<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/NCT03028155</url>
  </required_header>
  <id_info>
    <org_study_id>ZOLCOBOX1</org_study_id>
    <nct_id>NCT03028155</nct_id>
  </id_info>
  <brief_title>Concentration- Versus Body Surface Area-based HIPEC in Colorectal Peritoneal Carcinomatosis' Treatment</brief_title>
  <acronym>COBOX</acronym>
  <official_title>Concentration-based Versus Body Surface Area-based Peroperative Intraperitoneal Chemotherapy (HIPEC) After Optimal Cytoreductive Surgery in Colorectal Peritoneal Carcinomatosis' Treatment - Randomized Non-blinded Phase III Clinical Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hasselt University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ziekenhuis Oost-Limburg</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Hasselt University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Colorectal Cancer (CRC) is the third most common cancer and the fourth most common cause of&#xD;
      cancer-related death worldwide. CRC frequently gives rise to transcoelomic spread of tumor&#xD;
      cells in the peritoneal cavity, which ultimately leads to Peritoneal Carcinomatosis (PC). A&#xD;
      new loco-regional treatment modality combines Cytoreductive Surgery (CRS) and Hyperthermic&#xD;
      Intraperitoneal Peroperative Chemotherapy (HIPEC). The current HIPEC dosing regimens for the&#xD;
      treatment of colorectal PC can be divided into body surface area (BSA)-based protocols and&#xD;
      concentration-based protocols. Most groups currently use a drug dose based on calculated BSA&#xD;
      (mg/m2) in analogy to systemic chemotherapy regimens. These regimens take BSA as a measure&#xD;
      for the effective contact area, represented as the peritoneal surface in the formula for dose&#xD;
      intensification. However, an imperfect correlation exists between actual peritoneal surface&#xD;
      area and calculated BSA. Sex differences, but also altered pathophysiological characteristics&#xD;
      or frequent complications in patients (ascites) are responsible for differences in peritoneal&#xD;
      surface areas, which in turn affect absorption characteristics. This takes us away from the&#xD;
      initial homogenous drug concentration desired, increasing the variability in the systemic and&#xD;
      tumor exposure to the drug. Pharmacokinetic changes induced by the volume of chemotherapy&#xD;
      solution with constant drug dose, administered intraperitoneally, have already been reported.&#xD;
      This resulted in less precise predictions of the toxicity associated with the treatment. By&#xD;
      contrast, some groups use a totally different dosimetry regimen based on concentration. From&#xD;
      a pharmacologic point of view, the big advantage of a concentration-based system is that the&#xD;
      residual tumor nodules after CRS are exposed to a constant diffusional force and, thus,&#xD;
      cytotoxicity. Unfortunately the prize to be paid for a better prediction of the efficacy of&#xD;
      the IP chemotherapy is a high unpredictability of the levels of plasmatic cancer chemotherapy&#xD;
      and, thus, toxicity. This randomised non-blinded phase III clinical trial will be the first&#xD;
      trial to pharmacologically evaluate the two dosing regimens, BSA-based and&#xD;
      concentration-based, both applied as standard of care in current practice.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date>November 2016</start_date>
  <completion_date type="Anticipated">August 2018</completion_date>
  <primary_completion_date type="Anticipated">August 2018</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of pharmacologic advantage</measure>
    <time_frame>Day 2</time_frame>
    <description>the area-under-the-curve (AUC) ratio of the intraperitoneal (IP) exposure over the AUC of the intravenous (IV) exposure to oxaliplatin. Intraoperative sampling of plasma and peritoneal fluid at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure.&#xD;
The concentration of oxaliplatin will be determined in plasma and peritoneal fluid by means of a validated inductively coupled plasma mass spectrometry (ICP-MS). A concentration versus time curve will be set-up and the AUC will be determined.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of Pt excretion in urine</measure>
    <time_frame>day 2</time_frame>
    <description>Intraoperative sampling of urine at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in urine by means of a validated ICP-MS. A concentration versus time curve will be set-up and the AUC will be determined.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of efficacy in the tumor nodule as pharmacologic endpoint.</measure>
    <time_frame>day 2</time_frame>
    <description>At the day of surgery (day 2): intraoperative sampling of tumor nodules at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in tumor nodules by means of a validated ICP-MS. A concentration versus time curve will be set-up and the AUC will be determined.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of 3-month overall morbidity and mortality</measure>
    <time_frame>During 3 months postoperative.</time_frame>
    <description>Morbidity and mortality will be evaluated using the Clavien-Dindo classification. This classification consists of five grades: grade I, deviation from standard post-operative course within 'allowed therapeutic regimens'; grade II, complication requiring surgical, endoscopic or radiological intervention; grade IV, complication requiring ICU admission and grade V, complication resulting in death.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Assessment of one-year overall survival</measure>
    <time_frame>During one year postoperative.</time_frame>
    <description>One-year overall survival will be determined.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30</measure>
    <time_frame>Day 1</time_frame>
    <description>HRQOL will be determined by means of the EORTC QLQ-C-30 (version 3.0, 2001). This questionnaire is developed to evaluate quality of life (QOL) of cancer patients, translated and validated in Dutch. Scoring will be according to manufacturer's guidelines, EORTC scoring manual.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of health related quality of life (HRQOL): SF-36</measure>
    <time_frame>Day 1</time_frame>
    <description>HRQOL will be determined by means of the 36-item Short Form Survey (SF-36). This questionnaire is developed by RAND Health. Scoring will be according to instructions form RAND Health.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30</measure>
    <time_frame>up to 2 months</time_frame>
    <description>HRQOL will be determined by means of the EORTC QLQ-C-30 (version 3.0, 2001). This questionnaire is developed to evaluate quality of life (QOL) of cancer patients, translated and validated in Dutch. Scoring will be according to manufacturer's guidelines, EORTC scoring manual.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of health related quality of life (HRQOL): SF-36</measure>
    <time_frame>up to 2 months</time_frame>
    <description>HRQOL will be determined by means of the 36-item Short Form Survey (SF-36). This questionnaire is developed by RAND Health. Scoring will be according to instructions form RAND Health.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30</measure>
    <time_frame>month 3</time_frame>
    <description>HRQOL will be determined by means of the EORTC QLQ-C-30 (version 3.0, 2001). This questionnaire is developed to evaluate quality of life (QOL) of cancer patients, translated and validated in Dutch. Scoring will be according to manufacturer's guidelines, EORTC scoring manual</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of health related quality of life (HRQOL): SF-36</measure>
    <time_frame>month 3</time_frame>
    <description>HRQOL will be determined by means of the 36-item Short Form Survey (SF-36). This questionnaire is developed by RAND Health. Scoring will be according to instructions form RAND Health.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Colorectal Peritoneal Carcinomatosis</condition>
  <arm_group>
    <arm_group_label>Oxaliplatin: BSA-based HIPEC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention: oxaliplatin: BSA-based HIPEC HIPEC will be performed using oxaliplatin as chemotherapeutic agent at a dose of 460 mg/m2 mixed in 0.9% saline carrier solution during 30 minutes. Volume of the carrier solution: depended on the capacity of the abdominal cavity of the patient.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oxaliplatin: Concentration-based HIPEC</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intervention: oxaliplatin: concentration-based HIPEC HIPEC will be performed using oxaliplatin as chemotherapeutic agent at a dose of 460 mg/m2 mixed in 0.9% saline carrier solution at 2L/m2, which equals a concentration of 230 mg/L during 30 minutes.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin: BSA-based HIPEC</intervention_name>
    <description>oxaliplatin: 460 mg/m2 volume: dependent on the capacity of the peritoneal cavity of the patient</description>
    <arm_group_label>Oxaliplatin: BSA-based HIPEC</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin: Concentration-based HIPEC</intervention_name>
    <description>oxaliplatin: 230 mg/L</description>
    <arm_group_label>Oxaliplatin: Concentration-based HIPEC</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females with histologically proven synchronous or metachronous peritoneal&#xD;
             metastases from colorectal origin&#xD;
&#xD;
          -  Karnofsky index &gt; 70%&#xD;
&#xD;
          -  Age &gt;18 years&#xD;
&#xD;
          -  Fit for major surgery&#xD;
&#xD;
          -  Mentally capable of understanding the proposed treatment and the provided informed&#xD;
             consent&#xD;
&#xD;
          -  Estimated life expectancy of &gt; 6 months&#xD;
&#xD;
          -  Absence of other malignant disease&#xD;
&#xD;
          -  Serum creatinine &lt; or = 1.5 mg/dL or calculated glomerular filtration rate &gt; or = 60&#xD;
             mL/min/1.73m2&#xD;
&#xD;
          -  Serum total bilirubin &lt; or = 1.5 mg/dL except for known Gilbert's disease&#xD;
&#xD;
          -  Platelet count &gt; 100,000/µL&#xD;
&#xD;
          -  Hemoglobin &gt; 9 g/dL&#xD;
&#xD;
          -  Neutrophil granulocytes &gt; 1,500/mL&#xD;
&#xD;
          -  International normalized ratio &lt; or = 2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Alcohol or drug abuse&#xD;
&#xD;
          -  Inclusion in other trials interfering with the study protocol&#xD;
&#xD;
          -  Chronic systemic immune therapy&#xD;
&#xD;
          -  Chemotherapy or hormone therapy not indicated in the study protocol&#xD;
&#xD;
          -  Severe organ insufficiency&#xD;
&#xD;
          -  Pregnancy or breast feeding&#xD;
&#xD;
          -  Appearance of distant metastases (liver, lung) of a CT scan of the abdomen of chest&#xD;
             X-ray&#xD;
&#xD;
          -  Severe or uncontrolled cardiac pathology&#xD;
&#xD;
          -  &gt; 6 months occurrence of myocardial infarction&#xD;
&#xD;
          -  Presence of congestive cardiac failure of symptomatic angor pectoris despite optimal&#xD;
             medical treatment&#xD;
&#xD;
          -  Presence of congestive cardiac failure of cardiac arrhythmia requiring medical&#xD;
             treatment with insufficient rhythm control&#xD;
&#xD;
          -  Uncontrolled arterial hypertension&#xD;
&#xD;
          -  Active bacterial, viral or fungal infection&#xD;
&#xD;
          -  Active gastrointestinal ulcer&#xD;
&#xD;
          -  Any stage cirrhosis&#xD;
&#xD;
          -  Uncontrolled diabetes mellitus&#xD;
&#xD;
          -  Severe obstructive or restrictive respiratory insufficiency&#xD;
&#xD;
          -  Tumor in the presence of obstruction&#xD;
&#xD;
          -  Allergy to trial related drugs&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Kurt Van der Speeten, prof. dr.</last_name>
    <email>kurt.vanderspeeten@zol.be</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Lieselotte Lemoine, drs.</last_name>
    <email>lieselotte.lemoine@uhasselt.be</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Ziekenhuis Oost-Limburg</name>
      <address>
        <city>Genk</city>
        <zip>3600</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Lieselotte Lemoine, drs.</last_name>
      <email>lieselotte.lemoine@uhasselt.be</email>
    </contact>
    <investigator>
      <last_name>Kurt Van der Speeten, prof. dr.</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Belgium</country>
  </location_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>December 24, 2016</study_first_submitted>
  <study_first_submitted_qc>January 19, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 23, 2017</study_first_posted>
  <last_update_submitted>January 19, 2017</last_update_submitted>
  <last_update_submitted_qc>January 19, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 23, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Hasselt University</investigator_affiliation>
    <investigator_full_name>Kurt Van der Speeten</investigator_full_name>
    <investigator_title>prof. dr.</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Peritoneal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Oxaliplatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03028155
org study id: ZOLCOBOX1
nct id: NCT03028155
lead sponsor: 
collaborator: 
has dmc: No
Colorectal Cancer (CRC) is the third most common cancer and the fourth most common cause of
      cancer-related death worldwide. CRC frequently gives rise to transcoelomic spread of tumor
      cells in the peritoneal cavity, which ultimately leads to Peritoneal Carcinomatosis (PC). A
      new loco-regional treatment modality combines Cytoreductive Surgery (CRS) and Hyperthermic
      Intraperitoneal Peroperative Chemotherapy (HIPEC). The current HIPEC dosing regimens for the
      treatment of colorectal PC can be divided into body surface area (BSA)-based protocols and
      concentration-based protocols. Most groups currently use a drug dose based on calculated BSA
      (mg/m2) in analogy to systemic chemotherapy regimens. These regimens take BSA as a measure
      for the effective contact area, represented as the peritoneal surface in the formula for dose
      intensification. However, an imperfect correlation exists between actual peritoneal surface
      area and calculated BSA. Sex differences, but also altered pathophysiological characteristics
      or frequent complications in patients (ascites) are responsible for differences in peritoneal
      surface areas, which in turn affect absorption characteristics. This takes us away from the
      initial homogenous drug concentration desired, increasing the variability in the systemic and
      tumor exposure to the drug. Pharmacokinetic changes induced by the volume of chemotherapy
      solution with constant drug dose, administered intraperitoneally, have already been reported.
      This resulted in less precise predictions of the toxicity associated with the treatment. By
      contrast, some groups use a totally different dosimetry regimen based on concentration. From
      a pharmacologic point of view, the big advantage of a concentration-based system is that the
      residual tumor nodules after CRS are exposed to a constant diffusional force and, thus,
      cytotoxicity. Unfortunately the prize to be paid for a better prediction of the efficacy of
      the IP chemotherapy is a high unpredictability of the levels of plasmatic cancer chemotherapy
      and, thus, toxicity. This randomised non-blinded phase III clinical trial will be the first
      trial to pharmacologically evaluate the two dosing regimens, BSA-based and
      concentration-based, both applied as standard of care in current practice.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Assessment of pharmacologic advantage
time frame: Day 2
description: the area-under-the-curve (AUC) ratio of the intraperitoneal (IP) exposure over the AUC of the intravenous (IV) exposure to oxaliplatin. Intraoperative sampling of plasma and peritoneal fluid at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure.
The concentration of oxaliplatin will be determined in plasma and peritoneal fluid by means of a validated inductively coupled plasma mass spectrometry (ICP-MS). A concentration versus time curve will be set-up and the AUC will be determined.
measure: Assessment of Pt excretion in urine
time frame: day 2
description: Intraoperative sampling of urine at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in urine by means of a validated ICP-MS. A concentration versus time curve will be set-up and the AUC will be determined.
measure: Assessment of efficacy in the tumor nodule as pharmacologic endpoint.
time frame: day 2
description: At the day of surgery (day 2): intraoperative sampling of tumor nodules at seven time points (0, 5, 10, 15, 20, 25 and 30 minutes) during the 30-minute HIPEC procedure. The concentration of oxaliplatin will be determined in tumor nodules by means of a validated ICP-MS. A concentration versus time curve will be set-up and the AUC will be determined.
measure: Assessment of 3-month overall morbidity and mortality
time frame: During 3 months postoperative.
description: Morbidity and mortality will be evaluated using the Clavien-Dindo classification. This classification consists of five grades: grade I, deviation from standard post-operative course within 'allowed therapeutic regimens'; grade II, complication requiring surgical, endoscopic or radiological intervention; grade IV, complication requiring ICU admission and grade V, complication resulting in death.
measure: Assessment of one-year overall survival
time frame: During one year postoperative.
description: One-year overall survival will be determined.
measure: Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30
time frame: Day 1
description: HRQOL will be determined by means of the EORTC QLQ-C-30 (version 3.0, 2001). This questionnaire is developed to evaluate quality of life (QOL) of cancer patients, translated and validated in Dutch. Scoring will be according to manufacturer's guidelines, EORTC scoring manual.
measure: Assessment of health related quality of life (HRQOL): SF-36
time frame: Day 1
description: HRQOL will be determined by means of the 36-item Short Form Survey (SF-36). This questionnaire is developed by RAND Health. Scoring will be according to instructions form RAND Health.
measure: Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30
time frame: up to 2 months
description: HRQOL will be determined by means of the EORTC QLQ-C-30 (version 3.0, 2001). This questionnaire is developed to evaluate quality of life (QOL) of cancer patients, translated and validated in Dutch. Scoring will be according to manufacturer's guidelines, EORTC scoring manual.
measure: Assessment of health related quality of life (HRQOL): SF-36
time frame: up to 2 months
description: HRQOL will be determined by means of the 36-item Short Form Survey (SF-36). This questionnaire is developed by RAND Health. Scoring will be according to instructions form RAND Health.
measure: Assessment of health related quality of life (HRQOL): EORTC QLQ-C-30
time frame: month 3
description: HRQOL will be determined by means of the EORTC QLQ-C-30 (version 3.0, 2001). This questionnaire is developed to evaluate quality of life (QOL) of cancer patients, translated and validated in Dutch. Scoring will be according to manufacturer's guidelines, EORTC scoring manual
measure: Assessment of health related quality of life (HRQOL): SF-36
time frame: month 3
description: HRQOL will be determined by means of the 36-item Short Form Survey (SF-36). This questionnaire is developed by RAND Health. Scoring will be according to instructions form RAND Health.
arm group label: Oxaliplatin: BSA-based HIPEC
arm group type: Active Comparator
description: Intervention: oxaliplatin: BSA-based HIPEC HIPEC will be performed using oxaliplatin as chemotherapeutic agent at a dose of 460 mg/m2 mixed in 0.9% saline carrier solution during 30 minutes. Volume of the carrier solution: depended on the capacity of the abdominal cavity of the patient.
arm group label: Oxaliplatin: Concentration-based HIPEC
arm group type: Active Comparator
description: Intervention: oxaliplatin: concentration-based HIPEC HIPEC will be performed using oxaliplatin as chemotherapeutic agent at a dose of 460 mg/m2 mixed in 0.9% saline carrier solution at 2L/m2, which equals a concentration of 230 mg/L during 30 minutes.
intervention type: Drug
intervention name: Oxaliplatin: BSA-based HIPEC
description: oxaliplatin: 460 mg/m2 volume: dependent on the capacity of the peritoneal cavity of the patient
arm group label: Oxaliplatin: BSA-based HIPEC
intervention type: Drug
intervention name: Oxaliplatin: Concentration-based HIPEC
description: oxaliplatin: 230 mg/L
arm group label: Oxaliplatin: Concentration-based HIPEC
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Kurt Van der Speeten, prof. dr.
email: kurt.vanderspeeten@zol.be
last name: Lieselotte Lemoine, drs.
email: lieselotte.lemoine@uhasselt.be
facility: 
status: Recruiting
contact: 
investigator: 
country: Belgium
responsible party type: Principal Investigator
investigator affiliation: Hasselt University
investigator full name: Kurt Van der Speeten
investigator title: prof. dr.
mesh term: Carcinoma
mesh term: Peritoneal Neoplasms
mesh term: Oxaliplatin
sharing ipd: No