is missed by &gt;1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.&#xD;
Neoadjuvant chemotherapy:&#xD;
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>HD201</intervention_name>
    <description>Loading dose of 8mg/kg in Cycle 1 and 6mg/kg in subsequent cycles.</description>
    <arm_group_label>HD201 in combination with docetaxel</arm_group_label>
    <other_name>Trastuzumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Herceptin</intervention_name>
    <description>Loading dose of 8mg/kg in Cycle 1 and 6mg/kg in subsequent cycles.</description>
    <arm_group_label>Herceptin® in combination with docetaxel</arm_group_label>
    <other_name>Trastuzumab</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Docetaxel</intervention_name>
    <description>75mg/m2 via i.v. infusion during cycles 1 to 4.</description>
    <arm_group_label>HD201 in combination with docetaxel</arm_group_label>
    <arm_group_label>Herceptin® in combination with docetaxel</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Epirubicin</intervention_name>
    <description>75 mg/m2 via i.v. infusion during cycles 5-8.</description>
    <arm_group_label>HD201 in combination with docetaxel</arm_group_label>
    <arm_group_label>Herceptin® in combination with docetaxel</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cyclophosphamide</intervention_name>
    <description>500 mg/m2 via i.v. infusion during cycles 5-8.</description>
    <arm_group_label>HD201 in combination with docetaxel</arm_group_label>
    <arm_group_label>Herceptin® in combination with docetaxel</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Able and willing to give written informed consent.&#xD;
&#xD;
          2. Females ≥ 18 years of Age&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group (ECOG) performance Status (PS) &lt; 2.&#xD;
&#xD;
          4. Known Hormone receptor (oestrogen receptor and progesterone receptor) status.&#xD;
&#xD;
          5. HER2 overexpressed as assessed by&#xD;
&#xD;
               1. Immunohistochemistry (IHC) or&#xD;
&#xD;
               2. Fluorescent in situ hybridisation (FISH); FISH positive is defined as FISH&#xD;
                  amplification Ratio ≥ 2.0 / number of HER2 gene copies per cell &gt;2&#xD;
&#xD;
               3. Chromogenetic in stu hybridisation (CISH) positive&#xD;
&#xD;
               4. Patients with IHC score 3+ or positive FISH/CISH test&#xD;
&#xD;
               5. Patients with an IHC score 2+ must also have a positive FISH/CISH test&#xD;
&#xD;
          6. LVEF ≥ 50% or within the normal Level of the Institution, as assessed by&#xD;
             echocardiography or MUGA scan.&#xD;
&#xD;
          7. Life expectancy &gt; 12 weeks.&#xD;
&#xD;
          8. Adequate bone marrow function as evidenced by the following:&#xD;
&#xD;
               1. Absolute neutrophils count ≥ 1,500/μL&#xD;
&#xD;
               2. Haemoglobin ≥ 9 g/dL&#xD;
&#xD;
               3. Platelet count ≥ 100,000/μL Up to 5% Deviation is acceptable.&#xD;
&#xD;
          9. Adequate hepatic and renal function as evidenced by the following:&#xD;
&#xD;
               1. Creatinine clearance ≥ 60mL/min&#xD;
&#xD;
               2. total Bilirubin ≤ 1.5x upper limit of normal (ULN)&#xD;
&#xD;
               3. AST (SGOT) and ALT (SGPT) ≤ 2.5 x ULN Up to 10% deviation is acceptable.&#xD;
&#xD;
         10. Ability to comply with the study protocol.&#xD;
&#xD;
         11. Female patients of childbearing potential must have a negative Serum pregnancy test&#xD;
             within 7 days prior to first dose of study treatment and agree to use effective&#xD;
             contraception (intrauterine device, diaphragm, diaphragm with spermicide or a reliable&#xD;
             barrier method, eg condom with spermicide) throughout the study period and 7 months&#xD;
             after discontinuation of study drug.&#xD;
&#xD;
         12. Non-metastatic, unilateral, newly diagnosed, operable early breast cancer (EBC) of&#xD;
             clinical stage II and III including inflammatory breast cancer. Histologically&#xD;
             confirmed primary invasive carcinoma of the breast.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Patients meeting any of the following criteria must not be enrolled in the study:&#xD;
&#xD;
          1. Metastatic (stage IV) with exception of supraclavicular nodes.&#xD;
&#xD;
          2. Bilateral breast cancer&#xD;
&#xD;
          3. Multicentric breast cancer&#xD;
&#xD;
          4. History of any prior invasive breast carcinoma, except for subjects with a past&#xD;
             history of ductal carcinoma in situ (DCIS) treated with surgery.&#xD;
&#xD;
          5. History of malignant neoplasms within 5 years prior to randomisation, except for&#xD;
             curatively treated carcinoma in situ of uterine cervix, basal cell carcinoma of the&#xD;
             skin or squamous cell carcinoma of the skin (malignant neoplasms occurring more than 5&#xD;
             years prior to randomisation are permitted if curatively treated with surgery only).&#xD;
&#xD;
          6. Previous history of radiation therapy, anti-neoplastic immunotherapy, chemotherapy or&#xD;
             anti-neoplastic biotherapy (including prior HER2 directed therapy).&#xD;
&#xD;
          7. Major surgery within 2 weeks prior to randomisation&#xD;
&#xD;
          8. Serious cardiac illness that would preclude the use of trastuzumab such as:&#xD;
&#xD;
               -  history of documented congestive heart failure (CHF) (New York Heart Association,&#xD;
                  NYHA, class III or greater heart disease)&#xD;
&#xD;
               -  LVEF &lt; 50% by echocardiography or MUGA scan&#xD;
&#xD;
               -  angina pectoris requiring anti-anginal medication&#xD;
&#xD;
               -  evidence of transmural infarction on electrocardiogram (ECG)&#xD;
&#xD;
               -  uncontrolled hypertension (systolic &gt; 180 mmHg and/or diastolic &gt; 100 mmHg)&#xD;
&#xD;
               -  clinically significant valvular heart disease&#xD;
&#xD;
               -  high-risk uncontrolled arrhythmias.&#xD;
&#xD;
          9. Serious pulmonary illness enough to cause dyspnoea at rest or requiring supplementary&#xD;
             oxygen therapy.&#xD;
&#xD;
         10. Known history of active hepatitis B virus (HBV) and active hepatitis C virus (HCV)&#xD;
             infection.&#xD;
&#xD;
         11. Known HIV infection by patient declaration.&#xD;
&#xD;
         12. Other severe acute or chronic medical or psychiatric condition, or laboratory&#xD;
             abnormality that may increase the risk associated with study participation or study&#xD;
             drug administration, or may interfere with the interpretation of study results, and in&#xD;
             the judgment of the investigator would make the patient inappropriate for entry into&#xD;
             this study.&#xD;
&#xD;
         13. Known hypersensitivity to the IMPs, non-IMPs or any of the ingredients or excipients&#xD;
             of the IMPs or non-IMPs.&#xD;
&#xD;
         14. Known hypersensitivity to murine proteins.&#xD;
&#xD;
         15. Pre-existing peripheral sensory or motor neuropathy ≥ grade 2 (as defined by NCI-CTCAE&#xD;
             v4.03).&#xD;
&#xD;
         16. Lactating or pregnant woman. A pregnancy test is required for all women of&#xD;
             childbearing potential including women who had menopause onset within 2 years prior to&#xD;
             randomisation. Women of childbearing potential must agree to use contraceptive methods&#xD;
             during the study and for 7 months after the last dose of IMP.&#xD;
&#xD;
         17. Participation in any clinical study or having taken any investigational therapy during&#xD;
             the 1-month period immediately preceding administration of the first dose.&#xD;
&#xD;
         18. Patients unwilling to follow the study requirements.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Minsk Clinical Oncological Dispensary</name>
      <address>
        <city>Minsk</city>
        <zip>220013</zip>
        <country>Belarus</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Complex Oncology Center</name>
      <address>
        <city>Plovdiv</city>
        <zip>4002</zip>
        <country>Bulgaria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>East Tallinn Central Hospital</name>
      <address>
        <city>Tallinn</city>
        <zip>10138</zip>
        <country>Estonia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre René Huguenin (Institut Curie)</name>
      <address>
        <city>Saint-Cloud</city>
        <zip>92210</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>S. Khechinashvili University Hospital</name>
      <address>
        <city>Tbilisi</city>
        <zip>0179</zip>
        <country>Georgia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>National Institute of Oncology</name>
      <address>
        <city>Budapest</city>
        <zip>1122</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Debrecen</name>
      <address>
        <city>Debrecen</city>
        <zip>4032</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Modena Hospital</name>
      <address>
        <city>Modena</city>
        <zip>41124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Beacon International Specialist Centre</name>
      <address>
        <city>Kuala Lumpur</city>
        <zip>46050</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Kuala Lumpur</name>
      <address>
        <city>Kuala Lumpur</city>
        <zip>50586</zip>
        <country>Malaysia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Szpital Specjalistyczny Brzeziny</name>
      <address>
        <city>Brzeziny</city>
        <zip>95-060</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>LLC &quot;Vitamed&quot;</name>
      <address>
        <city>Moscow</city>
        <zip>129515</zip>
        <country>Russian Federation</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hospital Universitario Virgen Macarena</name>
      <address>
        <city>Sevilla</city>
        <zip>41009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Maharaj Nakorn Chiang Mai Hospital</name>
      <address>
        <city>Chiang Mai</city>
        <zip>50200</zip>
        <country>Thailand</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>GI &quot;V. T. Zaycev Institute General and Urgent Surgery of NAMS of Ukraine &quot;</name>
      <address>
        <city>Kharkiv</city>
        <zip>61018</zip>
        <country>Ukraine</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Belarus</country>
    <country>Bulgaria</country>
    <country>Estonia</country>
    <country>France</country>
    <country>Georgia</country>
    <country>Hungary</country>
    <country>Italy</country>
    <country>Malaysia</country>
    <country>Poland</country>
    <country>Russian Federation</country>
    <country>Spain</country>
    <country>Thailand</country>
    <country>Ukraine</country>
  </location_countries>
  <removed_countries>
    <country>Czechia</country>
    <country>Korea, Republic of</country>
    <country>Philippines</country>
  </removed_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 29, 2016</study_first_submitted>
  <study_first_submitted_qc>January 5, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 6, 2017</study_first_posted>
  <last_update_submitted>February 6, 2023</last_update_submitted>
  <last_update_submitted_qc>February 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>randomized</keyword>
  <keyword>double-blind</keyword>
  <keyword>parallel group</keyword>
  <keyword>equivalence</keyword>
  <keyword>multicentre</keyword>
  <keyword>phase III</keyword>
  <keyword>efficacy</keyword>
  <keyword>safety</keyword>
  <keyword>pharmacokinetics</keyword>
  <keyword>HD201</keyword>
  <keyword>docetaxel</keyword>
  <keyword>Herceptin</keyword>
  <keyword>HER2 positive</keyword>
  <keyword>breast cancer</keyword>
  <keyword>early breast cancer</keyword>
  <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>Cyclophosphamide</mesh_term>
    <mesh_term>Docetaxel</mesh_term>
    <mesh_term>Trastuzumab</mesh_term>
    <mesh_term>Epirubicin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03013504
org study id: TROIKA
nct id: NCT03013504
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
In the TROIKA study, the proposed biosimilar HD201 will be compared to its reference product
      Herceptin®. The aim of the study is to demonstrate equivalence of HD201 and Herceptin® in
      terms of efficacy, safety and pharmacokinetics.
This is a randomised, double-blind, parallel group, equivalence, multicentre Phase III study.
      500 patients with HER2+ early breast cancer (EBC) will be randomised (1:1) to receive either
      HD201 in combination with chemotherapy (n=250) or Herceptin® in combination with chemotherapy
      (n=250).

      HD201 or Herceptin® will be administered every 3 weeks for 8 cycles(24 weeks). After
      administration of the final neoadjuvant study drug dose, surgery will be done within 3-8
      weeks followed by an adjuvant treatment period for 10 cycles.

      Patients completing the 18 cycles of treatment and those discontinuing the study will attend
      an End of Treatment (EOT) visit 4 weeks (+/- 2 days), after last administration of study
      medication, followed by a follow-up period of 2 years.

      Patients will attend study visits every 3 weeks. At each visit, patients will undergo a
      complete physical examination, vital signs, weight, performance status, clinical laboratory
      tests and adverse events (AEs), concomitant medication will be recorded. After the EOT visit
      patients will be followed every 6 months for an additional 24 months or until death,
      whichever occurs first, to collect data on cardiac safety and disease status.

      Cardiac safety will be assessed by echocardiography or multigated acquisition (MUGA) scan to
      evaluate the left ventricular ejection fraction (LVEF) (at screening, before cycle 5, before
      surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the completion of
      trastuzumab (more frequent if necessary)) and by means of a 12-lead ECG (at screening, before
      cycle 5, before surgery, before cycles 12 and 16, EOT visit, and at 6 and 12 months after the
      completion of trastuzumab).

      The primary efficacy endpoint, total pathological complete response (tpCR) will be assessed
      at the time of surgery after neoadjuvant treatment completion after 24 weeks. tpCR will be
      assessed both by local and by central reading.

      Sampling for pharmacokinetics (PK) analysis (determination of Ctrough values) will be
      performed in all patients before cycle 5 and cycle 8.

      An Independent Data Monitoring Committee will be implemented that reviews accumulating data
      of the clinical trial with respect to any potential safety issues, study progress and
      critical efficacy endpoints. The members will be selected on the basis of relevant experience
      and understanding of clinical research and the issues specific to the therapeutic area, as
      well as previous data monitoring committee experience.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Care Provider, Investigator)
measure: total pathological complete response rate (tpCR)
time frame: After 24 weeks (end of cycle 8)
description: To compare the total pathological complete response rate (tpCR) in patients treated with HD201 plus chemotherapy to that in patients treated with Herceptin® plus chemotherapy.
measure: total breast pathological complete response rate (bpCR)
time frame: After 24 weeks (end of cycle 8)
description: To compare total breast pathological complete response rate (bpCR) between the two arms at the time of surgery.
measure: Overall response rate (ORR)
time frame: After 24 weeks (end of cycle 8)
description: ORR defined as proportion of patients whose best overall response is either complete response (CR) or partial response (PR) at the time of surgery.
measure: Overall Survival (OS)
time frame: From date of randomisation until death from any cause or two years after End of Treatment, whichever comes first
description: OS defined as the time from Day 1 of therapy until death from any cause
measure: Event-free Survival (EFS)
time frame: From date of randomisation until death from any cause or two years after End of Treatment, whichever comes first
description: EFS defined as the time from Day 1 of therapy (day of first infusion of medication on study) until progression of disease or death from any cause.
measure: Incidence of Treatment-Emergent Adverse Events (Safety and tolerability)
time frame: From baseline through study completion until 18 months or until death, whichever came first
description: Safety and tolerability will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events and CTC v4.03
measure: Cardiac dysfunction
time frame: Within 28 days before start of treatment, before cycle 5,12 and 16 (1 cycle is 3 weeks), before surgery (after 24 weeks), at end of treatment (4 weeks from last administration of drug medication) and one year after completion of trastuzumab therapy.
description: Cardiac dysfunction will be monitored by 12-Lead ECG and measurement of the LVEF by echocardiography or MUGA scan
measure: Immunogenecity
time frame: At baseline (within 28 days before start of treatment), before surgery (after 24 weeks), at end of treatment (4 weeks from last administration of drug medication) and one year after completion of trastuzumab therapy.
description: Incidence of human trastuzumab antibodies
measure: Clearance (Pharmacokinetic)
time frame: Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks)
description: Sampling will be performed in all patients to compare the PK through values of HD201 and Herceptin.
measure: Area under the curve (AUC, Pharmacokinetic)
time frame: Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks)
description: Sampling will be performed in all patients to compare the PK through values of HD201 and Herceptin.
measure: Plasma half life (Pharmacokinetic)
time frame: Before administration of treatment at Cycles 5 and 8 (1 cycle is 3 weeks)
description: Sampling will be performed in all patients to compare the PK through values of HD201 and Herceptin.
arm group label: HD201 in combination with docetaxel
arm group type: Experimental
description: 8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2-8), followed by surgery, then adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, and subsequent 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
arm group label: Herceptin® in combination with docetaxel
arm group type: Active Comparator
description: 8 mg/kg i.v. loading dose over 90 mins in Cycle 1 and 6 mg/kg i.v. dose every 3 weeks over 60 mins then 30 mins for subsequent cycles (cycles 2 -8) for cycles 2-8, followed by surgery, and subsequent adjuvant period of 8mg/kg i.v. loading dose over 90 mins in cycle 9, then 6mg/kg (if therapy is missed by >1 week, a re-loading dose of 8mg/kg should be given) over 30 mins for subsequent 9 cycles (cycles 10-18), disease progression, unacceptable toxicity, non-compliance, or withdrawal of consent by the patient, or the investigator decides to discontinue treatment, whichever occurs first.
Neoadjuvant chemotherapy:
Cycles 1-4: Docetaxel 75 mg/m² on day 1 of each 3-weeks cycle via 1h i.v. Infusion Cycles 5-8: EC on day 1 of each 3-weeks cycle: Epirubicin 75 mg/m² via 3-30 mins i.v. Infusion, Cyclophosphamide 500 mg/m² via 3-30 mins i.v. Infusion
intervention type: Drug
intervention name: HD201
description: Loading dose of 8mg/kg in Cycle 1 and 6mg/kg in subsequent cycles.
arm group label: HD201 in combination with docetaxel
other name: Trastuzumab
intervention type: Drug
intervention name: Herceptin
description: Loading dose of 8mg/kg in Cycle 1 and 6mg/kg in subsequent cycles.
arm group label: Herceptin® in combination with docetaxel
other name: Trastuzumab
intervention type: Drug
intervention name: Docetaxel
description: 75mg/m2 via i.v. infusion during cycles 1 to 4.
arm group label: HD201 in combination with docetaxel
arm group label: Herceptin® in combination with docetaxel
intervention type: Drug
intervention name: Epirubicin
description: 75 mg/m2 via i.v. infusion during cycles 5-8.
arm group label: HD201 in combination with docetaxel
arm group label: Herceptin® in combination with docetaxel
intervention type: Drug
intervention name: Cyclophosphamide
description: 500 mg/m2 via i.v. infusion during cycles 5-8.
arm group label: HD201 in combination with docetaxel
arm group label: Herceptin® in combination with docetaxel
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
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country: Belarus
country: Bulgaria
country: Estonia
country: France
country: Georgia
country: Hungary
country: Italy
country: Malaysia
country: Poland
country: Russian Federation
country: Spain
country: Thailand
country: Ukraine
country: Czechia
country: Korea, Republic of
country: Philippines
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Cyclophosphamide
mesh term: Docetaxel
mesh term: Trastuzumab
mesh term: Epirubicin
sharing ipd: No