<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/NCT01660711</url>
  </required_header>
  <id_info>
    <org_study_id>EH12-267</org_study_id>
    <nct_id>NCT01660711</nct_id>
  </id_info>
  <brief_title>A Pilot Study of Pre- and Post-surgery Chemotherapy With mFOLFIRINOX in Localized, Resectable Pancreatic Adenocarcinoma</brief_title>
  <official_title>A Pilot Study of Neoadjuvant and Adjuvant mFOLFIRINOX in Localized, Resectable Pancreatic Adenocarcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>NorthShore University HealthSystem</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Chicago</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>NorthShore University HealthSystem</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of the study is to demonstrate that it is possible to administer chemotherapy&#xD;
      prior to and following surgery for pancreatic cancer which is considered operable. The&#xD;
      chemotherapy chosen is that which has been shown to be the most effective in treating&#xD;
      metastatic disease, and the goal is both to investigate whether this is tolerable and also to&#xD;
      investigate the efficacy of this approach in terms of disease response and survival.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Pancreatic ductal adenocarcinoma is a highly lethal disease. It is estimated that in 2010&#xD;
      there were approximately 43,140 new cases in the United States and 36,800 deaths which ranks&#xD;
      fourth among cancer related deaths . At diagnosis, roughly 17,000 of the initial 43,000&#xD;
      patients have disease which appears to be localized to the pancreatic bed, but unfortunately,&#xD;
      only a minority of these patients (15-20%) are immediately operable (on imaging studies their&#xD;
      disease appears to be both localized to the pancreas and technically resectable with clear&#xD;
      margins, and at surgery no unexpected findings preclude an R0 resection ). It should be noted&#xD;
      that of those patients deemed immediately operable on clinical grounds, between 20 and 57%&#xD;
      are found to have inoperable disease on exploration depending on the series and on the extent&#xD;
      and nature of preoperative staging. The majority of patients have locally advanced,&#xD;
      borderline resectable or unresectable disease owing to involvement of critical structures,&#xD;
      most particularly sentinel blood vessels such as the SMA, celiac axis, hepatic artery, SMV,&#xD;
      or portal vein. Furthermore, despite recent advances in systemic therapy, even those&#xD;
      fortunate few able to undergo immediate surgery remain largely incurable, with a five year&#xD;
      survival of slightly less than 20%.&#xD;
&#xD;
      The current standard of care for adjuvant therapy in resectable pancreatic cancer is based on&#xD;
      the CONKO-001 study which randomized patients to 6 cycles of postoperative adjuvant therapy&#xD;
      with gemcitabine versus observation alone. Results favored adjuvant gemcitabine in both&#xD;
      disease free survival (13.4 vs 6.9 months, p&lt;0.001) and overall survival (24.2 months vs 20.5&#xD;
      months p=0.02) strongly supporting the use of adjuvant gemcitabine in the setting of both R0&#xD;
      and R1 resections. An RTOG study - 97-04 - concluded that gemcitabine was probably superior&#xD;
      to 5FU when used pre and postoperatively in combination with 5FU/RT, with a HR of 0.82. The&#xD;
      role of radiation therapy in this setting remains controversial, with studies such as the&#xD;
      GITSG trial (pro) and ESPAC 1 (con) criticized either for questionable design, outdated&#xD;
      chemotherapy or unconventional radiation therapy. Current studies in progress examining&#xD;
      postoperative therapy include RTOG 0848 (phase III looking at adjuvant gemcitabine versus&#xD;
      gemcitabine plus erlotinib plus/minus chemo/RT using fluorouracil), ACOSOG Z5041 evaluating&#xD;
      gemcitabine plus erlotinib in the pre and postoperative setting and ESPAC 4 evaluating&#xD;
      gemcitabine versus gemcitabine plus capecitabine.&#xD;
&#xD;
      Many studies have explored the use of neoadjuvant therapy in initially resectable, borderline&#xD;
      resectable and unresectable disease. The majority of these have been single arm, single&#xD;
      institution phase I/II studies, and results have been mixed. Potential benefits of a&#xD;
      neoadjuvant approach include: downstaging of disease with an increased percentage of margin&#xD;
      negative and lymph node negative resections; no delay in systemic therapy aimed at&#xD;
      eradicating micrometastatic disease; the detection of biologically aggressive tumors, as&#xD;
      evidenced by early progression/metastases during this phase of therapy, thereby avoiding&#xD;
      inappropriate surgery; and the greater likelihood of completing all intended therapy as&#xD;
      opposed to postoperative treatment, where fully 22 - 35% of patients do not complete their&#xD;
      intended program.&#xD;
&#xD;
      A comprehensive meta-analysis and systematic review of neoadjuvant therapy in both resectable&#xD;
      and unresectable pancreatic cancer has recently been published. The conclusion reached in&#xD;
      resectable patients was that resection frequency and survival following neoadjuvant therapy&#xD;
      was similar to that in patients undergoing primary resection followed by adjuvant therapy. In&#xD;
      patients with initially unresectable disease, fully one third had resectable tumors following&#xD;
      neoadjuvant therapy with survival comparable to initially resectable patients. In aggregate,&#xD;
      these observations indicate that a neoadjuvant approach is feasible and effective, and that&#xD;
      this sequence does not compromise resectability or survival, even in those patients with the&#xD;
      best prognosis.&#xD;
&#xD;
      With respect to specific studies in resectable disease, investigators at MD Anderson Cancer&#xD;
      Center have published their most recent results. In their first study, 86 patients with&#xD;
      resectable disease in the head of the pancreas received radiation therapy (30 Gy in 10&#xD;
      fractions over 2 weeks) plus 7 weekly infusions of gemcitabine at 400 mg/m2/week. 85% of&#xD;
      these patients were taken to surgery and 74% were able to undergo the intended&#xD;
      pancreaticoduodenectomy. Median survival for patients whose disease was resected was 34&#xD;
      months, but it was only 7 months for those whose disease could not be resected. In a second&#xD;
      study of patients with resectable adenocarcinoma of the pancreatic head, 90 patients were&#xD;
      enrolled with the goal of administering chemotherapy alone for eight weeks, using gemcitabine&#xD;
      and cisplatin, followed by combined low dose gemcitabine and radiation therapy (30 Gy in 10&#xD;
      fractions). Ultimately, 79 (88%) patients completed the full course of preoperative therapy&#xD;
      and 62 of these (78%) patients were taken to surgery. 52 (66%) had their disease resected&#xD;
      with a median survival of 31 months for those who had surgery, versus 10.5 months for those&#xD;
      who did not. They concluded that initial combination chemotherapy with gemcitabine and&#xD;
      cisplatin followed by chemotherapy/RT did not improve on the results achieved with&#xD;
      chemotherapy/RT alone. This result is perhaps not surprising as gemcitabine, both alone and&#xD;
      in doublet combinations, has simply not been active enough to materially impact on the&#xD;
      outcome of this disease. Interestingly, the longer preoperative interval did not result in&#xD;
      local tumor progression.&#xD;
&#xD;
      These findings are similar to those of other major centers reporting studies of neoadjuvant&#xD;
      gemcitabine based chemoradiation for potentially resectable disease, and suggest that this is&#xD;
      a valid strategy for further study in this setting.&#xD;
&#xD;
      Recently, investigators in Europe reported their results with a novel combination of&#xD;
      docetaxel 30 mg/m2 weekly and RT of 45 Gy in 34 patients with resectable disease. 32% had&#xD;
      progression, 59% stable disease and 9% partial remission. 50% of the original cohort had&#xD;
      pancreaticoduodenectomy with 100% R0 resection and a median survival of 32 months. The&#xD;
      numbers are small and the overall resection rate disappointingly low, but the R0 resection&#xD;
      rate and median survival for those resected is equivalent to patients receiving gemcitabine&#xD;
      based regimens.&#xD;
&#xD;
      In locally advanced, unresectable disease, results have recently been reported from Austria&#xD;
      with neoadjuvant gemcitabine/oxaliplatin without RT (39% of patients undergoing resection of&#xD;
      disease with 69% R0 and 22 months median survival), Italy with neoadjuvant PEFG/PEXG&#xD;
      (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel&#xD;
      substituting for epirubicin) followed by RT plus X, F or G (14% resected with median survival&#xD;
      16.2 months)and Japan with neoadjuvant gemcitabine 1000 mg/m2/wk and RT 50 Gy in T3 disease&#xD;
      followed by postoperative 5FU liver perfusion (82% of patients with disease resected, 43% 5&#xD;
      year survival). In each of these studies, there is a mixture of borderline resectable and&#xD;
      unresectable disease with the result that the interpretation of outcomes is problematic.&#xD;
      However, it is clear that a neoadjuvant approach is feasible and active.&#xD;
&#xD;
      It is clear from an examination of the NCI CTEP database that the neoadjuvant approach has&#xD;
      been widely embraced for future study. More than 40 active protocols are listed, including&#xD;
      the following select few: a UVA study of hypofractionated RT plus chronomodulated&#xD;
      capecitabine in resectable and borderline resectable disease; a UT Southwestern phase I study&#xD;
      of SBRT or SBRT plus gemcitabine; an Emory phase I study of FOLFIRINOX and SBRT; a Fred&#xD;
      Hutchinson study of GTX and oxaliplatin with IMRT and adjuvant gemcitabine; a UF phase II&#xD;
      study of risk adapted gemcitabine plus abraxane; a European randomized phase II study of&#xD;
      gemcitabine plus oxaliplatin pre and gemcitabine postoperatively versus gemcitabine&#xD;
      postoperatively only; a Memorial Sloan Kettering phase II study of gemcitabine plus&#xD;
      oxaliplatin preoperatively plus gemcitabine postoperatively; and an ACOSOG study of&#xD;
      gemcitabine plus erlotinib pre and postoperatively.&#xD;
&#xD;
      Looking to the future there have been a number of recent innovations in chemotherapy. In an&#xD;
      ongoing effort to discover non-gemcitabine based chemotherapy for those who have progressed&#xD;
      on gemcitabine, and also a new regimen with more efficacy than those currently used in&#xD;
      patients with pancreatic cancer, the combination of 5FU, leucovorin, oxaliplatin and&#xD;
      irinotecan has been tested. This combination was initially studied in colorectal cancer, in a&#xD;
      regimen known as FOLFOXIRI. It was established that this combination was both tolerable and&#xD;
      effective in this setting. Subsequently, the regimen was modified slightly to the current&#xD;
      FOLFIRINOX format (oxaliplatin 85mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 , 5FU 400&#xD;
      mg/m2 on day 1, then 5FU 2400 mg/m2 as a 46 hour continuous infusion) and tested in a phase&#xD;
      II study in pancreatic cancer. 47 chemotherapy-naïve patients with metastatic disease were&#xD;
      enrolled and 46 were treated. Confirmed response rate was 26% with 4% complete responses.&#xD;
      Median time to progression was 8.2 months and median overall survival was 10.2 months. Grade&#xD;
      3/4 toxicities included neutropenia (52%), nausea (20%), vomiting (17%), diarrhea (15%), and&#xD;
      neuropathy (15%). No toxic death occurred. FOLFIRINOX was then tested after failure of&#xD;
      previous gemcitabine therapy in metastatic disease and was deemed to be promising. 13&#xD;
      patients were treated, with 9 evaluable for response - 6 had stable disease with a mean time&#xD;
      to progression of 6.6 months, and 3 progressed.&#xD;
&#xD;
      As a consequence of the previously mentioned phase II study in chemo-naïve patients, a&#xD;
      randomized phase II/phase III study comparing gemcitabine (G) to FOLFIRINOX (F) as first line&#xD;
      treatment of metastatic pancreatic cancer was conducted. This study was terminated&#xD;
      prematurely by the study IDMC as it was determined that additional patient accrual would not&#xD;
      add to the statistical power of the study. 342 patients were accrued with roughly one third&#xD;
      of the primary disease involving the head of the pancreas. Overall objective response rate&#xD;
      was 32% for F versus 9.4% for G. PFS was 6.4 months versus 3.4 months and overall survival&#xD;
      11.1 months versus 6.8 months, all in favor of F.&#xD;
&#xD;
      The overall survival rate of 11.1 months is the best result achieved thus far in a randomized&#xD;
      phase III study of chemotherapy in metastatic pancreatic cancer. Notable toxicities of at&#xD;
      least grade III/IV, which were all worse with F, were neutropenia (45.7 vs 18.7%), febrile&#xD;
      neutropenia (5.4 vs 0.6%), fatigue (23.7 vs 14.2%), vomiting (14.5 vs 4.7%) and diarrhea&#xD;
      (12.7 vs 1.2%). These results indicate that this is a notably active regimen with an&#xD;
      encouraging response rate. However, the potential toxicities are significant, and it is a&#xD;
      regimen that should be offered only to patients with ECOG 0-1 performance status and&#xD;
      excellent supportive care. In this regard, in an attempt to ameliorate these toxicities,&#xD;
      modifications to the published regimen have already been proposed by the French group and&#xD;
      others. In their forthcoming study of FOLFIRINOX in the adjuvant setting, the French will&#xD;
      omit the bolus of 5FU which contributes significantly to the myelosuppression but which is&#xD;
      thought to have minimal impact on the therapeutic efficacy. In addition, most physicians now&#xD;
      incorporate the routine use of neulasta with each treatment cycle. This study will similarly&#xD;
      incorporate these modifications and the regimen will be named mFOLFIRINOX.&#xD;
&#xD;
      Thus, in the context of perioperative therapy, we have identified a regimen - FOLFIRINOX -&#xD;
      with the best results to date in the treatment of metastatic disease and by inference,&#xD;
      promise of improved outcome in those patients with resectable disease. If successful, this&#xD;
      has the potential to improve DFS and overall survival (until now no better than 15-20% at 5&#xD;
      years) in these patients, and may establish a new paradigm for future studies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">August 22, 2018</completion_date>
  <primary_completion_date type="Actual">August 22, 2018</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percentage Able to Complete Full Course of Preoperative Chemotherapy</measure>
    <time_frame>Following completion of all planned therapy, an expected average of 4 months</time_frame>
    <description>The percentage of participants able to complete the full course of preoperative chemotherapy and undergo a resection. This will be the primary determinant of success for this pilot study. - Early withdrawals due to toxicity, disease progression, or intercurrent illness will be considered failures.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Percentage Able to Complete Full Course of Therapy</measure>
    <time_frame>On completion of all planned therapy, an expected average of 8 months</time_frame>
    <description>The percentage of participants able to complete the full course of therapy, including preoperative chemotherapy, surgical resection and postoperative chemotherapy.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Treatment Related Toxicity</measure>
    <time_frame>1 year</time_frame>
    <description>Treatment related toxicity and other adverse events (AEs) during Toxicity of preoperative and postoperative therapy and the safety of this approach.</description>
  </other_outcome>
  <other_outcome>
    <measure>R0 Resection Rate</measure>
    <time_frame>3 months</time_frame>
    <description>Assessment of the percentage of patients able to have an R0 resection following preoperative chemotherapy.</description>
  </other_outcome>
  <other_outcome>
    <measure>Progression-free and Overall Survival</measure>
    <time_frame>5 years</time_frame>
    <description>Assessment of progression-free survival and overall survival from the start of study treatment.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">22</enrollment>
  <condition>Pancreatic Adenocarcinoma</condition>
  <arm_group>
    <arm_group_label>FOLFIRINOX chemotherapy</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>5FU 2400 mg/m2 IV over 48 hours Irinotecan 180 mg/m2 IV day 1 Oxaliplatin 85 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1&#xD;
Cycles administered every 14 days for 4 cycles before and 4 cycles after surgery.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5 Fluorouracil</intervention_name>
    <description>2400 mg/m2 by continuous intravenous infusion over 46 hours</description>
    <arm_group_label>FOLFIRINOX chemotherapy</arm_group_label>
    <other_name>Adrucil,5FU</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Leucovorin</intervention_name>
    <description>400 mg/m2 by IV infusion over 2 hours</description>
    <arm_group_label>FOLFIRINOX chemotherapy</arm_group_label>
    <other_name>Folinic acid, Wellcovorin, citrovorum factor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <description>180 mg/m² IV infusion on Day 1 over 90-120 minutes (infusion via a Y connector during the infusion of leucovorin)</description>
    <arm_group_label>FOLFIRINOX chemotherapy</arm_group_label>
    <other_name>camptosar, CPT11</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Oxaliplatin</intervention_name>
    <description>85 mg/m² IV infusion on Day 1 over 2 hours</description>
    <arm_group_label>FOLFIRINOX chemotherapy</arm_group_label>
    <other_name>Eloxatin,</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologic or cytologic diagnosis of adenocarcinoma of the pancreas.&#xD;
&#xD;
          -  Resectable primary tumor of the head, body or tail of the pancreas defined as a&#xD;
             visible mass in the pancreas and:&#xD;
&#xD;
          -  No extrapancreatic disease&#xD;
&#xD;
          -  A patent superior mesenteric (SMV)- portal vein (PV) confluence (assuming the&#xD;
             technical ability to resect and reconstruct this venous confluence if needed)&#xD;
&#xD;
          -  A definable tissue plane between the tumor and regional arterial structures including&#xD;
             the celiac axis, common hepatic artery, and SMA.&#xD;
&#xD;
          -  Confirmation of resectability by surgical oncology consultation.&#xD;
&#xD;
          -  Presentation at a multidisciplinary conference at either University of Chicago or&#xD;
             NorthShore University&#xD;
&#xD;
          -  No previous therapy for pancreatic cancer&#xD;
&#xD;
          -  Short removable metal stents rather than plastic stents are preferred but not required&#xD;
             for palliation of initial obstructive jaundice&#xD;
&#xD;
          -  Karnofsky performance status 80 or better&#xD;
&#xD;
          -  Age &gt; 21 years&#xD;
&#xD;
          -  No currently active second malignancy&#xD;
&#xD;
          -  No CVA within 6 months, no MI within 6 months&#xD;
&#xD;
          -  The effects of mFOLFIRINOX on the developing human fetus are unknown. For this reason&#xD;
             and because chemotherapy agents as well as other therapeutic agents used in this trial&#xD;
             are known to be teratogenic, women of child-bearing potential and men must agree to&#xD;
             use adequate contraception (hormonal or barrier method of birth control; abstinence)&#xD;
             prior to study entry and for the duration of study participation. Should a woman&#xD;
             become pregnant or suspect she is pregnant while she or her partner is participating&#xD;
             in this study, she should inform her treating physician immediately.&#xD;
&#xD;
          -  Negative pregnancy test in females of reproductive age&#xD;
&#xD;
          -  Life expectancy of greater than 3 months.&#xD;
&#xD;
          -  Anticoagulation is permitted but patients may only be on lovenox for this purpose.&#xD;
&#xD;
          -  Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
               -  absolute neutrophil count &gt;1,500/mcL&#xD;
&#xD;
               -  platelets &gt;100,000/mcL&#xD;
&#xD;
               -  total bilirubin &lt;1.5X upper limits of normal&#xD;
&#xD;
               -  AST(SGOT)/ALT(SGPT) &lt;2.5 X institutional upper limit of normal&#xD;
&#xD;
               -  creatinine within normal institutional limits OR&#xD;
&#xD;
               -  creatinine clearance &gt;60 mL/min/ per Cockcroft-Gault equation for patients with&#xD;
                  creatinine levels above institutional normal.&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients who have had previous chemotherapy or radiotherapy for pancreatic&#xD;
             adenocarcinoma prior to entering the study.&#xD;
&#xD;
          -  Pathologic subtypes other than pure adenocarcinoma; acinar cell carcinoma, squamous&#xD;
             cell carcinoma, spindle cell carcinoma, neuroendocrine cancer, and mixed types are not&#xD;
             eligible.&#xD;
&#xD;
          -  Patients who are receiving any investigational agents.&#xD;
&#xD;
          -  Patients with borderline resectable, locally advanced or metastatic disease.&#xD;
&#xD;
          -  History of allergic reactions attributed to 5FU, leucovorin, irinotecan or oxaliplatin&#xD;
             or to compounds of similar chemical or biologic composition.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia, active liver disease including viral or non-viral hepatitis and cirrhosis,&#xD;
             chronic diarrhea or inflammatory disease of the colon or rectum, or psychiatric&#xD;
             illness/social situations that would limit compliance with study requirements.&#xD;
&#xD;
          -  Pregnant women are excluded from this study. mFOLFIRINOX is a regimen containing more&#xD;
             than one chemotherapy agent with the potential for teratogenic or abortifacient&#xD;
             effects. Because there is an unknown but potential risk for adverse events in nursing&#xD;
             infants secondary to treatment of the mother with FOLFIRINOX, breastfeeding should be&#xD;
             discontinued if the mother is treated with these agents. These potential risks may&#xD;
             also apply to other agents used in this study.&#xD;
&#xD;
          -  HIV-positive patients on combination antiretroviral therapy are ineligible because of&#xD;
             the potential for pharmacokinetic interactions with mFOLFIRINOX. In addition, these&#xD;
             patients are at increased risk of lethal infections when treated with&#xD;
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients&#xD;
             receiving combination antiretroviral therapy when indicated.&#xD;
&#xD;
          -  Currently active second malignancy other than non-melanoma skin cancer or carcinoma&#xD;
             in-situ of the cervix. Patients are not considered to have a &quot;currently active&quot;&#xD;
             malignancy if they have completed therapy and have no evidence of recurrence for at&#xD;
             least 5 years.&#xD;
&#xD;
          -  Pre-existing neuropathy greater than grade 1.&#xD;
&#xD;
          -  Anticoagulants other than low molecular weight heparin.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>NorthShore University HealthSystem</name>
      <address>
        <city>Evanston</city>
        <state>Illinois</state>
        <zip>60201</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>August 3, 2012</study_first_submitted>
  <study_first_submitted_qc>August 6, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 9, 2012</study_first_posted>
  <results_first_submitted>March 1, 2021</results_first_submitted>
  <results_first_submitted_qc>November 4, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">November 8, 2021</results_first_posted>
  <last_update_submitted>November 4, 2021</last_update_submitted>
  <last_update_submitted_qc>November 4, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>NorthShore University HealthSystem</investigator_affiliation>
    <investigator_full_name>Robert de W Marsh MD</investigator_full_name>
    <investigator_title>Section Chief Gastrointestinal Oncology, Clinical Professor University of Chicago</investigator_title>
  </responsible_party>
  <keyword>neoadjuvant</keyword>
  <keyword>chemotherapy</keyword>
  <keyword>resectable</keyword>
  <keyword>adjuvant</keyword>
  <keyword>pancreas</keyword>
  <keyword>cancer</keyword>
  <keyword>adenocarcinoma</keyword>
  <keyword>surgery</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leucovorin</mesh_term>
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Oxaliplatin</mesh_term>
    <mesh_term>Irinotecan</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 13, 2013</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/11/NCT01660711/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>FOLFIRINOX Chemotherapy</title>
          <description>5FU 2400 mg/m2 IV over 48 hours Irinotecan 180 mg/m2 IV day 1 Oxaliplatin 85 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1&#xD;
Cycles administered every 14 days for 4 cycles before and 4 cycles after surgery.&#xD;
5 Fluorouracil: 2400 mg/m2 by continuous intravenous infusion over 46 hours&#xD;
Leucovorin: 400 mg/m2 by IV infusion over 2 hours&#xD;
Irinotecan: 180 mg/m² IV infusion on Day 1 over 90-120 minutes (infusion via a Y connector during the infusion of leucovorin)&#xD;
Oxaliplatin: 85 mg/m² IV infusion on Day 1 over 2 hours</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="14"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>FOLFIRINOX Chemotherapy</title>
          <description>All participants.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="22"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <population>1 person registered was ineligible and did not participate.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="22"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="22"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="22"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage Able to Complete Full Course of Preoperative Chemotherapy</title>
        <description>The percentage of participants able to complete the full course of preoperative chemotherapy and undergo a resection. This will be the primary determinant of success for this pilot study. - Early withdrawals due to toxicity, disease progression, or intercurrent illness will be considered failures.</description>
        <time_frame>Following completion of all planned therapy, an expected average of 4 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>FOLFIRINOX Chemotherapy</title>
            <description>5FU 2400 mg/m2 IV over 48 hours Irinotecan 180 mg/m2 IV day 1 Oxaliplatin 85 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1&#xD;
Cycles administered every 14 days for 4 cycles before and 4 cycles after surgery.&#xD;
5 Fluorouracil: 2400 mg/m2 by continuous intravenous infusion over 46 hours&#xD;
Leucovorin: 400 mg/m2 by IV infusion over 2 hours&#xD;
Irinotecan: 180 mg/m² IV infusion on Day 1 over 90-120 minutes (infusion via a Y connector during the infusion of leucovorin)&#xD;
Oxaliplatin: 85 mg/m² IV infusion on Day 1 over 2 hours</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage Able to Complete Full Course of Preoperative Chemotherapy</title>
          <description>The percentage of participants able to complete the full course of preoperative chemotherapy and undergo a resection. This will be the primary determinant of success for this pilot study. - Early withdrawals due to toxicity, disease progression, or intercurrent illness will be considered failures.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage Able to Complete Full Course of Therapy</title>
        <description>The percentage of participants able to complete the full course of therapy, including preoperative chemotherapy, surgical resection and postoperative chemotherapy.</description>
        <time_frame>On completion of all planned therapy, an expected average of 8 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>FOLFIRINOX Chemotherapy</title>
            <description>5FU 2400 mg/m2 IV over 48 hours Irinotecan 180 mg/m2 IV day 1 Oxaliplatin 85 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1&#xD;
Cycles administered every 14 days for 4 cycles before and 4 cycles after surgery.&#xD;
5 Fluorouracil: 2400 mg/m2 by continuous intravenous infusion over 46 hours&#xD;
Leucovorin: 400 mg/m2 by IV infusion over 2 hours&#xD;
Irinotecan: 180 mg/m² IV infusion on Day 1 over 90-120 minutes (infusion via a Y connector during the infusion of leucovorin)&#xD;
Oxaliplatin: 85 mg/m² IV infusion on Day 1 over 2 hours</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage Able to Complete Full Course of Therapy</title>
          <description>The percentage of participants able to complete the full course of therapy, including preoperative chemotherapy, surgical resection and postoperative chemotherapy.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="22"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Treatment Related Toxicity</title>
        <description>Treatment related toxicity and other adverse events (AEs) during Toxicity of preoperative and postoperative therapy and the safety of this approach.</description>
        <time_frame>1 year</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>R0 Resection Rate</title>
        <description>Assessment of the percentage of patients able to have an R0 resection following preoperative chemotherapy.</description>
        <time_frame>3 months</time_frame>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Progression-free and Overall Survival</title>
        <description>Assessment of progression-free survival and overall survival from the start of study treatment.</description>
        <time_frame>5 years</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>FOLFIRINOX Chemotherapy</title>
          <description>FOLFIRINOX chemotherapy in all participants.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>MedDRA (10.0)</default_vocab>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="14" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="22"/>
              </event>
              <event>
                <sub_title>anorexia</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>peripheral neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="22"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr Robert Marsh</name_or_title>
      <organization>NorthShore University/University of Chicago</organization>
      <phone>847-5702112</phone>
      <email>rmarsh@northshore.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01660711
org study id: EH12-267
nct id: NCT01660711
lead sponsor: 
collaborator: 
has dmc: Yes
The purpose of the study is to demonstrate that it is possible to administer chemotherapy
      prior to and following surgery for pancreatic cancer which is considered operable. The
      chemotherapy chosen is that which has been shown to be the most effective in treating
      metastatic disease, and the goal is both to investigate whether this is tolerable and also to
      investigate the efficacy of this approach in terms of disease response and survival.
Pancreatic ductal adenocarcinoma is a highly lethal disease. It is estimated that in 2010
      there were approximately 43,140 new cases in the United States and 36,800 deaths which ranks
      fourth among cancer related deaths . At diagnosis, roughly 17,000 of the initial 43,000
      patients have disease which appears to be localized to the pancreatic bed, but unfortunately,
      only a minority of these patients (15-20%) are immediately operable (on imaging studies their
      disease appears to be both localized to the pancreas and technically resectable with clear
      margins, and at surgery no unexpected findings preclude an R0 resection ). It should be noted
      that of those patients deemed immediately operable on clinical grounds, between 20 and 57%
      are found to have inoperable disease on exploration depending on the series and on the extent
      and nature of preoperative staging. The majority of patients have locally advanced,
      borderline resectable or unresectable disease owing to involvement of critical structures,
      most particularly sentinel blood vessels such as the SMA, celiac axis, hepatic artery, SMV,
      or portal vein. Furthermore, despite recent advances in systemic therapy, even those
      fortunate few able to undergo immediate surgery remain largely incurable, with a five year
      survival of slightly less than 20%.

      The current standard of care for adjuvant therapy in resectable pancreatic cancer is based on
      the CONKO-001 study which randomized patients to 6 cycles of postoperative adjuvant therapy
      with gemcitabine versus observation alone. Results favored adjuvant gemcitabine in both
      disease free survival (13.4 vs 6.9 months, p<0.001) and overall survival (24.2 months vs 20.5
      months p=0.02) strongly supporting the use of adjuvant gemcitabine in the setting of both R0
      and R1 resections. An RTOG study - 97-04 - concluded that gemcitabine was probably superior
      to 5FU when used pre and postoperatively in combination with 5FU/RT, with a HR of 0.82. The
      role of radiation therapy in this setting remains controversial, with studies such as the
      GITSG trial (pro) and ESPAC 1 (con) criticized either for questionable design, outdated
      chemotherapy or unconventional radiation therapy. Current studies in progress examining
      postoperative therapy include RTOG 0848 (phase III looking at adjuvant gemcitabine versus
      gemcitabine plus erlotinib plus/minus chemo/RT using fluorouracil), ACOSOG Z5041 evaluating
      gemcitabine plus erlotinib in the pre and postoperative setting and ESPAC 4 evaluating
      gemcitabine versus gemcitabine plus capecitabine.

      Many studies have explored the use of neoadjuvant therapy in initially resectable, borderline
      resectable and unresectable disease. The majority of these have been single arm, single
      institution phase I/II studies, and results have been mixed. Potential benefits of a
      neoadjuvant approach include: downstaging of disease with an increased percentage of margin
      negative and lymph node negative resections; no delay in systemic therapy aimed at
      eradicating micrometastatic disease; the detection of biologically aggressive tumors, as
      evidenced by early progression/metastases during this phase of therapy, thereby avoiding
      inappropriate surgery; and the greater likelihood of completing all intended therapy as
      opposed to postoperative treatment, where fully 22 - 35% of patients do not complete their
      intended program.

      A comprehensive meta-analysis and systematic review of neoadjuvant therapy in both resectable
      and unresectable pancreatic cancer has recently been published. The conclusion reached in
      resectable patients was that resection frequency and survival following neoadjuvant therapy
      was similar to that in patients undergoing primary resection followed by adjuvant therapy. In
      patients with initially unresectable disease, fully one third had resectable tumors following
      neoadjuvant therapy with survival comparable to initially resectable patients. In aggregate,
      these observations indicate that a neoadjuvant approach is feasible and effective, and that
      this sequence does not compromise resectability or survival, even in those patients with the
      best prognosis.

      With respect to specific studies in resectable disease, investigators at MD Anderson Cancer
      Center have published their most recent results. In their first study, 86 patients with
      resectable disease in the head of the pancreas received radiation therapy (30 Gy in 10
      fractions over 2 weeks) plus 7 weekly infusions of gemcitabine at 400 mg/m2/week. 85% of
      these patients were taken to surgery and 74% were able to undergo the intended
      pancreaticoduodenectomy. Median survival for patients whose disease was resected was 34
      months, but it was only 7 months for those whose disease could not be resected. In a second
      study of patients with resectable adenocarcinoma of the pancreatic head, 90 patients were
      enrolled with the goal of administering chemotherapy alone for eight weeks, using gemcitabine
      and cisplatin, followed by combined low dose gemcitabine and radiation therapy (30 Gy in 10
      fractions). Ultimately, 79 (88%) patients completed the full course of preoperative therapy
      and 62 of these (78%) patients were taken to surgery. 52 (66%) had their disease resected
      with a median survival of 31 months for those who had surgery, versus 10.5 months for those
      who did not. They concluded that initial combination chemotherapy with gemcitabine and
      cisplatin followed by chemotherapy/RT did not improve on the results achieved with
      chemotherapy/RT alone. This result is perhaps not surprising as gemcitabine, both alone and
      in doublet combinations, has simply not been active enough to materially impact on the
      outcome of this disease. Interestingly, the longer preoperative interval did not result in
      local tumor progression.

      These findings are similar to those of other major centers reporting studies of neoadjuvant
      gemcitabine based chemoradiation for potentially resectable disease, and suggest that this is
      a valid strategy for further study in this setting.

      Recently, investigators in Europe reported their results with a novel combination of
      docetaxel 30 mg/m2 weekly and RT of 45 Gy in 34 patients with resectable disease. 32% had
      progression, 59% stable disease and 9% partial remission. 50% of the original cohort had
      pancreaticoduodenectomy with 100% R0 resection and a median survival of 32 months. The
      numbers are small and the overall resection rate disappointingly low, but the R0 resection
      rate and median survival for those resected is equivalent to patients receiving gemcitabine
      based regimens.

      In locally advanced, unresectable disease, results have recently been reported from Austria
      with neoadjuvant gemcitabine/oxaliplatin without RT (39% of patients undergoing resection of
      disease with 69% R0 and 22 months median survival), Italy with neoadjuvant PEFG/PEXG
      (cisplatin, epirubicin, 5-fluorouracil (F)/capecitabine (X), gemcitabine) or PDXG (docetaxel
      substituting for epirubicin) followed by RT plus X, F or G (14% resected with median survival
      16.2 months)and Japan with neoadjuvant gemcitabine 1000 mg/m2/wk and RT 50 Gy in T3 disease
      followed by postoperative 5FU liver perfusion (82% of patients with disease resected, 43% 5
      year survival). In each of these studies, there is a mixture of borderline resectable and
      unresectable disease with the result that the interpretation of outcomes is problematic.
      However, it is clear that a neoadjuvant approach is feasible and active.

      It is clear from an examination of the NCI CTEP database that the neoadjuvant approach has
      been widely embraced for future study. More than 40 active protocols are listed, including
      the following select few: a UVA study of hypofractionated RT plus chronomodulated
      capecitabine in resectable and borderline resectable disease; a UT Southwestern phase I study
      of SBRT or SBRT plus gemcitabine; an Emory phase I study of FOLFIRINOX and SBRT; a Fred
      Hutchinson study of GTX and oxaliplatin with IMRT and adjuvant gemcitabine; a UF phase II
      study of risk adapted gemcitabine plus abraxane; a European randomized phase II study of
      gemcitabine plus oxaliplatin pre and gemcitabine postoperatively versus gemcitabine
      postoperatively only; a Memorial Sloan Kettering phase II study of gemcitabine plus
      oxaliplatin preoperatively plus gemcitabine postoperatively; and an ACOSOG study of
      gemcitabine plus erlotinib pre and postoperatively.

      Looking to the future there have been a number of recent innovations in chemotherapy. In an
      ongoing effort to discover non-gemcitabine based chemotherapy for those who have progressed
      on gemcitabine, and also a new regimen with more efficacy than those currently used in
      patients with pancreatic cancer, the combination of 5FU, leucovorin, oxaliplatin and
      irinotecan has been tested. This combination was initially studied in colorectal cancer, in a
      regimen known as FOLFOXIRI. It was established that this combination was both tolerable and
      effective in this setting. Subsequently, the regimen was modified slightly to the current
      FOLFIRINOX format (oxaliplatin 85mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2 , 5FU 400
      mg/m2 on day 1, then 5FU 2400 mg/m2 as a 46 hour continuous infusion) and tested in a phase
      II study in pancreatic cancer. 47 chemotherapy-naïve patients with metastatic disease were
      enrolled and 46 were treated. Confirmed response rate was 26% with 4% complete responses.
      Median time to progression was 8.2 months and median overall survival was 10.2 months. Grade
      3/4 toxicities included neutropenia (52%), nausea (20%), vomiting (17%), diarrhea (15%), and
      neuropathy (15%). No toxic death occurred. FOLFIRINOX was then tested after failure of
      previous gemcitabine therapy in metastatic disease and was deemed to be promising. 13
      patients were treated, with 9 evaluable for response - 6 had stable disease with a mean time
      to progression of 6.6 months, and 3 progressed.

      As a consequence of the previously mentioned phase II study in chemo-naïve patients, a
      randomized phase II/phase III study comparing gemcitabine (G) to FOLFIRINOX (F) as first line
      treatment of metastatic pancreatic cancer was conducted. This study was terminated
      prematurely by the study IDMC as it was determined that additional patient accrual would not
      add to the statistical power of the study. 342 patients were accrued with roughly one third
      of the primary disease involving the head of the pancreas. Overall objective response rate
      was 32% for F versus 9.4% for G. PFS was 6.4 months versus 3.4 months and overall survival
      11.1 months versus 6.8 months, all in favor of F.

      The overall survival rate of 11.1 months is the best result achieved thus far in a randomized
      phase III study of chemotherapy in metastatic pancreatic cancer. Notable toxicities of at
      least grade III/IV, which were all worse with F, were neutropenia (45.7 vs 18.7%), febrile
      neutropenia (5.4 vs 0.6%), fatigue (23.7 vs 14.2%), vomiting (14.5 vs 4.7%) and diarrhea
      (12.7 vs 1.2%). These results indicate that this is a notably active regimen with an
      encouraging response rate. However, the potential toxicities are significant, and it is a
      regimen that should be offered only to patients with ECOG 0-1 performance status and
      excellent supportive care. In this regard, in an attempt to ameliorate these toxicities,
      modifications to the published regimen have already been proposed by the French group and
      others. In their forthcoming study of FOLFIRINOX in the adjuvant setting, the French will
      omit the bolus of 5FU which contributes significantly to the myelosuppression but which is
      thought to have minimal impact on the therapeutic efficacy. In addition, most physicians now
      incorporate the routine use of neulasta with each treatment cycle. This study will similarly
      incorporate these modifications and the regimen will be named mFOLFIRINOX.

      Thus, in the context of perioperative therapy, we have identified a regimen - FOLFIRINOX -
      with the best results to date in the treatment of metastatic disease and by inference,
      promise of improved outcome in those patients with resectable disease. If successful, this
      has the potential to improve DFS and overall survival (until now no better than 15-20% at 5
      years) in these patients, and may establish a new paradigm for future studies.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage Able to Complete Full Course of Preoperative Chemotherapy
time frame: Following completion of all planned therapy, an expected average of 4 months
description: The percentage of participants able to complete the full course of preoperative chemotherapy and undergo a resection. This will be the primary determinant of success for this pilot study. - Early withdrawals due to toxicity, disease progression, or intercurrent illness will be considered failures.
measure: Percentage Able to Complete Full Course of Therapy
time frame: On completion of all planned therapy, an expected average of 8 months
description: The percentage of participants able to complete the full course of therapy, including preoperative chemotherapy, surgical resection and postoperative chemotherapy.
measure: Treatment Related Toxicity
time frame: 1 year
description: Treatment related toxicity and other adverse events (AEs) during Toxicity of preoperative and postoperative therapy and the safety of this approach.
measure: R0 Resection Rate
time frame: 3 months
description: Assessment of the percentage of patients able to have an R0 resection following preoperative chemotherapy.
measure: Progression-free and Overall Survival
time frame: 5 years
description: Assessment of progression-free survival and overall survival from the start of study treatment.
arm group label: FOLFIRINOX chemotherapy
arm group type: Experimental
description: 5FU 2400 mg/m2 IV over 48 hours Irinotecan 180 mg/m2 IV day 1 Oxaliplatin 85 mg/m2 IV day 1 Leucovorin 400 mg/m2 IV day 1
Cycles administered every 14 days for 4 cycles before and 4 cycles after surgery.
intervention type: Drug
intervention name: 5 Fluorouracil
description: 2400 mg/m2 by continuous intravenous infusion over 46 hours
arm group label: FOLFIRINOX chemotherapy
other name: Adrucil,5FU
intervention type: Drug
intervention name: Leucovorin
description: 400 mg/m2 by IV infusion over 2 hours
arm group label: FOLFIRINOX chemotherapy
other name: Folinic acid, Wellcovorin, citrovorum factor
intervention type: Drug
intervention name: Irinotecan
description: 180 mg/m² IV infusion on Day 1 over 90-120 minutes (infusion via a Y connector during the infusion of leucovorin)
arm group label: FOLFIRINOX chemotherapy
other name: camptosar, CPT11
intervention type: Drug
intervention name: Oxaliplatin
description: 85 mg/m² IV infusion on Day 1 over 2 hours
arm group label: FOLFIRINOX chemotherapy
other name: Eloxatin,
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: NorthShore University HealthSystem
investigator full name: Robert de W Marsh MD
investigator title: Section Chief Gastrointestinal Oncology, Clinical Professor University of Chicago
mesh term: Adenocarcinoma
mesh term: Leucovorin
mesh term: Fluorouracil
mesh term: Oxaliplatin
mesh term: Irinotecan
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 