<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/NCT04425239</url>
  </required_header>
  <id_info>
    <org_study_id>IMPROVE</org_study_id>
    <nct_id>NCT04425239</nct_id>
  </id_info>
  <brief_title>Intermittent or Continuous Panitumumab Plus FOLFIRI for RAS/B-RAF Wild-type Metastatic Colorectal Cancer</brief_title>
  <acronym>IMPROVE</acronym>
  <official_title>Intermittent or Continuous Panitumumab Plus FOLFIRI for First-line Treatment of Patients With RAS/B-RAF Wild-type Metastatic Colorectal Cancer: a Randomized Phase 2 Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute, Naples</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute, Naples</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators hypothesize that intermittent first-line Panitumumab plus FOLFIRI is&#xD;
      effective as the same regimen given continuously, in unresectable metastatic RAS and BRAF&#xD;
      wild type colorectal cancer patients. Correlative studies on tumor and blood samples could&#xD;
      identify potential biomarkers of efficacy and help defining personalized treatment strategy.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This will be a multicenter open label randomized phase II study. The study population will&#xD;
      include untreated RAS wild-type metastatic colorectal (mCRC) patients with unresectable&#xD;
      disease. A total of 136 patients will be enrolled.&#xD;
&#xD;
      All Patients will receive an induction treatment with panitumumab as 1 hour intravenous&#xD;
      infusion at the dosage of 6 mg/kg, given every two weeks, plus FOLFIRI chemotherapy as&#xD;
      standard guidelines.&#xD;
&#xD;
      Before start of FOLFIRI plus panitumumab, at the time of enrollment, patients will be&#xD;
      immediately randomized electronically 1:1 to one of the two arms. Induction treatment with&#xD;
      FOLFIRI plus panitumumab will continue until progressive disease, unacceptable toxicity or&#xD;
      informed consent withdrawal, or for up to 8 cycles. At the end of induction treatment, in&#xD;
      presence of complete or partial response, or stable disease, non-progressing patients will be&#xD;
      allocated to one of the two pre-assigned arms:&#xD;
&#xD;
      A) CONTINOUS: FOLFIRI plus panitumumab until progressive disease, unacceptable toxicity or&#xD;
      informed consent withdrawal. Panitumumab will be administered as a 6 mg/kg intravenous&#xD;
      infusion over 60 minutes (day 1) every 2 weeks. The dose of Panitumumab should be&#xD;
      administered prior to chemotherapy. Irinotecan will be administered as a 180 mg/m2&#xD;
      intravenous infusion over 60 minutes (day 1) every 2 weeks. Folinic acid will be administered&#xD;
      as a 200 mg/m2 intravenous infusion over 120 minutes before 5- fluorouracil infusion (day 1)&#xD;
      every 2 weeks. 5-fluorouracil will be administered as a 400 mg/m2 intravenous bolus injection&#xD;
      (day 1) followed by 2400 mg/m246-hours continuous infusion (day 1), every 2 weeks. Cycle&#xD;
      length will be 2 weeks +/- 3 days.&#xD;
&#xD;
      B) INTERMITTENT: treatment free interval until progressive disease; followed by up to 8&#xD;
      cycles of FOLFIRI plus panitumumab; in presence of complete or partial response, or stable&#xD;
      disease, non-progressing patients will undergo again to treatment free interval until PD,&#xD;
      when they will restart treatment. Treatment cycling will continue till any progressive&#xD;
      disease on treatment. Panitumumab will be administered at same dose and infusion with&#xD;
      FOLFIRI.&#xD;
&#xD;
      All measurable and non-measurable lesions must be documented at screening (within 21 days&#xD;
      prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks&#xD;
      while the patient is on study). Tumor assessment by CT scan of chest, abdomen and pelvis;&#xD;
      CEA, CA 19.9; and any other tests having resulted positive during baseline staging, will be&#xD;
      performed at week 8 and every 8 weeks thereafter, until disease progression, accordingly with&#xD;
      RECIST V 1.1 criteria.&#xD;
&#xD;
      Toxicities will be evaluated throughout the study treatment and graded according to the NCI&#xD;
      Common Toxicity Criteria.&#xD;
&#xD;
      The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTC-AE)&#xD;
      Version 4.03 will be used to evaluate the clinical safety of the treatment in this study.&#xD;
      Patients will be assessed for AEs at each clinical visit and as necessary throughout the&#xD;
      study.&#xD;
&#xD;
      Quality of Life is assessed by the EORTC QLQ-C30, v. 3.0 questionnaire that are completed by&#xD;
      patients at baseline, at week 16 and every 8 weeks thereafter.&#xD;
&#xD;
      Biomarkers ancillary study Correlative biological studies will be performed for the&#xD;
      evaluation of the biomarkers indicated above on the biological samples available&#xD;
      (paraffin-embedded tissue, frozen tissue, blood, serum, etc.). Biomarkers will be evaluated&#xD;
      on archival tumor tissues or on newly obtained biopsies at baseline, and during treatment&#xD;
      when available. Blood Samples will be collected at baseline, at week 8, 16 and thereafter&#xD;
      every 8 weeks concomitantly with tumor assessment.&#xD;
&#xD;
      The sample size is calculated on the basis of median progression-free survival on treatment&#xD;
      with intermittent vs continuous Panitumumab plus FOLFIRI, taking into account a median PFS of&#xD;
      11 months observed in the CRYSTAL trial.&#xD;
&#xD;
      The study is designed as a phase II trial with a random assignment to a calibration arm&#xD;
      (continous) and to the experimental arm (intermittent). The sample size for intermittent arm&#xD;
      is calculated according to the binomial test. The calibration arm has the same sample size,&#xD;
      its role is to give a parallel estimation of median PFS to ensure that sample is&#xD;
      representative and results are consistent However considering a 5% of drop-outs mainly due to&#xD;
      losses to follow-up, the sample size is increased from 130 to 136 patients.&#xD;
&#xD;
      Randomization will be performed with a minimization procedure that will account for center;&#xD;
      ECOG (PS 0-1 vs 2); primary site of tumor (Right versus Left); adjuvant treatment (yes vs&#xD;
      no); metastatic sites (1 vs&gt;1).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 21, 2018</start_date>
  <completion_date type="Actual">April 3, 2022</completion_date>
  <primary_completion_date type="Actual">July 2, 2021</primary_completion_date>
  <phase>Phase 2</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>Progression-free Survival</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>Progression Free Survival on treatment (PFSOT) is defined as the time from randomization to the first objective disease progression documented in patients undergoing treatment cycle (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>Overall Survival is defined as the time from randomization to the date of death</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Toxicities</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>Toxicities will be assessed in terms of incidence of Adverse Events (AE) that will be graded according to the NCI CTC-AE Version 4.03 criteria</description>
  </other_outcome>
  <other_outcome>
    <measure>Assessment of patients'-health-related quality of life</measure>
    <time_frame>up to 6 months last patients randomized</time_frame>
    <description>Quality of Life will be assessed by the European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, v.3.0 questionnaire at baseline and at week 12 and 24 during treatment, in both arms</description>
  </other_outcome>
  <other_outcome>
    <measure>Overall Response Rate</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>Objective Response Rate will be evaluated according to RECIST</description>
  </other_outcome>
  <other_outcome>
    <measure>Duration of response</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>calculated as the time from the date of the first documented response, complete (CR) or partial (PR), until the date of the first documented progression or death.</description>
  </other_outcome>
  <other_outcome>
    <measure>Early Tumor Shrinkage</measure>
    <time_frame>up to 8 weeks last patients randomized</time_frame>
    <description>Early Tumor Shrinkage is defined as the reduction of at least 20% in the sum of longest diameter of the target lesions at week 8 compared with baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Depth of response</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>Depth of response is defined as reduction in the sum of longest diameter of the target lesions at the nadir, compared with baseline,in the absence of new lesions or progression of non-target lesions</description>
  </other_outcome>
  <other_outcome>
    <measure>Genetic Alterations on tumor samples</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>To evaluate the prognostic and predictive value genetic alterations, by next generation sequencing performed on archived tumor samples or on newly obtained biopsies. Analysis is exploratory and will be performed retrospectively after the main study analysis is completed. Analysis will target mainly all relevant clinical mutation in KRAS, NRAS, BRAF, PI3K, EGFR, cKIT and PDGFR genes. Since the identification of new markers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of analyses remains to be determined; however, it will include a comparative baseline DNA mutational status analysis vs cfDNA</description>
  </other_outcome>
  <other_outcome>
    <measure>Circulating tumor DNA (liquid biopsy)</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>To evaluate potential biomarkers of primary and secondary resistance analyzing, by Next-generation sequencing, circulating tumor DNA obtained from blood samples (&quot;liquid biopsy&quot;) collected at baseline, at week 8, 16 and thereafter every 8 weeks concomitantly with tumor assessment. Analysis of cfDNA mutations on peripheral blood is exploratory and will be performed retrospectively after the main study analysis is completed. Analysis will target mainly all relevant clinical mutation in KRAS, NRAS, BRAF, PI3K, EGFR, cKIT and PDGFR genes. Since the identification of new markers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of analyses remains to be determined; however, it will include a comparative baseline DNA mutational status analysis vs cfDNA</description>
  </other_outcome>
  <other_outcome>
    <measure>Metabolomic profiling</measure>
    <time_frame>up to 1 year last patients randomized</time_frame>
    <description>Metabolomic profiling in peripheral blood at baseline and during treatment evaluated by NMR Spectrometer (600 MHz). The metabolite assignments will be based on the comparison of chemical shifts and spin-spin couplings with reference spectra and tables present in the SBASE-1-1-1 database by AMIX package (Bruker, Biospin, Germany), the human metabolome database (HMDB) and the biological magnetic resonance database (BMRB).</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">151</enrollment>
  <condition>Colorectal Cancer Stage IV</condition>
  <arm_group>
    <arm_group_label>CONTINUOUS ARM:</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>INTERMITTENT ARM:</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Panitumumab</intervention_name>
    <description>Continuous administation</description>
    <arm_group_label>INTERMITTENT ARM:</arm_group_label>
    <other_name>Irinotecan</other_name>
    <other_name>Fluorouracil plus folinic acid</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Panitumumab</intervention_name>
    <description>Intermittent administation</description>
    <arm_group_label>CONTINUOUS ARM:</arm_group_label>
    <other_name>Irinotecan</other_name>
    <other_name>Fluorouracil plus folinic acid</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent to study procedures and to molecular analyses;&#xD;
&#xD;
          2. Histologically proven diagnosis of colorectal cancer with wildtype RAS and BRAF status&#xD;
             in certified laboratories;&#xD;
&#xD;
          3. Initially unresectable metastatic colorectal cancer not previously treated with&#xD;
             chemotherapy for metastatic disease;&#xD;
&#xD;
          4. At least one measurable lesion according to RECIST1.1 criteria;&#xD;
&#xD;
          5. Availability of a tumor sample (primary and/or metastatic sites) for exploratory&#xD;
             research;&#xD;
&#xD;
          6. Age ≥ 18 years;&#xD;
&#xD;
          7. ECOG PS ≤ 2;&#xD;
&#xD;
          8. Life expectancy of at least 12 weeks;&#xD;
&#xD;
          9. Previous adjuvant chemotherapy allowed only if more than 6 months elapsed between the&#xD;
             end of adjuvant and first relapse;&#xD;
&#xD;
         10. Neutrophils ≥ 1.5 x 109/L, Platelets ≥100 x 109/L, Hgb ≥ 9 g/dl;&#xD;
&#xD;
         11. Total bilirubin ≤1.5 time the upper-normal limits (UNL) of the normal values and ASAT&#xD;
             (SGOT) and/or ALAT (SGPT) ≤ 2.5 x UNL (or &lt; 5 x UNL in case of liver metastases)&#xD;
             alkaline phosphatase ≤ 2.5 x UNL (or &lt; 5 x UNL in case of liver metastases);&#xD;
&#xD;
         12. Creatinine clearance ≥50 mL/min or serum creatinine ≤ 1.5 x UNL;&#xD;
&#xD;
         13. Female with a childbearing potential and male subjects must be willing to use adequate&#xD;
             contraception (barrier contraceptive measure, oral contraception, intrauterine&#xD;
             device);&#xD;
&#xD;
         14. Will and ability to comply with the protocol.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous treatment for metastatic disease;&#xD;
&#xD;
          2. Radiotherapy to any site within 4 weeks before the study;&#xD;
&#xD;
          3. Any contraindication to use Panitumumab, Irinotecan, 5-FU or folinic acid&#xD;
&#xD;
          4. Known or clinically suspected brain metastases.&#xD;
&#xD;
          5. History or evidence upon physical examination of CNS disease unless adequately&#xD;
             treated.&#xD;
&#xD;
          6. Ascites, pleural effusion or pericardial fluid requiring drainage in last 4 weeks.&#xD;
&#xD;
          7. Diagnosis of interstitial pneumonitis or pulmonary fibrosis;&#xD;
&#xD;
          8. Active uncontrolled infections or other clinically relevant concomitant illness&#xD;
             contraindicating chemotherapy administration or which, in the investigating&#xD;
             physician's opinion, rules out the patient's participation in the study;&#xD;
&#xD;
          9. Clinically significant (i.e. active) cardiovascular disease for example&#xD;
             cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable&#xD;
             angina, New York Heart Association (NYHA) grade II or greater congestive heart failure&#xD;
             (CHF), serious cardiac arrhythmia requiring medication;&#xD;
&#xD;
         10. Treatment with any investigational drug within 30 days prior to enrolment;&#xD;
&#xD;
         11. Other co-existing malignancies or malignancies diagnosed within the last 5 years with&#xD;
             the exception of localized basal and squamous cell carcinoma or cervical cancer in&#xD;
             situ;&#xD;
&#xD;
         12. Lack of physical integrity of the gastrointestinal tract or history of acute or&#xD;
             sub-acute intestinal occlusion or chronic inflammatory bowel disease or chronic&#xD;
             diarrhea.&#xD;
&#xD;
         13. Disease that is deemed potentially resectable.&#xD;
&#xD;
         14. Known hypersensitivity to trial drugs or hypersensitivity to any other component of&#xD;
             the trial drugs.&#xD;
&#xD;
         15. Any concomitant drugs contraindicated for use with the trial drugs according to the&#xD;
             product information of the pharmaceutical companies.&#xD;
&#xD;
         16. Breastfeeding&#xD;
&#xD;
         17. Sexually active males and females (of childbearing potential) unwilling to practice&#xD;
             contraception (barrier contraceptive measure or oral contraception) during the study&#xD;
             and until 6 months after the last trial treatment.&#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>Antonio Avallone, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Istituto Nazionale dei Tumori di Napoli - IRCCS - Fondazione G. Pascale</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Istituto Nazionale Tumori di Napoli - IRCCS - Fondazione G. Pascale</name>
      <address>
        <city>Napoli</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <verification_date>September 2021</verification_date>
  <study_first_submitted>May 3, 2020</study_first_submitted>
  <study_first_submitted_qc>June 8, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>April 6, 2022</last_update_submitted>
  <last_update_submitted_qc>April 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">April 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>metastatic colorectal cancer</keyword>
  <keyword>RAS and BRAF wild type</keyword>
  <keyword>intermittent therapy</keyword>
  <keyword>liquid biopsy</keyword>
  <keyword>panitumumab</keyword>
  <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>Leucovorin</mesh_term>
    <mesh_term>Folic Acid</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
    <mesh_term>Panitumumab</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/NCT04425239
org study id: IMPROVE
nct id: NCT04425239
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
The investigators hypothesize that intermittent first-line Panitumumab plus FOLFIRI is
      effective as the same regimen given continuously, in unresectable metastatic RAS and BRAF
      wild type colorectal cancer patients. Correlative studies on tumor and blood samples could
      identify potential biomarkers of efficacy and help defining personalized treatment strategy.
This will be a multicenter open label randomized phase II study. The study population will
      include untreated RAS wild-type metastatic colorectal (mCRC) patients with unresectable
      disease. A total of 136 patients will be enrolled.

      All Patients will receive an induction treatment with panitumumab as 1 hour intravenous
      infusion at the dosage of 6 mg/kg, given every two weeks, plus FOLFIRI chemotherapy as
      standard guidelines.

      Before start of FOLFIRI plus panitumumab, at the time of enrollment, patients will be
      immediately randomized electronically 1:1 to one of the two arms. Induction treatment with
      FOLFIRI plus panitumumab will continue until progressive disease, unacceptable toxicity or
      informed consent withdrawal, or for up to 8 cycles. At the end of induction treatment, in
      presence of complete or partial response, or stable disease, non-progressing patients will be
      allocated to one of the two pre-assigned arms:

      A) CONTINOUS: FOLFIRI plus panitumumab until progressive disease, unacceptable toxicity or
      informed consent withdrawal. Panitumumab will be administered as a 6 mg/kg intravenous
      infusion over 60 minutes (day 1) every 2 weeks. The dose of Panitumumab should be
      administered prior to chemotherapy. Irinotecan will be administered as a 180 mg/m2
      intravenous infusion over 60 minutes (day 1) every 2 weeks. Folinic acid will be administered
      as a 200 mg/m2 intravenous infusion over 120 minutes before 5- fluorouracil infusion (day 1)
      every 2 weeks. 5-fluorouracil will be administered as a 400 mg/m2 intravenous bolus injection
      (day 1) followed by 2400 mg/m246-hours continuous infusion (day 1), every 2 weeks. Cycle
      length will be 2 weeks +/- 3 days.

      B) INTERMITTENT: treatment free interval until progressive disease; followed by up to 8
      cycles of FOLFIRI plus panitumumab; in presence of complete or partial response, or stable
      disease, non-progressing patients will undergo again to treatment free interval until PD,
      when they will restart treatment. Treatment cycling will continue till any progressive
      disease on treatment. Panitumumab will be administered at same dose and infusion with
      FOLFIRI.

      All measurable and non-measurable lesions must be documented at screening (within 21 days
      prior to randomization) and re-assessed at each subsequent tumor evaluation (every 8 weeks
      while the patient is on study). Tumor assessment by CT scan of chest, abdomen and pelvis;
      CEA, CA 19.9; and any other tests having resulted positive during baseline staging, will be
      performed at week 8 and every 8 weeks thereafter, until disease progression, accordingly with
      RECIST V 1.1 criteria.

      Toxicities will be evaluated throughout the study treatment and graded according to the NCI
      Common Toxicity Criteria.

      The National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTC-AE)
      Version 4.03 will be used to evaluate the clinical safety of the treatment in this study.
      Patients will be assessed for AEs at each clinical visit and as necessary throughout the
      study.

      Quality of Life is assessed by the EORTC QLQ-C30, v. 3.0 questionnaire that are completed by
      patients at baseline, at week 16 and every 8 weeks thereafter.

      Biomarkers ancillary study Correlative biological studies will be performed for the
      evaluation of the biomarkers indicated above on the biological samples available
      (paraffin-embedded tissue, frozen tissue, blood, serum, etc.). Biomarkers will be evaluated
      on archival tumor tissues or on newly obtained biopsies at baseline, and during treatment
      when available. Blood Samples will be collected at baseline, at week 8, 16 and thereafter
      every 8 weeks concomitantly with tumor assessment.

      The sample size is calculated on the basis of median progression-free survival on treatment
      with intermittent vs continuous Panitumumab plus FOLFIRI, taking into account a median PFS of
      11 months observed in the CRYSTAL trial.

      The study is designed as a phase II trial with a random assignment to a calibration arm
      (continous) and to the experimental arm (intermittent). The sample size for intermittent arm
      is calculated according to the binomial test. The calibration arm has the same sample size,
      its role is to give a parallel estimation of median PFS to ensure that sample is
      representative and results are consistent However considering a 5% of drop-outs mainly due to
      losses to follow-up, the sample size is increased from 130 to 136 patients.

      Randomization will be performed with a minimization procedure that will account for center;
      ECOG (PS 0-1 vs 2); primary site of tumor (Right versus Left); adjuvant treatment (yes vs
      no); metastatic sites (1 vs>1).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Progression-free Survival
time frame: up to 1 year last patients randomized
description: Progression Free Survival on treatment (PFSOT) is defined as the time from randomization to the first objective disease progression documented in patients undergoing treatment cycle (objective disease progression during treatment free intervals are excluded) or death due to any cause, whichever occurs first.
measure: Overall Survival (OS)
time frame: up to 1 year last patients randomized
description: Overall Survival is defined as the time from randomization to the date of death
measure: Toxicities
time frame: up to 1 year last patients randomized
description: Toxicities will be assessed in terms of incidence of Adverse Events (AE) that will be graded according to the NCI CTC-AE Version 4.03 criteria
measure: Assessment of patients'-health-related quality of life
time frame: up to 6 months last patients randomized
description: Quality of Life will be assessed by the European Organization for Research and Treatment of Cancer [EORTC] QLQ-C30, v.3.0 questionnaire at baseline and at week 12 and 24 during treatment, in both arms
measure: Overall Response Rate
time frame: up to 1 year last patients randomized
description: Objective Response Rate will be evaluated according to RECIST
measure: Duration of response
time frame: up to 1 year last patients randomized
description: calculated as the time from the date of the first documented response, complete (CR) or partial (PR), until the date of the first documented progression or death.
measure: Early Tumor Shrinkage
time frame: up to 8 weeks last patients randomized
description: Early Tumor Shrinkage is defined as the reduction of at least 20% in the sum of longest diameter of the target lesions at week 8 compared with baseline
measure: Depth of response
time frame: up to 1 year last patients randomized
description: Depth of response is defined as reduction in the sum of longest diameter of the target lesions at the nadir, compared with baseline,in the absence of new lesions or progression of non-target lesions
measure: Genetic Alterations on tumor samples
time frame: up to 1 year last patients randomized
description: To evaluate the prognostic and predictive value genetic alterations, by next generation sequencing performed on archived tumor samples or on newly obtained biopsies. Analysis is exploratory and will be performed retrospectively after the main study analysis is completed. Analysis will target mainly all relevant clinical mutation in KRAS, NRAS, BRAF, PI3K, EGFR, cKIT and PDGFR genes. Since the identification of new markers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of analyses remains to be determined; however, it will include a comparative baseline DNA mutational status analysis vs cfDNA
measure: Circulating tumor DNA (liquid biopsy)
time frame: up to 1 year last patients randomized
description: To evaluate potential biomarkers of primary and secondary resistance analyzing, by Next-generation sequencing, circulating tumor DNA obtained from blood samples ("liquid biopsy") collected at baseline, at week 8, 16 and thereafter every 8 weeks concomitantly with tumor assessment. Analysis of cfDNA mutations on peripheral blood is exploratory and will be performed retrospectively after the main study analysis is completed. Analysis will target mainly all relevant clinical mutation in KRAS, NRAS, BRAF, PI3K, EGFR, cKIT and PDGFR genes. Since the identification of new markers correlating with disease activity and the efficacy or safety of treatment are rapidly evolving, the definitive list of analyses remains to be determined; however, it will include a comparative baseline DNA mutational status analysis vs cfDNA
measure: Metabolomic profiling
time frame: up to 1 year last patients randomized
description: Metabolomic profiling in peripheral blood at baseline and during treatment evaluated by NMR Spectrometer (600 MHz). The metabolite assignments will be based on the comparison of chemical shifts and spin-spin couplings with reference spectra and tables present in the SBASE-1-1-1 database by AMIX package (Bruker, Biospin, Germany), the human metabolome database (HMDB) and the biological magnetic resonance database (BMRB).
arm group label: CONTINUOUS ARM:
arm group type: Active Comparator
description: Patients will receive Panitumumab plus FOLFIRI until progressive disease, unacceptable toxicity or informed consent withdrawal.
arm group label: INTERMITTENT ARM:
arm group type: Experimental
description: Patients will have a treatment free interval until progressive disease (PD), when they will receive up to 8 cycles of Panitumumab plus FOLFIRI. In the presence of complete or partial response, or stable disease, non-progressing patients will undergo again to treatment free interval until PD, when they will restart treatment. Treatment cycling will continue till any PD on treatment.
intervention type: Drug
intervention name: Panitumumab
description: Continuous administation
arm group label: INTERMITTENT ARM:
other name: Irinotecan
other name: Fluorouracil plus folinic acid
intervention type: Drug
intervention name: Panitumumab
description: Intermittent administation
arm group label: CONTINUOUS ARM:
other name: Irinotecan
other name: Fluorouracil plus folinic acid
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antonio Avallone, MD
role: Principal Investigator
affiliation: Istituto Nazionale dei Tumori di Napoli - IRCCS - Fondazione G. Pascale
facility: 
country: Italy
responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Leucovorin
mesh term: Folic Acid
mesh term: Fluorouracil
mesh term: Irinotecan
mesh term: Panitumumab
mesh term: Levoleucovorin