<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/NCT03293654</url>
  </required_header>
  <id_info>
    <org_study_id>MB02 A 02 17</org_study_id>
    <nct_id>NCT03293654</nct_id>
  </id_info>
  <brief_title>A Pharmacokinetic Study Comparing MB02 And US And EU Avastin® In Healthy Male Volunteers</brief_title>
  <official_title>A Randomised, Double Blind, Three-Arm, Single Dose, Parallel Study To Compare the Pharmacokinetics, Safety and Immunogenicity of MB02 (Bevacizumab Biosimilar Drug), US Licenced Avastin® and EU Approved Avastin® in Healthy Male Volunteers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>mAbxience Research S.L.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>mAbxience Research S.L.</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare&#xD;
      the Pharmacokinetics (PK), safety and immunogenicity profile of MB02 with US and EU Avastin®&#xD;
      in healthy male subjects.&#xD;
&#xD;
      During the course of the study, the similarity in pharmacokinetics will be assessed by&#xD;
      sampling the levels of drug in the blood, and by comparing these levels among the different&#xD;
      administration arms. Safety, tolerability, and immunologic response to the administered drugs&#xD;
      will also be evaluated throughout.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The primary PK parameters are Cmax and AUC(0-∞). The PK parameters for bevacizumab will be&#xD;
      calculated using standard noncompartmental methods. An analysis of covariance model will be&#xD;
      used to analyse the log-transformed primary PK parameters (AUC[0-∞].and Cmax) and AUC(0-t).&#xD;
      The model will include a fixed effect for treatment and body weight as a covariate.&#xD;
&#xD;
      All other PK parameters will not be subject to inferential statistical analysis. Estimates of&#xD;
      geometric mean ratios together with the corresponding 90% confidence intervals will be&#xD;
      derived for the comparisons of the PK parameters as follows:&#xD;
&#xD;
        -  MB02 versus EU Avastin®&#xD;
&#xD;
        -  MB02 versus US Avastin®&#xD;
&#xD;
        -  EU Avastin® versus US Avastin®&#xD;
&#xD;
      PK similarity will be achieved if the 90% confidence intervals (CIs) for the&#xD;
      biosimilar-to-reference ratios of PK endpoints (AUC[0-∞] and Cmax) fall within the predefined&#xD;
      0.80-1.25 acceptance similarity criteria for all 3 pairwise comparisons; MB02 versus&#xD;
      EU-approved Avastin®; MB02 versus US-licenced Avastin®; and EU-approved Avastin® versus&#xD;
      US-licenced Avastin®.&#xD;
&#xD;
      All AEs will be listed and summarised using descriptive methodology. All observed or&#xD;
      patient-reported AEs will be graded by the National Cancer Institute Common Terminology&#xD;
      Criteria for Adverse Events (CTCAE) version 4.03. The incidence of AEs for each treatment&#xD;
      will be presented by severity and by association with the study drugs as determined by the&#xD;
      Investigator (or designee). All safety data will be listed and summarised as appropriate&#xD;
&#xD;
      Immunogenicity data (overall anti-drug antibody [ADA] incidence and titers, and neutralising&#xD;
      ADA results) will be listed. A summary of the number and percent of subjects testing positive&#xD;
      for ADA or neutralising antibodies before the dose of MB02, EU Avastin®, or US Avastin® (Day&#xD;
      1) and at scheduled postdose assessments will be presented by treatment arm.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 7, 2017</start_date>
  <completion_date type="Actual">May 29, 2019</completion_date>
  <primary_completion_date type="Actual">May 29, 2019</primary_completion_date>
  <phase>Phase 1</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>Other</primary_purpose>
    <masking>Triple (Participant, Care Provider, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cmax: Maximum Observed Serum Concentration</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of Cmax) to establish bioequivalence between the 3 study arms.&#xD;
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric LS means ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>AUC(0-∞); Area Under the Serum Concentration-time Curve From Time Zero to Infinity</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of AUC[0-∞]) to establish bioequivalence between the 3 study arms.&#xD;
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric least square means (GLSM) ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Tmax: Time of Maximum Observed Serum Concentration</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>To evaluate the tmax of MB02, US Avastin® and EU Avastin® .</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(0-t) = Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration;</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>To evaluate the AUC[0-t] of MB02, US Avastin® and EU Avastin®.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CL: Total Body Drug Clearance After IV Administration</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>To evaluate the CL of MB02, US Avastin® and EU Avastin®</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>t1/2: Apparent Serum Terminal Elimination Half-life</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>To evaluate the t1/2 of MB02, US Avastin® and EU Avastin®</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunogenicity</measure>
    <time_frame>Day -1, Day 14, 28, 56, and 78</time_frame>
    <description>Incidence of anti-bevacizumab antibodies (ADA), including neutralizing antibodies (Nab). Subjects who tested positive at baseline are not included here.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety (Incidence of Treatment-related Adverse Events Using CTCAE v4.03)</measure>
    <time_frame>Day 1 - Day 100</time_frame>
    <description>Compare the incidence of TEAEs reported in each treatment arm.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>AUC(0-∞) Adjusted: Protein-adjusted Area Under the Serum Concentration-time Curve From Time Zero to Infinity</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameter), protein-adjusted AUC(0-∞) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
  </other_outcome>
  <other_outcome>
    <measure>AUC(0-t) Adjusted: Protein Adjusted Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameters), protein-adjusted AUC(0-t) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
  </other_outcome>
  <other_outcome>
    <measure>Cmax Adjusted: Protein Adjusted Maximum Observed Serum Concentration</measure>
    <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
    <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as Cmax is a dose-dependent PK parameters), protein-adjusted Cmax was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">114</enrollment>
  <condition>Healthy Volunteers</condition>
  <arm_group>
    <arm_group_label>MB02 (Bevacizumab Biosimilar)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>US licenced Avastin®</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>EU approved Avastin®</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MB02</intervention_name>
    <description>Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
    <arm_group_label>MB02 (Bevacizumab Biosimilar)</arm_group_label>
    <other_name>MB02 (Bevacizumab Biosimilar)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>US licenced Avastin®</intervention_name>
    <description>Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
    <arm_group_label>US licenced Avastin®</arm_group_label>
    <other_name>Bevacizumab (United States)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>EU approved Avastin®</intervention_name>
    <description>Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
    <arm_group_label>EU approved Avastin®</arm_group_label>
    <other_name>Bevacizumab (European Union)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Males of any race, between 18 and 55 years of age, inclusive, at Screening.&#xD;
&#xD;
          2. Body mass index between 18.5 and 29.9 kg/m2, inclusive, at Screening.&#xD;
&#xD;
          3. Total body weight between 60 and 95 kg, inclusive, at Screening.&#xD;
&#xD;
          4. In good health, determined by no clinically significant findings from medical history,&#xD;
             physical examination, 12-lead ECG, vital sign measurements, and clinical laboratory&#xD;
             evaluations (congenital nonhaemolytic hyperbilirubinemia [eg, Gilbert's syndrome] is&#xD;
             acceptable) at Screening or Check-in as assessed by the Investigator (or designee).&#xD;
&#xD;
          5. Relevant clinical laboratory evaluations of haematology, coagulation, urinalysis and&#xD;
             clinical chemistry within normal range at Screening and Check in as follows. A single&#xD;
             repeat test will be allowed at each timepoint.&#xD;
&#xD;
               -  Absolute neutrophil count ≥1.5 × 109 L&#xD;
&#xD;
               -  Platelet count ≥100 × 109 L&#xD;
&#xD;
               -  Haemoglobin &gt;10 g/dl&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ ULN&#xD;
&#xD;
               -  Alkaline phosphatase (ALP) ≤1.5 × ULN&#xD;
&#xD;
               -  Total bilirubin &lt;1.5 × ULN (&lt;51.30 µmol/L in subjects with Gilbert's syndrome)&#xD;
&#xD;
               -  Blood urea nitrogen ≤1.5 × ULN&#xD;
&#xD;
               -  Creatinine &lt; 132.63 µmol/L&#xD;
&#xD;
               -  Serum albumin: &gt;35 g/L&#xD;
&#xD;
               -  Low density lipoprotein cholesterol ≤ ULN&#xD;
&#xD;
               -  High density lipoprotein cholesterol ≥ lower limit of normal&#xD;
&#xD;
               -  Creatine kinase (CK) &lt; × 2 ULN&#xD;
&#xD;
               -  International normalised ratio (INR) 0.8-1.3&#xD;
&#xD;
               -  Urine dipstick for proteinuria &lt;2+&#xD;
&#xD;
          6. Systolic blood pressure ≥90 mmHg and ≤140 mmHg and diastolic blood pressure ≥50 mmHg&#xD;
             and ≤90 mmHg at Screening and Check in.&#xD;
&#xD;
          7. Subjects agree to use contraception as detailed in protocol.&#xD;
&#xD;
          8. Able to comprehend and willing to sign an informed consent form (ICF) and to abide by&#xD;
             the study restrictions. Subjects must have signed an informed consent before any&#xD;
             study-related procedure or evaluation is performed.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Significant history or clinical manifestation of any metabolic, allergic,&#xD;
             dermatological, hepatic, renal, haematological, pulmonary, cardiovascular,&#xD;
             gastrointestinal, neurological, respiratory, endocrine, or psychiatric disorder, as&#xD;
             determined by the Investigator (or designee).&#xD;
&#xD;
          2. History of significant hypersensitivity, intolerance, or allergy to any drug compound,&#xD;
             food, or other substance, unless approved by the Investigator (or designee).&#xD;
&#xD;
          3. Any current or recent history of active infections, including localised infections.&#xD;
&#xD;
          4. History of, or planned surgery, including suturing, dental surgery or wound dehiscence&#xD;
             within 30 days of dosing, or within 30 days of the last study visit.&#xD;
&#xD;
          5. Presence of a nonhealing wound or fracture.&#xD;
&#xD;
          6. Known history of clinically significant essential hypertension, orthostatic&#xD;
             hypotension, fainting spells or blackouts for any reason, cardiac failure or history&#xD;
             of thromboembolic conditions.&#xD;
&#xD;
          7. Medically significant dental disease or dental neglect, with signs and/or symptoms of&#xD;
             local or systemic infection that would likely require a dental procedure during the&#xD;
             course of the study.&#xD;
&#xD;
          8. Clinically relevant history of alcoholism, addiction or drug/chemical abuse prior to&#xD;
             Check-in, and/or positive alcohol breath test and/or urinary drug test screen at&#xD;
             Screening or Check in.&#xD;
&#xD;
          9. History of bleeding disorders or protein C, protein S, and/or factor V Leiden&#xD;
             deficiency.&#xD;
&#xD;
         10. History of clinically signifiant haemorrhage, epistaxis, GI bleeding, haemorrhoids&#xD;
             and/or haemoptysis.&#xD;
&#xD;
         11. History of GI perforation, ulcers, gastro oesophageal reflux, inflammatory bowel&#xD;
             disease, diverticular disease, or any fistulae.&#xD;
&#xD;
         12. Alcohol consumption of &gt;24 units per week. One unit of alcohol equals ½ pint (285 mL)&#xD;
             of beer or lager, 1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits.&#xD;
&#xD;
         13. Positive hepatitis panel, positive human immunodeficiency test. Subjects whose results&#xD;
             are compatible with prior immunisation and not infection may be included at the&#xD;
             discretion of the Investigator.&#xD;
&#xD;
         14. Participation in a clinical study involving administration of an investigational drug&#xD;
             (new chemical entity) in the past 90 days prior to Check-in, or within 5 half lives of&#xD;
             the investigational drug used in the study.&#xD;
&#xD;
         15. Use or intend to use slow-release medications/products considered to still be active&#xD;
             within 30 days prior to Check-in, unless deemed acceptable by the Investigator (or&#xD;
             designee).&#xD;
&#xD;
         16. Use or intend use of any prescription medications/ nonprescription products known to&#xD;
             alter drug absorption, metabolism, or elimination processes, including St. John's&#xD;
             Wort, within 30 days prior to Check-in, unless deemed acceptable by the Investigator&#xD;
             or designee.&#xD;
&#xD;
         17. Use or intend to use any nonprescription medications/products including vitamins,&#xD;
             minerals, and phytotherapeutic/herbal/plant derived preparations within 7 days prior&#xD;
             to Check-in, unless deemed acceptable by the Investigator (or designee).&#xD;
&#xD;
         18. Have received a live or attenuated vaccine from 3 months prior to Screening, or have&#xD;
             the intention to receive a vaccine during the study.&#xD;
&#xD;
         19. Intend to travel to a region where a vaccination will be required due to endemic&#xD;
             disease within 3 months of dosing.&#xD;
&#xD;
         20. Previous treatment with an anti VEGF antibody or any other protein or antibody&#xD;
             targeting the VEGF receptor.&#xD;
&#xD;
         21. Use of tobacco- or nicotine-containing products within 5 years prior to Check-in, or&#xD;
             positive cotinine test upon Screening or Check-in.&#xD;
&#xD;
         22. Receipt of blood products within 60 days prior to Check-in.&#xD;
&#xD;
         23. Donation of blood from 90 days prior to Screening, plasma from 14 days prior to&#xD;
             Screening, or platelets from 42 days prior to Screening.&#xD;
&#xD;
         24. Poor peripheral venous access.&#xD;
&#xD;
         25. History of abnormal peripheral sensation including paraesthesia and/or numbness in&#xD;
             arms and/or legs.&#xD;
&#xD;
         26. Have previously completed or withdrawn from this study or any other study&#xD;
             investigating bevacizumab, and/or have previously received bevacizumab.&#xD;
&#xD;
         27. Subjects who, in the opinion of the Investigator (or designee), should not participate&#xD;
             in this study.&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Only male subjects may be enrolled</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sunu Valasseri, MBBS, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Covance</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Muna Albayaty, MBChB,FFPM,MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Parexel</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>PAREXEL International - Northwick Park Hospital</name>
      <address>
        <city>Harrow</city>
        <zip>HA1 3UJ</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Covance Clinical Research Unit Limited</name>
      <address>
        <city>Leeds</city>
        <zip>LS2 9LH</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>September 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 26, 2017</study_first_posted>
  <results_first_submitted>May 28, 2020</results_first_submitted>
  <results_first_submitted_qc>May 28, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">June 16, 2020</results_first_posted>
  <last_update_submitted>March 1, 2021</last_update_submitted>
  <last_update_submitted_qc>March 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 23, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bevacizumab</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>March 25, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/54/NCT03293654/Prot_004.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>June 5, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/54/NCT03293654/SAP_005.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>MB02 (Bevacizumab Biosimilar)</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="P2">
          <title>US Licenced Avastin®</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="P3">
          <title>EU Approved Avastin®</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="38"/>
                <participants group_id="P2" count="38"/>
                <participants group_id="P3" count="38"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="38"/>
                <participants group_id="P2" count="37"/>
                <participants group_id="P3" count="38"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>MB02 (Bevacizumab Biosimilar)</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="B2">
          <title>US Licenced Avastin®</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="B3">
          <title>EU Approved Avastin®</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="38"/>
            <count group_id="B2" value="38"/>
            <count group_id="B3" value="38"/>
            <count group_id="B4" value="114"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="38"/>
                    <measurement group_id="B3" value="38"/>
                    <measurement group_id="B4" value="114"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36" spread="10.8"/>
                    <measurement group_id="B2" value="35" spread="9.1"/>
                    <measurement group_id="B3" value="38" spread="9.9"/>
                    <measurement group_id="B4" value="37" spread="9.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="38"/>
                    <measurement group_id="B2" value="38"/>
                    <measurement group_id="B3" value="38"/>
                    <measurement group_id="B4" value="114"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="35"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="30"/>
                    <measurement group_id="B4" value="95"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Weight</title>
          <units>kg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="76.9" spread="9.38"/>
                    <measurement group_id="B2" value="77.9" spread="8.11"/>
                    <measurement group_id="B3" value="77.8" spread="8.29"/>
                    <measurement group_id="B4" value="77.6" spread="8.55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>BMI</title>
          <units>kg/m^2</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24.3" spread="2.66"/>
                    <measurement group_id="B2" value="24.3" spread="2.61"/>
                    <measurement group_id="B3" value="25.0" spread="2.07"/>
                    <measurement group_id="B4" value="24.5" spread="2.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Cmax: Maximum Observed Serum Concentration</title>
        <description>To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of Cmax) to establish bioequivalence between the 3 study arms.&#xD;
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric LS means ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <population>Overall number of participants analyzed equals to number of subjects who contributed to summary statistics.</population>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax: Maximum Observed Serum Concentration</title>
          <description>To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of Cmax) to establish bioequivalence between the 3 study arms.&#xD;
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric LS means ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.</description>
          <population>Overall number of participants analyzed equals to number of subjects who contributed to summary statistics.</population>
          <units>(ng/mL)/(mg/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="38"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83000" spread="22.4"/>
                    <measurement group_id="O2" value="65200" spread="21.9"/>
                    <measurement group_id="O3" value="74400" spread="25.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (Cmax) falls completely within the range 0.80-1.25. The PK parameter Cmax was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.28</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.18</ci_lower_limit>
            <ci_upper_limit>1.39</ci_upper_limit>
            <estimate_desc>For the comparison, MB02 represents the numerator and US Avastin represents the denominator.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (Cmax) falls completely within the range 0.80-1.25. The PK parameter Cmax was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.12</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.03</ci_lower_limit>
            <ci_upper_limit>1.22</ci_upper_limit>
            <estimate_desc>For the comparison, MB02 represents the numerator and EU Avastin represents the denominator.</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (Cmax) falls completely within the range 0.80-1.25. The PK parameter Cmax was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.14</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.05</ci_lower_limit>
            <ci_upper_limit>1.24</ci_upper_limit>
            <estimate_desc>Ratio of GLSM, EU is the numerator and US Avastin acts as the denominator</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>AUC(0-∞); Area Under the Serum Concentration-time Curve From Time Zero to Infinity</title>
        <description>To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of AUC[0-∞]) to establish bioequivalence between the 3 study arms.&#xD;
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric least square means (GLSM) ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <population>Overall number of participants analyzed equals to number of subjects who contributed to summary statistics.</population>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-∞); Area Under the Serum Concentration-time Curve From Time Zero to Infinity</title>
          <description>To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of AUC[0-∞]) to establish bioequivalence between the 3 study arms.&#xD;
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric least square means (GLSM) ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.</description>
          <population>Overall number of participants analyzed equals to number of subjects who contributed to summary statistics.</population>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="28200000" spread="16.3"/>
                    <measurement group_id="O2" value="22900000" spread="17.8"/>
                    <measurement group_id="O3" value="24500000" spread="15.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.16</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.09</ci_lower_limit>
            <ci_upper_limit>1.22</ci_upper_limit>
            <other_analysis_desc>For the comparison, MB02 represents the numerator and US Avastin represents the denominator</other_analysis_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.16</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.09</ci_lower_limit>
            <ci_upper_limit>1.22</ci_upper_limit>
            <estimate_desc>MB02 represents the numerator and EU Avastin represents the denominator</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.07</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1</ci_lower_limit>
            <ci_upper_limit>1.13</ci_upper_limit>
            <estimate_desc>EU Avastin corresponds to the numerator and US Avastin corresponds to the denominator</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Tmax: Time of Maximum Observed Serum Concentration</title>
        <description>To evaluate the tmax of MB02, US Avastin® and EU Avastin® .</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Tmax: Time of Maximum Observed Serum Concentration</title>
          <description>To evaluate the tmax of MB02, US Avastin® and EU Avastin® .</description>
          <units>h</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="38"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.51" lower_limit="1.62" upper_limit="71.98"/>
                    <measurement group_id="O2" value="4.00" lower_limit="1.62" upper_limit="11.98"/>
                    <measurement group_id="O3" value="3.00" lower_limit="1.57" upper_limit="12.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(0-t) = Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration;</title>
        <description>To evaluate the AUC[0-t] of MB02, US Avastin® and EU Avastin®.</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-t) = Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration;</title>
          <description>To evaluate the AUC[0-t] of MB02, US Avastin® and EU Avastin®.</description>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="27400000" spread="15.5"/>
                    <measurement group_id="O2" value="22300000" spread="16.9"/>
                    <measurement group_id="O3" value="23700000" spread="14.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>CL: Total Body Drug Clearance After IV Administration</title>
        <description>To evaluate the CL of MB02, US Avastin® and EU Avastin®</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>CL: Total Body Drug Clearance After IV Administration</title>
          <description>To evaluate the CL of MB02, US Avastin® and EU Avastin®</description>
          <units>l/h</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.00814" spread="16.5"/>
                    <measurement group_id="O2" value="0.0101" spread="17.9"/>
                    <measurement group_id="O3" value="0.00947" spread="15.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>t1/2: Apparent Serum Terminal Elimination Half-life</title>
        <description>To evaluate the t1/2 of MB02, US Avastin® and EU Avastin®</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>t1/2: Apparent Serum Terminal Elimination Half-life</title>
          <description>To evaluate the t1/2 of MB02, US Avastin® and EU Avastin®</description>
          <units>h</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="451" spread="14.4"/>
                    <measurement group_id="O2" value="437" spread="15.5"/>
                    <measurement group_id="O3" value="449" spread="19.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Immunogenicity</title>
        <description>Incidence of anti-bevacizumab antibodies (ADA), including neutralizing antibodies (Nab). Subjects who tested positive at baseline are not included here.</description>
        <time_frame>Day -1, Day 14, 28, 56, and 78</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Immunogenicity</title>
          <description>Incidence of anti-bevacizumab antibodies (ADA), including neutralizing antibodies (Nab). Subjects who tested positive at baseline are not included here.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="38"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>ADA positive</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>nAb positive</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>NO seroconversion</title>
                  <measurement_list>
                    <measurement group_id="O1" value="35"/>
                    <measurement group_id="O2" value="36"/>
                    <measurement group_id="O3" value="37"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Safety (Incidence of Treatment-related Adverse Events Using CTCAE v4.03)</title>
        <description>Compare the incidence of TEAEs reported in each treatment arm.</description>
        <time_frame>Day 1 - Day 100</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Safety (Incidence of Treatment-related Adverse Events Using CTCAE v4.03)</title>
          <description>Compare the incidence of TEAEs reported in each treatment arm.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="38"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Subjects with TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="28"/>
                    <measurement group_id="O3" value="25"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Subjects with SAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Subjects discontinued due to TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Related TEAEs</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="3"/>
                    <measurement group_id="O3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEAEs of mild severity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="25"/>
                    <measurement group_id="O3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEAEs of moderate severity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="10"/>
                    <measurement group_id="O3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TEAEs of severe severity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>AUC(0-∞) Adjusted: Protein-adjusted Area Under the Serum Concentration-time Curve From Time Zero to Infinity</title>
        <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameter), protein-adjusted AUC(0-∞) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-∞) Adjusted: Protein-adjusted Area Under the Serum Concentration-time Curve From Time Zero to Infinity</title>
          <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameter), protein-adjusted AUC(0-∞) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1040000" spread="16.3"/>
                    <measurement group_id="O2" value="981000" spread="18.1"/>
                    <measurement group_id="O3" value="1020000" spread="14.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.02</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.962</ci_lower_limit>
            <ci_upper_limit>1.07</ci_upper_limit>
            <estimate_desc>MB02 in numerator and EU Avastin in denominator</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.06</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.996</ci_lower_limit>
            <ci_upper_limit>1.13</ci_upper_limit>
            <estimate_desc>MB02 is numerator and US Avastin is denominator</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.04</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.983</ci_lower_limit>
            <ci_upper_limit>1.11</ci_upper_limit>
            <estimate_desc>EU Avastin in the numerator and US Avastin in the denominator</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>AUC(0-t) Adjusted: Protein Adjusted Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration</title>
        <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameters), protein-adjusted AUC(0-t) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(0-t) Adjusted: Protein Adjusted Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration</title>
          <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameters), protein-adjusted AUC(0-t) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
          <units>ng*h/mL</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="37"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1010000" spread="15.5"/>
                    <measurement group_id="O2" value="955000" spread="17.2"/>
                    <measurement group_id="O3" value="991000" spread="13.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.02</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.969</ci_lower_limit>
            <ci_upper_limit>1.07</ci_upper_limit>
            <estimate_desc>MB02: EU Avastin</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.06</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.998</ci_lower_limit>
            <ci_upper_limit>1.12</ci_upper_limit>
            <estimate_desc>MB02: US Avastin</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.04</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.981</ci_lower_limit>
            <ci_upper_limit>1.1</ci_upper_limit>
            <estimate_desc>EU Avastin: US Avastin</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Cmax Adjusted: Protein Adjusted Maximum Observed Serum Concentration</title>
        <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as Cmax is a dose-dependent PK parameters), protein-adjusted Cmax was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
        <time_frame>Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>MB02 (Bevacizumab Biosimilar)</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O2">
            <title>US Licenced Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
          <group group_id="O3">
            <title>EU Approved Avastin®</title>
            <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
          </group>
        </group_list>
        <measure>
          <title>Cmax Adjusted: Protein Adjusted Maximum Observed Serum Concentration</title>
          <description>Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as Cmax is a dose-dependent PK parameters), protein-adjusted Cmax was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.&#xD;
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.</description>
          <units>(ng/mL)/(mg/mL)</units>
          <param>Geometric Mean</param>
          <dispersion>Geometric Coefficient of Variation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="38"/>
                <count group_id="O3" value="38"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3050" spread="22.4"/>
                    <measurement group_id="O2" value="2790" spread="22.1"/>
                    <measurement group_id="O3" value="3110" spread="25.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>0.986</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.903</ci_lower_limit>
            <ci_upper_limit>1.08</ci_upper_limit>
            <estimate_desc>MB02: EU Avastin</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.1</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.01</ci_lower_limit>
            <ci_upper_limit>1.19</ci_upper_limit>
            <estimate_desc>MB02: US Avastin</estimate_desc>
          </analysis>
          <analysis>
            <group_id_list>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Two treatments are judged not to be different from one another if the 90% CI of the ratio of a log-transformed exposure measure (AUC) falls completely within the range 0.80-1.25. The PK parameter AUC[0-∞] was log-transformed (base e) prior to analysis and was analysed using an ANCOVA model. The model included treatment as a fixed effect and body weight as a covariate.</non_inferiority_desc>
            <param_type>Ratio of GLSM</param_type>
            <param_value>1.12</param_value>
            <dispersion_type>Standard Deviation</dispersion_type>
            <dispersion_value>0.05</dispersion_value>
            <ci_percent>90</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>1.02</ci_lower_limit>
            <ci_upper_limit>1.22</ci_upper_limit>
            <estimate_desc>EU Avastin: US Avastin</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Study duration (Day 1 - Day 100)</time_frame>
      <desc>Coded according to Medical Dictionary for Regulatory Activities (version 20.1), and graded on the basis of the US National Cancer Institute's Common Terminology for Adverse Events (version 4.03).&#xD;
Following a request from the Medicines and Healthcare products Regulatory Authority (MHRA) all serious adverse reactions were considered unexpected and reported as SUSARs, for the purpose of safety reporting in healthy volunteers.</desc>
      <group_list>
        <group group_id="E1">
          <title>MB02 (Bevacizumab Biosimilar)</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
MB02: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="E2">
          <title>US Licenced Avastin®</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
US licenced Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
        <group group_id="E3">
          <title>EU Approved Avastin®</title>
          <description>Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.&#xD;
EU approved Avastin®: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA 20.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Purpura</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>MedDRA 20.1</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="24" subjects_at_risk="38"/>
                <counts group_id="E2" subjects_affected="28" subjects_at_risk="38"/>
                <counts group_id="E3" subjects_affected="25" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="5" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="5" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Toothache</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Diarrhoea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Gingival pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Influenza like illness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Seasonal allergy</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory tract infection</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" events="12" subjects_affected="11" subjects_at_risk="38"/>
                <counts group_id="E3" events="7" subjects_affected="6" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Nasophyringitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="6" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E3" events="6" subjects_affected="5" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Conjunctivitis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Gingivitis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Contusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" events="8" subjects_affected="7" subjects_at_risk="38"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Muscle spasms</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="9" subjects_affected="6" subjects_at_risk="38"/>
                <counts group_id="E2" events="10" subjects_affected="8" subjects_at_risk="38"/>
                <counts group_id="E3" events="10" subjects_affected="8" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Oropharyngeal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="38"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="38"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="38"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="38"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="38"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="38"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Susana Millan</name_or_title>
      <organization>mAbxience</organization>
      <phone>+34917711500</phone>
      <email>susana.millan@mabxience.com</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03293654
org study id: MB02 A 02 17
nct id: NCT03293654
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: Yes
Randomized, double blind, parallel group, single dose, 3 arm study to investigate and compare
      the Pharmacokinetics (PK), safety and immunogenicity profile of MB02 with US and EU Avastin®
      in healthy male subjects.

      During the course of the study, the similarity in pharmacokinetics will be assessed by
      sampling the levels of drug in the blood, and by comparing these levels among the different
      administration arms. Safety, tolerability, and immunologic response to the administered drugs
      will also be evaluated throughout.
The primary PK parameters are Cmax and AUC(0-∞). The PK parameters for bevacizumab will be
      calculated using standard noncompartmental methods. An analysis of covariance model will be
      used to analyse the log-transformed primary PK parameters (AUC[0-∞].and Cmax) and AUC(0-t).
      The model will include a fixed effect for treatment and body weight as a covariate.

      All other PK parameters will not be subject to inferential statistical analysis. Estimates of
      geometric mean ratios together with the corresponding 90% confidence intervals will be
      derived for the comparisons of the PK parameters as follows:

        -  MB02 versus EU Avastin®

        -  MB02 versus US Avastin®

        -  EU Avastin® versus US Avastin®

      PK similarity will be achieved if the 90% confidence intervals (CIs) for the
      biosimilar-to-reference ratios of PK endpoints (AUC[0-∞] and Cmax) fall within the predefined
      0.80-1.25 acceptance similarity criteria for all 3 pairwise comparisons; MB02 versus
      EU-approved Avastin®; MB02 versus US-licenced Avastin®; and EU-approved Avastin® versus
      US-licenced Avastin®.

      All AEs will be listed and summarised using descriptive methodology. All observed or
      patient-reported AEs will be graded by the National Cancer Institute Common Terminology
      Criteria for Adverse Events (CTCAE) version 4.03. The incidence of AEs for each treatment
      will be presented by severity and by association with the study drugs as determined by the
      Investigator (or designee). All safety data will be listed and summarised as appropriate

      Immunogenicity data (overall anti-drug antibody [ADA] incidence and titers, and neutralising
      ADA results) will be listed. A summary of the number and percent of subjects testing positive
      for ADA or neutralising antibodies before the dose of MB02, EU Avastin®, or US Avastin® (Day
      1) and at scheduled postdose assessments will be presented by treatment arm.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Triple (Participant, Care Provider, Investigator)
measure: Cmax: Maximum Observed Serum Concentration
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of Cmax) to establish bioequivalence between the 3 study arms.
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric LS means ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.
measure: AUC(0-∞); Area Under the Serum Concentration-time Curve From Time Zero to Infinity
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: To compare the pharmacokinetic (PK) profiles of MB02, US Avastin® and EU Avastin® (in terms of AUC[0-∞]) to establish bioequivalence between the 3 study arms.
For the PK similarity assessments, regulatory guidelines on bioequivalence were followed whereby two treatments are judged not to be different from one another if the 90% confidence interval (CI) for the geometric least square means (GLSM) ratios are fully contained within the predefined bioequivalence limits of 0.80 to 1.25.
measure: Tmax: Time of Maximum Observed Serum Concentration
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: To evaluate the tmax of MB02, US Avastin® and EU Avastin® .
measure: AUC(0-t) = Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration;
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: To evaluate the AUC[0-t] of MB02, US Avastin® and EU Avastin®.
measure: CL: Total Body Drug Clearance After IV Administration
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: To evaluate the CL of MB02, US Avastin® and EU Avastin®
measure: t1/2: Apparent Serum Terminal Elimination Half-life
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: To evaluate the t1/2 of MB02, US Avastin® and EU Avastin®
measure: Immunogenicity
time frame: Day -1, Day 14, 28, 56, and 78
description: Incidence of anti-bevacizumab antibodies (ADA), including neutralizing antibodies (Nab). Subjects who tested positive at baseline are not included here.
measure: Safety (Incidence of Treatment-related Adverse Events Using CTCAE v4.03)
time frame: Day 1 - Day 100
description: Compare the incidence of TEAEs reported in each treatment arm.
measure: AUC(0-∞) Adjusted: Protein-adjusted Area Under the Serum Concentration-time Curve From Time Zero to Infinity
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameter), protein-adjusted AUC(0-∞) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.
measure: AUC(0-t) Adjusted: Protein Adjusted Area Under the Serum Concentration-time Curve From Time Zero to the Time of the Last Observable Concentration
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as AUC is a dose-dependent PK parameters), protein-adjusted AUC(0-t) was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.
measure: Cmax Adjusted: Protein Adjusted Maximum Observed Serum Concentration
time frame: Predose, 1.5 h after end of infusion, 2, 3, 4, 5, 6, 8, 12, 24 h post-dose on Day 1-8, Day 10, Day 14, Day 21, Day 28, Day 42, Day 56, Day 78, and Day 100.
description: Due to variability in the actual protein content between the study drugs and study drug batches which had the potential to influence the study results (as Cmax is a dose-dependent PK parameters), protein-adjusted Cmax was also derived for each individual by dividing each parameter by the actual protein content of the product batch that the individual subjects received.
The 3 mg/kg IV dose of MB02 and US Avastin®, MB02 and EU Avastin®, and EU and US Avastin® were all considered bioequivalent in terms of the protein-adjusted AUCs and Cmax as the 90% CI for the geometric LS means ratios were fully contained within the predefined bioequivalence limits of 0.80 to 1.25 for all 3 comparisons. In general, as assessed from the geometric CV%, between-subject variability remained similar following protein adjustment compared to the unadjusted AUCs and Cmax.
arm group label: MB02 (Bevacizumab Biosimilar)
arm group type: Experimental
description: Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
arm group label: US licenced Avastin®
arm group type: Active Comparator
description: Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
arm group label: EU approved Avastin®
arm group type: Active Comparator
description: Intervention Description: Sterile vial 400mg/16ml, single-dose 3mg/kg administered as 90-minute infusion on day 1.
intervention type: Drug
intervention name: MB02
description: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.
arm group label: MB02 (Bevacizumab Biosimilar)
other name: MB02 (Bevacizumab Biosimilar)
intervention type: Drug
intervention name: US licenced Avastin®
description: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.
arm group label: US licenced Avastin®
other name: Bevacizumab (United States)
intervention type: Drug
intervention name: EU approved Avastin®
description: Solution for intravenous infusion, single dose of 3mg/kg, administered as 90-minute infusion.
arm group label: EU approved Avastin®
other name: Bevacizumab (European Union)
criteria: 
gender: Male
gender based: Yes
gender description: Only male subjects may be enrolled
minimum age: 18 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Sunu Valasseri, MBBS, MSc
role: Principal Investigator
affiliation: Covance
last name: Muna Albayaty, MBChB,FFPM,MSc
role: Principal Investigator
affiliation: Parexel
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Bevacizumab
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 