<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/NCT01729481</url>
  </required_header>
  <id_info>
    <org_study_id>2011-005471-17</org_study_id>
    <nct_id>NCT01729481</nct_id>
  </id_info>
  <brief_title>Gemcitabine Plus Erlotinib in RASH-positive Patients With Metastatic Pancreatic Cancer</brief_title>
  <acronym>ML22774</acronym>
  <official_title>Phase II Study to Evaluatate the Efficacy of Gemcitabine Plus Erlotinib for RASH-positive Patients With Metastatic Pancreatic Cancer and Friendly Risk Circumstances</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ludwig-Maximilians - University of Munich</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Roche Pharma AG</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Ludwig-Maximilians - University of Munich</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the current study it is examined whether patients with good risk factors (age &lt;75 years,&#xD;
      total serum bilirubin &lt; 1,5xULN, no history of cardiovascular diseases) treated with&#xD;
      gemcitabine and erlotinib who developed skin rash of any grade during the first 4 weeks of&#xD;
      treatment have a comparable outcome as patients who receive FOLFIRINOX.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The study by Burris et al. 1997 revealed a superiority of gemcitabine vs. 5-FU in terms of&#xD;
      improvement of general condition, pain symptoms and overall survival in patients with locally&#xD;
      advanced or metastatic pancreatic cancer. Subsequently, gemcitabine was established as a&#xD;
      standard treatment for locally advanced and metastatic pancreatic cancer.&#xD;
&#xD;
      In a series of studies gemcitabine was combined with other chemotherapeutic agents or&#xD;
      targeted therapies. For the first time, the PA.03 study showed a significant improvement of&#xD;
      overall survival. Patients who were treated with gemcitabine plus erlotinib had a survival of&#xD;
      6.24 months, compared with 5.91 months for those treated with gemcitabine plus placebo (HR&#xD;
      0.82, 95% CI 0.69-0.99, p=0.038). The one-year-survival rate was 23% for gemcitabine plus&#xD;
      erlotinib vs. 17% for gemcitabine plus placebo.&#xD;
&#xD;
      In a subgroup analysis of the PA.03 study, patients developing a skin rash NCI CTC ≥ grade 2&#xD;
      had an advanced survival (one-year-survival rate 43%) vs. those with grade 1 or 0&#xD;
      (one-year-survival rate 16% and 9%, respectively). Later studies confirmed the correlation&#xD;
      between skin rash and survival.&#xD;
&#xD;
      While patients developing a skin rash of any grade seem to profit most from treatment with&#xD;
      erlotinib, the prognosis for those without rash is rather dismal. In this population,&#xD;
      survival varied between 3.3 and 4.8 months in clinical trials (Verslype et al. 2009, Boeck et&#xD;
      al. 2010, Manzano et al. 2010). In this patients, a modification of the treatment strategy&#xD;
      should be considered. Which kind of treatment might lead to optimal results in these patients&#xD;
      is not yet clear.&#xD;
&#xD;
      In patients with excellent general condition complying with further prerequisits (age &lt;75&#xD;
      years, total serum bilirubin &lt; 1,5xULN, no history of cardiovascular diseases) the French&#xD;
      Prodige study-group could show a statistical superiority for the gemcitabine-free&#xD;
      FOLFIRINOX-scheme in terms of overall survival, progression free survival and response rate&#xD;
      compared to gemcitabine alone. However, this superiority was gained at the expense of&#xD;
      treatment tolerability. During treatment with FOLFIRINOX a grade 3-4 neutropenia was observed&#xD;
      in 5.4% and a grade 3-4 diarrhea in 12.7% of patients (Conroy et al. 2011). For patients who&#xD;
      comply with the above-named criteria FOLFIRINOX is considered an established standard of&#xD;
      care.&#xD;
&#xD;
      If a comparable efficacy of gemcitabine plus erlotinib with the published FOLFIRINOX data can&#xD;
      be seen in the selected population, this would favour, due to the worse tolerability of&#xD;
      FOLFIRINOX, the use of gemcitabine plus erlotinib.&#xD;
&#xD;
      In summary, the following selections are conducted during the study:&#xD;
&#xD;
        1. Selection due to the inclusion criteria for treatment with FOLFIRINOX provided by Conroy&#xD;
           et al.&#xD;
&#xD;
        2. Selection due to the development of a skin rash within four weeks of treatment&#xD;
&#xD;
        3. No signs of clinical tumour progression within the run-in phase within the first four&#xD;
           weeks of treatment&#xD;
&#xD;
      Patients who do not develope a skin rash of any grade should be treated with FOLFIRINOX. The&#xD;
      efficacy of FOLFIRINOX in rash-negative patients has not yet been investigated.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Active, not recruiting</last_known_status>
  <start_date>July 2012</start_date>
  <completion_date type="Anticipated">December 2017</completion_date>
  <primary_completion_date type="Actual">July 2015</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>1-year Survial rate of &quot;good-risk&quot; patients</measure>
    <time_frame>Follow-Up Phase (1.5 years)</time_frame>
    <description>1-year Survial rate of &quot;good-risk&quot; patients of patients under gemcitabine plus erlotinib with RASH</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evalutation of overall response rate, disease control rate and progression free survival</measure>
    <time_frame>Approximately 12 months</time_frame>
    <description>Evaluation of Parameters by RASH positve and negative patients:&#xD;
ORR&#xD;
DCR&#xD;
PFS&#xD;
OS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of adverse events</measure>
    <time_frame>Treatment Phase (1.5 Years)</time_frame>
    <description>Assesment with NCI-CTCAE V4.0 Evalutation of side effects including picture documentation of skin-rash</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Translational Projects</measure>
    <time_frame>Approximately 24 months</time_frame>
    <description>Evaluation of Parameters for EGFR signal transduction&#xD;
Evaluation Molecularbiological Parametrs of RASH&#xD;
Picture Documentation of RASH. Corellation with clinical and molecularbiological Parameters</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">150</enrollment>
  <condition>Metastatic Pancreatic Adenocarcinoma</condition>
  <arm_group>
    <arm_group_label>RASH positive</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Run-In-Phase during 4 weeks:&#xD;
Gemcitabine 1000 mg/m², weekly Erlotinib 100 mg, weekly&#xD;
Thereafter Treatment in patients with RASH-positve outcome after 4 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>RASH-negative</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Run-In-Phase during 4 weeks:&#xD;
Gemcitabine 1000 mg/m², weekly Erlotinib 100 mg, weekly&#xD;
RASH-negative patients quit treatment with Gemcitabine + Erlotinib and continue treatment with FOLFIRINOX:&#xD;
Oxaliplatin 85mg/m2 Irinotecan 180 mg/m2 Folinic acid 400 mg/m2 5-FU 400 mg/m2 bolus iv 5-FU 2400 mg/m2 46-hours continous infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>1000 mg/m² iv weekly</description>
    <arm_group_label>RASH positive</arm_group_label>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erlotinib</intervention_name>
    <description>100mg, once per day</description>
    <arm_group_label>RASH positive</arm_group_label>
    <other_name>Tarceva</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>85mg/m², q2weeks</description>
    <arm_group_label>RASH-negative</arm_group_label>
    <other_name>Eloxatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Folinic Acid</intervention_name>
    <description>400 mg/m², q2weeks</description>
    <arm_group_label>RASH-negative</arm_group_label>
    <other_name>Leucovorin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>180 mg/m², q2weeks</description>
    <arm_group_label>RASH-negative</arm_group_label>
    <other_name>Campto</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5-FU</intervention_name>
    <description>400 mg/m² Day 1; 2400 mg/m² 46 hour invusion, q2weeks</description>
    <arm_group_label>RASH-negative</arm_group_label>
    <other_name>5-Flourouracil</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically (not cytologically) confirmed metastatic pancreatic adenocarcinoma&#xD;
             (stage IV according to UICC, each T, each N, M1 according to TNM)&#xD;
&#xD;
          -  At least one measurable index lesion (CT or MRI) according to RECIST criteria (V 1.1)&#xD;
&#xD;
          -  ECOG PS 0 and 1&#xD;
&#xD;
          -  Age 18-75 years&#xD;
&#xD;
          -  Serum bilirubin ≤1,5x ULN (a placed biliary tract stent without concurrent cholangitis&#xD;
             is not considered a contraindication)&#xD;
&#xD;
          -  Availability of tumour samples (no cytologic samples)&#xD;
&#xD;
          -  Written informed consent by the patient for collecting blood- and tumour-samples for&#xD;
             translational research according to study protocol&#xD;
&#xD;
          -  Live expectancy of at least three months&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
          -  Negative pregnancy test in women with childbearing potential (to be performed within 7&#xD;
             days prior to treatment start)&#xD;
&#xD;
          -  Adequate kidney-, liver- and bone-marrow function: neutrophils &gt;= 1500/µl, platelets&#xD;
             &gt;= 100.000/µ, and hemoglobin &gt;= 8g/dl, liver transaminases&lt;= 2,5x ULN, in case of&#xD;
             liver metastases &lt;= 5x ULN, serum creatinine &lt;= 1,25x ULN, creatinine clearance ≥ 30&#xD;
             ml/min&#xD;
&#xD;
          -  Legal capacity of the patient&#xD;
&#xD;
          -  Option for constant long-term follow-up&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Resectable pancreatic carcinoma&#xD;
&#xD;
          -  Locally advanced pancreatic cancer (non-resectable tumour without distant metastasis)&#xD;
&#xD;
          -  Previous palliative chemotherapy for metastatic or locally advanced, non-resectable&#xD;
             pancreatic cancer&#xD;
&#xD;
          -  Previous palliative radiation or chemoradiation for locally advanced, non-resectable&#xD;
             pancreatic cancer&#xD;
&#xD;
          -  Radiation therapy within four weeks prior to study enrolment or radiation of indicator&#xD;
             lesions&#xD;
&#xD;
          -  Adjuvant Chemotherapy or Radiochemotherapy for pancreatic cancer ≤ 6 months prior to&#xD;
             study ernrolment&#xD;
&#xD;
          -  All previously occurred metastatic cancers or cured neoplasias diagnosed within the&#xD;
             last 5 years before study enrolment&#xD;
&#xD;
          -  Major surgery within 2 weeks before study start&#xD;
&#xD;
          -  Chronic diarrhea&#xD;
&#xD;
          -  Known glucuronidation-deficiency (Gilbert´s syndrome)&#xD;
&#xD;
          -  Acute or subacute ileus or chronic inflammatory bowel disease&#xD;
&#xD;
          -  Preexisting polyneuropathy &gt; Grade I according to NCI-CTCAE v.4.0&#xD;
&#xD;
          -  Relevant comorbidities which might impair patient eligibility or safety for study&#xD;
             participation like active infections, hepatic, renal or metabolic diseases&#xD;
&#xD;
          -  Clinically significant cardiovascular diseases within 12 months prior to study start&#xD;
             (e.g. unstable angina pectoris, myocardial infarction, heart failure ≥ NYHA II,&#xD;
             cardiac arrhythmias requiring treatment)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Volker Heinemann, Professor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Medical Department III and Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Munich</name>
      <address>
        <city>Munich</city>
        <zip>81377</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <link>
    <url>http://www.klinikum.uni-muenchen.de/Pankreaszentrum-Muenchen/de/startseitenmeldungen/index.html</url>
    <description>Homepage of the PancreasCenter at LMU Munich</description>
  </link>
  <verification_date>July 2017</verification_date>
  <study_first_submitted>October 23, 2012</study_first_submitted>
  <study_first_submitted_qc>November 13, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 20, 2012</study_first_posted>
  <last_update_submitted>July 16, 2017</last_update_submitted>
  <last_update_submitted_qc>July 16, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">July 19, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Ludwig-Maximilians - University of Munich</investigator_affiliation>
    <investigator_full_name>PD Dr. med. Volker Heinemann</investigator_full_name>
    <investigator_title>Clinical Professor</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Levoleucovorin</mesh_term>
  </intervention_browse>
  <!-- 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/NCT01729481
org study id: 2011-005471-17
nct id: NCT01729481
lead sponsor: 
collaborator: 
has dmc: Yes
In the current study it is examined whether patients with good risk factors (age <75 years,
      total serum bilirubin < 1,5xULN, no history of cardiovascular diseases) treated with
      gemcitabine and erlotinib who developed skin rash of any grade during the first 4 weeks of
      treatment have a comparable outcome as patients who receive FOLFIRINOX.
The study by Burris et al. 1997 revealed a superiority of gemcitabine vs. 5-FU in terms of
      improvement of general condition, pain symptoms and overall survival in patients with locally
      advanced or metastatic pancreatic cancer. Subsequently, gemcitabine was established as a
      standard treatment for locally advanced and metastatic pancreatic cancer.

      In a series of studies gemcitabine was combined with other chemotherapeutic agents or
      targeted therapies. For the first time, the PA.03 study showed a significant improvement of
      overall survival. Patients who were treated with gemcitabine plus erlotinib had a survival of
      6.24 months, compared with 5.91 months for those treated with gemcitabine plus placebo (HR
      0.82, 95% CI 0.69-0.99, p=0.038). The one-year-survival rate was 23% for gemcitabine plus
      erlotinib vs. 17% for gemcitabine plus placebo.

      In a subgroup analysis of the PA.03 study, patients developing a skin rash NCI CTC ≥ grade 2
      had an advanced survival (one-year-survival rate 43%) vs. those with grade 1 or 0
      (one-year-survival rate 16% and 9%, respectively). Later studies confirmed the correlation
      between skin rash and survival.

      While patients developing a skin rash of any grade seem to profit most from treatment with
      erlotinib, the prognosis for those without rash is rather dismal. In this population,
      survival varied between 3.3 and 4.8 months in clinical trials (Verslype et al. 2009, Boeck et
      al. 2010, Manzano et al. 2010). In this patients, a modification of the treatment strategy
      should be considered. Which kind of treatment might lead to optimal results in these patients
      is not yet clear.

      In patients with excellent general condition complying with further prerequisits (age <75
      years, total serum bilirubin < 1,5xULN, no history of cardiovascular diseases) the French
      Prodige study-group could show a statistical superiority for the gemcitabine-free
      FOLFIRINOX-scheme in terms of overall survival, progression free survival and response rate
      compared to gemcitabine alone. However, this superiority was gained at the expense of
      treatment tolerability. During treatment with FOLFIRINOX a grade 3-4 neutropenia was observed
      in 5.4% and a grade 3-4 diarrhea in 12.7% of patients (Conroy et al. 2011). For patients who
      comply with the above-named criteria FOLFIRINOX is considered an established standard of
      care.

      If a comparable efficacy of gemcitabine plus erlotinib with the published FOLFIRINOX data can
      be seen in the selected population, this would favour, due to the worse tolerability of
      FOLFIRINOX, the use of gemcitabine plus erlotinib.

      In summary, the following selections are conducted during the study:

        1. Selection due to the inclusion criteria for treatment with FOLFIRINOX provided by Conroy
           et al.

        2. Selection due to the development of a skin rash within four weeks of treatment

        3. No signs of clinical tumour progression within the run-in phase within the first four
           weeks of treatment

      Patients who do not develope a skin rash of any grade should be treated with FOLFIRINOX. The
      efficacy of FOLFIRINOX in rash-negative patients has not yet been investigated.
allocation: Non-Randomized
intervention model: Crossover Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: 1-year Survial rate of "good-risk" patients
time frame: Follow-Up Phase (1.5 years)
description: 1-year Survial rate of "good-risk" patients of patients under gemcitabine plus erlotinib with RASH
measure: Evalutation of overall response rate, disease control rate and progression free survival
time frame: Approximately 12 months
description: Evaluation of Parameters by RASH positve and negative patients:
ORR
DCR
PFS
OS
measure: Evaluation of adverse events
time frame: Treatment Phase (1.5 Years)
description: Assesment with NCI-CTCAE V4.0 Evalutation of side effects including picture documentation of skin-rash
measure: Translational Projects
time frame: Approximately 24 months
description: Evaluation of Parameters for EGFR signal transduction
Evaluation Molecularbiological Parametrs of RASH
Picture Documentation of RASH. Corellation with clinical and molecularbiological Parameters
arm group label: RASH positive
arm group type: Experimental
description: Run-In-Phase during 4 weeks:
Gemcitabine 1000 mg/m², weekly Erlotinib 100 mg, weekly
Thereafter Treatment in patients with RASH-positve outcome after 4 weeks.
arm group label: RASH-negative
arm group type: Active Comparator
description: Run-In-Phase during 4 weeks:
Gemcitabine 1000 mg/m², weekly Erlotinib 100 mg, weekly
RASH-negative patients quit treatment with Gemcitabine + Erlotinib and continue treatment with FOLFIRINOX:
Oxaliplatin 85mg/m2 Irinotecan 180 mg/m2 Folinic acid 400 mg/m2 5-FU 400 mg/m2 bolus iv 5-FU 2400 mg/m2 46-hours continous infusion
intervention type: Drug
intervention name: Gemcitabine
description: 1000 mg/m² iv weekly
arm group label: RASH positive
other name: Gemzar
intervention type: Drug
intervention name: Erlotinib
description: 100mg, once per day
arm group label: RASH positive
other name: Tarceva
intervention type: Drug
intervention name: Oxaliplatin
description: 85mg/m², q2weeks
arm group label: RASH-negative
other name: Eloxatin
intervention type: Drug
intervention name: Folinic Acid
description: 400 mg/m², q2weeks
arm group label: RASH-negative
other name: Leucovorin
intervention type: Drug
intervention name: Irinotecan
description: 180 mg/m², q2weeks
arm group label: RASH-negative
other name: Campto
intervention type: Drug
intervention name: 5-FU
description: 400 mg/m² Day 1; 2400 mg/m² 46 hour invusion, q2weeks
arm group label: RASH-negative
other name: 5-Flourouracil
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Volker Heinemann, Professor
role: Principal Investigator
affiliation: Medical Department III and Comprehensive Cancer Center
facility: 
country: Germany
url: http://www.klinikum.uni-muenchen.de/Pankreaszentrum-Muenchen/de/startseitenmeldungen/index.html
description: Homepage of the PancreasCenter at LMU Munich
responsible party type: Principal Investigator
investigator affiliation: Ludwig-Maximilians - University of Munich
investigator full name: PD Dr. med. Volker Heinemann
investigator title: Clinical Professor
mesh term: Leucovorin
mesh term: Folic Acid
mesh term: Gemcitabine
mesh term: Oxaliplatin
mesh term: Irinotecan
mesh term: Levoleucovorin