<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/NCT03295084</url>
  </required_header>
  <id_info>
    <org_study_id>AA1446</org_study_id>
    <nct_id>NCT03295084</nct_id>
  </id_info>
  <brief_title>Safety, Tolerability and Pharmacokinetics of Oral Tablet of Irinotecan in Adult Patients With Solid Tumors</brief_title>
  <official_title>Irinotecan Gastro-resistant Tablet. An Open Label Phase I, Dose Escalating Study Evaluating Safety, Tolerability and Pharmacokinetics of Oral Administration of Irinotecan in Adult Patients With Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dorte Nielsen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Herlev Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study evaluates the safety, tolerability and pharmacokinetics of oral administration of&#xD;
      irinotecan in adult patients. Oral irinotecan will be administered as monotherapy in a dose&#xD;
      escalation trial to establish the Maximal Tolerated Dose. Totally 25 patients will be treated&#xD;
      with irinotecan tablets as mono-therapy. As an extension trial 12 patients will be treated&#xD;
      with oral irinotecan in combination with oral capecitabine&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study is a phase I, open-label, dose escalation single center study in patients with&#xD;
      solid tumors. The study will investigate safety, tolerability and Maximal Tolerated Dose as&#xD;
      primary end-points of an irinotecan tablet given as single agent or in combination with oral&#xD;
      capecitabine. Secondary end-points are pharmacokinetics and preliminary anti-tumor response.&#xD;
&#xD;
      Cohorts of 3 patients will be treated on selected dose level with oral irinotecan in order to&#xD;
      identify Dose Limiting Toxicity (DLT) and Maximal Tolerated Dose (MTD). Totally 12 subjects&#xD;
      will be treated at the MTD level. Patients will receive irinotecan tablets once daily in the&#xD;
      morning for 14 consecutive days within 3 week treatment cycles. As an extension trial totally&#xD;
      12 subjects will be treated with oral irinotecan in combination with oral capecitabine.&#xD;
      Patients treated in combination therapy will receive irinotecan tablets once daily in the&#xD;
      morning for 14 consecutive days in combination with capecitabine dosed twice daily for 14&#xD;
      consecutive days within 3 week treatment cycles.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 15, 2015</start_date>
  <completion_date type="Actual">October 30, 2018</completion_date>
  <primary_completion_date type="Actual">July 3, 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Open labelled study with enrollment in the order of confirmation of eligibility. Escalating doses of study drug in sequential patient cohorts for identification of DLT and MTD (Phase 1)</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximal Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of oral Irinotecan based on incidence of Treatment-Emergent Adverse Events</measure>
    <time_frame>2 treatment cycles of 3 weeks</time_frame>
    <description>Number of patients with Treatment Related Adverse Events as assessed according to the NCI Common Terminology Criteria for Adverse events CTCAE version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicity (DLT) of oral Irinotecan in combination with oral Capecitabine based on incidence of Treatment-Emergent Adverse Events</measure>
    <time_frame>2 treatment cycles of 3 weeks</time_frame>
    <description>Number of patients with Treatment Related Adverse Events as assessed according to the NCI Common Terminology Criteria for Adverse events CTCAE version 4.0</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the Concentration-Time-Curve (AUC) for Irinotecan and its metabolites SN-38 and SN-38 glucoronide</measure>
    <time_frame>Day 1 and Day 14 of first 3 weeks treatment cycle</time_frame>
    <description>PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Maximum Serum Concentration (Cmax) for irinotecan and its metabolites SN-38 and SN-38 glucoronide</measure>
    <time_frame>Day 1 and Day 14 of first 3 weeks treatment cycle</time_frame>
    <description>PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Maximum Serum Concentration (Tmax) for irinotecan and its metabolites SN-38 and SN-38 glucoronide</measure>
    <time_frame>Day 1 and Day 14 of first 3 weeks treatment cycle</time_frame>
    <description>PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-life (t½) for irinotecan and its metabolites SN-38 and SN-38 glucoronide</measure>
    <time_frame>Day 1 and Day 14 of first 3 weeks treatment cycle</time_frame>
    <description>PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum concentration 24 hours after dosing and prior to administration of the next dose (C24) for Irinotecan and its metabolites SN-38 and SN-38 glucoronide</measure>
    <time_frame>Day 1 and Day 14 of first 3 weeks treatment cycle</time_frame>
    <description>PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective tumor response to treatment based on RECIST 1.1 criteria</measure>
    <time_frame>2 treatment cycles of 3 weeks</time_frame>
    <description>CT scans with tumor response as assessed using RECIST 1.1. criteria</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">39</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Irinotecan</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose escalation study in cohorts of minimum 3 patients of an Irinotecan tablet taken once daily for 14 days within 3 week treatment cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Irinotecan with Capecitabine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose escalation study in cohorts of minimum 3 patients of an Irinotecan tablet taken once daily in combination with Capecitabine tablet taken twice daily for 14 days within 3 week treatment cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>Dose Escalation</description>
    <arm_group_label>Irinotecan</arm_group_label>
    <arm_group_label>Irinotecan with Capecitabine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine</intervention_name>
    <description>Dose Escalation</description>
    <arm_group_label>Irinotecan with Capecitabine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written Informed Consent&#xD;
&#xD;
          -  18 years of age or older&#xD;
&#xD;
          -  Capable of understanding the protocol requirements and risk associated with the study&#xD;
&#xD;
          -  Patients must have histological confirmed malignancy (solid tumor) that is metastatic&#xD;
             or unresectable and for which standard curative or palliative measures do not exist or&#xD;
             are no longer effective&#xD;
&#xD;
          -  Patients with either measurable disease according to RECIST 1.1 or non-measurable&#xD;
             disease&#xD;
&#xD;
          -  Performance status 0-1 (ECOG)&#xD;
&#xD;
          -  Life expectancy ≥ 3 months&#xD;
&#xD;
          -  Coagulation INR &lt; 1.3 and APTT within normal limits&#xD;
&#xD;
          -  WBC ≥ 3000/mm3&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1500/mm3&#xD;
&#xD;
          -  Hemoglobin ≥ 6.0 mmol/L&#xD;
&#xD;
          -  Platelet count ≥ 100.000/mm3&#xD;
&#xD;
          -  Bilirubin ≤ 1.5 times upper limit of normal (ULN)&#xD;
&#xD;
          -  AST and ALT ≤ 2.5 times ULN AST and ALT ≤ 2.5 times ULN. For patients with liver&#xD;
             metastasis adequate hepatic function is defined by aspartate aminotransferase (AST) ≤&#xD;
             5 x ULN and alanine aminotransferase ALT ≤ 5 x ULN&#xD;
&#xD;
          -  No severe or uncontrolled renal condition (creatinine ≤ than 1.5 ULN)&#xD;
&#xD;
          -  No significant cardiovascular disease (New York Heart Association Class III and IV)&#xD;
&#xD;
          -  No other severe cardiac condition not defined above&#xD;
&#xD;
          -  No significant cardiovascular disease (incl. myocardial infarction, unstable angina,&#xD;
             symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) ≤ 1&#xD;
             year prior for patients to be enrolled and treated in combination with oral&#xD;
             capecitabine&#xD;
&#xD;
          -  No severe or uncontrolled pulmonary condition&#xD;
&#xD;
          -  No known prior hypersensitivity reaction to irinotecan&#xD;
&#xD;
          -  No known prior hypersensitivity to capecitabine or 5-fluorouracil for patients to be&#xD;
             enrolled and treated in combination with oral capecitabine&#xD;
&#xD;
          -  No chronic enteropathy (e.g. active inflammatory bowel disease, extensive intestinal&#xD;
             resection or chronic diarrhea)&#xD;
&#xD;
          -  No bowel obstruction or sub-obstruction&#xD;
&#xD;
          -  No prior history of intestinal malabsorption&#xD;
&#xD;
          -  Patients have to be able to swallow normally and have to be willing to comply with the&#xD;
             intake of tablets&#xD;
&#xD;
          -  No psychiatric condition that would preclude study participation&#xD;
&#xD;
          -  No co-existing active infection requiring antibiotics or any co-existing medical&#xD;
             conditions likely to interfere with study procedures&#xD;
&#xD;
          -  No other condition that will preclude study participation&#xD;
&#xD;
          -  A negative pregnancy test for women of childbearing potential. For men and women of&#xD;
             child-producing potential, the use of effective contraceptives methods during the&#xD;
             study and at least 3 months after discontinuations of the study drug is required.&#xD;
&#xD;
          -  Not pregnant or nursing&#xD;
&#xD;
          -  Peripheral neuropathy NCI CTCAE grade less than 2 for patients to be enrolled and&#xD;
             treated in combination with oral capecitabine&#xD;
&#xD;
          -  The patient is willing and able to comply with hospitalization for treatment and&#xD;
             scheduled follow-up visits and examinations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Simultaneous participation in any other study involving investigational drugs or&#xD;
             having participated in a study within 4 weeks prior to start of study treatment&#xD;
&#xD;
          -  Symptomatic brain metastases&#xD;
&#xD;
          -  Intake of any prohibited concomitant medication&#xD;
&#xD;
          -  Known Dihydropyrimidine dehydrogenase (DPD) deficiency for patients to be enrolled and&#xD;
             treated in combination with oral capecitabine.&#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_official>
    <last_name>Benny Vittrup</last_name>
    <role>Principal Investigator</role>
    <affiliation>Herlev Hospital, Department of Oncology, Denmark</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Herlev Hospital</name>
      <address>
        <city>Herlev</city>
        <zip>2730</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>September 11, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>October 1, 2020</last_update_submitted>
  <last_update_submitted_qc>October 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">October 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Herlev Hospital</investigator_affiliation>
    <investigator_full_name>Dorte Nielsen</investigator_full_name>
    <investigator_title>Professor, MD, DMSci</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03295084
org study id: AA1446
nct id: NCT03295084
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study evaluates the safety, tolerability and pharmacokinetics of oral administration of
      irinotecan in adult patients. Oral irinotecan will be administered as monotherapy in a dose
      escalation trial to establish the Maximal Tolerated Dose. Totally 25 patients will be treated
      with irinotecan tablets as mono-therapy. As an extension trial 12 patients will be treated
      with oral irinotecan in combination with oral capecitabine
The study is a phase I, open-label, dose escalation single center study in patients with
      solid tumors. The study will investigate safety, tolerability and Maximal Tolerated Dose as
      primary end-points of an irinotecan tablet given as single agent or in combination with oral
      capecitabine. Secondary end-points are pharmacokinetics and preliminary anti-tumor response.

      Cohorts of 3 patients will be treated on selected dose level with oral irinotecan in order to
      identify Dose Limiting Toxicity (DLT) and Maximal Tolerated Dose (MTD). Totally 12 subjects
      will be treated at the MTD level. Patients will receive irinotecan tablets once daily in the
      morning for 14 consecutive days within 3 week treatment cycles. As an extension trial totally
      12 subjects will be treated with oral irinotecan in combination with oral capecitabine.
      Patients treated in combination therapy will receive irinotecan tablets once daily in the
      morning for 14 consecutive days in combination with capecitabine dosed twice daily for 14
      consecutive days within 3 week treatment cycles.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: Open labelled study with enrollment in the order of confirmation of eligibility. Escalating doses of study drug in sequential patient cohorts for identification of DLT and MTD (Phase 1)
primary purpose: Other
masking: None (Open Label)
measure: Maximal Tolerated Dose (MTD) and Dose Limiting Toxicity (DLT) of oral Irinotecan based on incidence of Treatment-Emergent Adverse Events
time frame: 2 treatment cycles of 3 weeks
description: Number of patients with Treatment Related Adverse Events as assessed according to the NCI Common Terminology Criteria for Adverse events CTCAE version 4.0
measure: Maximum Tolerated Dose (MTD) and the Dose Limiting Toxicity (DLT) of oral Irinotecan in combination with oral Capecitabine based on incidence of Treatment-Emergent Adverse Events
time frame: 2 treatment cycles of 3 weeks
description: Number of patients with Treatment Related Adverse Events as assessed according to the NCI Common Terminology Criteria for Adverse events CTCAE version 4.0
measure: Area under the Concentration-Time-Curve (AUC) for Irinotecan and its metabolites SN-38 and SN-38 glucoronide
time frame: Day 1 and Day 14 of first 3 weeks treatment cycle
description: PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile
measure: Maximum Serum Concentration (Cmax) for irinotecan and its metabolites SN-38 and SN-38 glucoronide
time frame: Day 1 and Day 14 of first 3 weeks treatment cycle
description: PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile
measure: Time to Maximum Serum Concentration (Tmax) for irinotecan and its metabolites SN-38 and SN-38 glucoronide
time frame: Day 1 and Day 14 of first 3 weeks treatment cycle
description: PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile
measure: Half-life (t½) for irinotecan and its metabolites SN-38 and SN-38 glucoronide
time frame: Day 1 and Day 14 of first 3 weeks treatment cycle
description: PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile
measure: Serum concentration 24 hours after dosing and prior to administration of the next dose (C24) for Irinotecan and its metabolites SN-38 and SN-38 glucoronide
time frame: Day 1 and Day 14 of first 3 weeks treatment cycle
description: PK samples will be collected at predetermined time intervals and pharmacokinetic parameter calculated and reported based on the plasma concentration profile
measure: Objective tumor response to treatment based on RECIST 1.1 criteria
time frame: 2 treatment cycles of 3 weeks
description: CT scans with tumor response as assessed using RECIST 1.1. criteria
arm group label: Irinotecan
arm group type: Experimental
description: Dose escalation study in cohorts of minimum 3 patients of an Irinotecan tablet taken once daily for 14 days within 3 week treatment cycle
arm group label: Irinotecan with Capecitabine
arm group type: Experimental
description: Dose escalation study in cohorts of minimum 3 patients of an Irinotecan tablet taken once daily in combination with Capecitabine tablet taken twice daily for 14 days within 3 week treatment cycle
intervention type: Drug
intervention name: Irinotecan
description: Dose Escalation
arm group label: Irinotecan
arm group label: Irinotecan with Capecitabine
intervention type: Drug
intervention name: Capecitabine
description: Dose Escalation
arm group label: Irinotecan with Capecitabine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Benny Vittrup
role: Principal Investigator
affiliation: Herlev Hospital, Department of Oncology, Denmark
facility: 
country: Denmark
responsible party type: Sponsor-Investigator
investigator affiliation: Herlev Hospital
investigator full name: Dorte Nielsen
investigator title: Professor, MD, DMSci
mesh term: Colorectal Neoplasms
mesh term: Capecitabine
mesh term: Irinotecan
sharing ipd: Undecided