<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/NCT04475159</url>
  </required_header>
  <id_info>
    <org_study_id>6881-20-SMC</org_study_id>
    <nct_id>NCT04475159</nct_id>
  </id_info>
  <brief_title>Combined Neoadjuvant Systemic and PIPAC Therapy (NASPIT) for Patients With Colorectal Peritoneal Metastasis Eligible for CRS and HIPEC: A Prospective Phase II Trial</brief_title>
  <official_title>Combined Neoadjuvant Systemic and PIPAC Therapy (NASPIT) for Patients With Colorectal Peritoneal Metastasis Eligible for CRS and HIPEC: A Prospective Phase II Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Prof. Aviram Nissan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sheba Medical Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug-delivery system&#xD;
      developed to deliver, effectively and safely, small doses of cytotoxic agents into peritoneal&#xD;
      tumor deposits. It is currently used for palliation and for down-staging of patients who are&#xD;
      non-eligible for cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy&#xD;
      (HIPEC).&#xD;
&#xD;
      The aim of this study is to evaluate the efficacy of PIPAC used in neoadjuvant setting to&#xD;
      enhance the response of patients with colorectal peritoneal metastasis when combined with&#xD;
      neoadjuvant systemic therapy for patients eligible to CRS/HIPEC prior to planned surgery.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open label, single arm, single center, phase II trial to study the added efficacy&#xD;
      benefit of PIPAC administered in the neoadjuvant setting in combination with systemic therapy&#xD;
      for patients eligible for CRS/HIPEC.&#xD;
&#xD;
      the following procedures will be done to all study population. Visit 0 (Week #0) screening -&#xD;
      Clinical evaluation and baseline cross-sectional imaging. Patients will be evaluated for&#xD;
      their eligibility and recruited if found suitable.&#xD;
&#xD;
      (Week #1) tumor board discussion to ensure eligibility and staging (Week #2-4) Initiation of&#xD;
      systemic therapy, if not been already started (2 cycles): Systemic therapy will be&#xD;
      administered and tailored by the treating oncologist as per patient tolerability. If already&#xD;
      on chemotherapy at visit 0, patients will continue chemotherapy until first PIPAC.&#xD;
&#xD;
      Visit 1 (Week #4) first PIPAC: Diagnostic laparoscopy, staging, PCI evaluation and biopsies&#xD;
      will be taken as described earlier.&#xD;
&#xD;
      Systemic therapy (2 cycles, Week #4-8): Systemic therapy will be administered and tailored by&#xD;
      the treating oncologist as per patient tolerability.&#xD;
&#xD;
      Visit 2 (Week #6) - post first PIPAC - Surgical Oncology Clinic: evaluation of PIPAC&#xD;
      tolerability and possible side effects or complications. Cross sectional imaging to monitor&#xD;
      progression prior to the upcoming second PIPAC.&#xD;
&#xD;
      Visit 3 (Week #8) - second PIPAC: Diagnostic laparoscopy, staging, PCI evaluation and&#xD;
      biopsies will be taken as described earlier.&#xD;
&#xD;
      Systemic therapy (2 cycles, Week #8-12): Systemic therapy will be administered and tailored&#xD;
      by the treating oncologist as per patient tolerability. Systemic therapy will be stopped at&#xD;
      week#12 (2-4 weeks) prior to planned CRS/HIPEC Visit 4 (Week #10) - post second PIPAC -&#xD;
      Surgical Oncology Clinic: evaluation of PIPAC tolerability, quality of life, and possible&#xD;
      side effects or complications after PIPAC.&#xD;
&#xD;
      Visit 5 (Week #12-14) - Surgical evaluation and cross-sectional imaging - Surgical Oncology&#xD;
      Clinic: Planning for upcoming CRS/HIPEC Visit 6 (Week #14-16) - CRS/HIPEC: proper PCI&#xD;
      evaluation, complete tumor cytoreduction and HIPEC will be targeted. The extent of surgery,&#xD;
      technical difficulties including OR time and blood loss will be documented.&#xD;
&#xD;
      Visit 7 follow up visit: will be conducted within 1 month after hospital discharge.&#xD;
      Tolerability and possible complications post-surgery will be evaluated.&#xD;
&#xD;
      Visit 8-11 follow up visits: Surgical Oncology Clinic evaluation: cross sectional imaging,&#xD;
      Tumor markers and clinical evaluation will be conducted for any signs of possible recurrence&#xD;
      on 3 monthly bases Visit 12-13 follow up: Surgical oncology clinic: cross sectional imaging,&#xD;
      Tumor markers and clinical evaluation will be conducted for any signs of possible recurrence&#xD;
      on 6 monthly bases. The follow up for the trial will be concluded at this stage (total of 3&#xD;
      years follow up).&#xD;
&#xD;
      To be noted that patient systemic chemotherapy would not be interrupted throughout the&#xD;
      treatment protocol and PIPAC therapy will be delivered in-between chemotherapy cycles.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">August 1, 2020</start_date>
  <completion_date type="Anticipated">August 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">August 1, 2022</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>Best Overall Response Rates (BORR)</measure>
    <time_frame>12 months after last patient recruitment</time_frame>
    <description>Clinically, at time of laparoscopic exploration, tumor burden and distribution will be assessed. Peritoneal cancer index (PCI) will be documented. Final evaluation of tumor burden, PCI and clinical response will be evaluated at time of CRS/HIPEC. Radiologically, a baseline abdominal computed tomography (CT) scan will be acquired &lt;4 weeks before the initiation of the treatment plan and will be repeated before CRS/HIPEC. Response will be evaluated by an independent radiologist as per RECIST criteria 1.1. Pathologically, biopsies from representative lesions will be taken. During the first procedure, before PIPAC delivery one sample from each abdominal quadrant and will be submitted to histopathology examination. Each biopsy site will be marked by a sliver clip for subsequent biopsies in the following PIPAC. Final pathological assessment will be done from specimens obtained at time of cytoreductive surgery .</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Recurrence free survival (RFS)</measure>
    <time_frame>3 years after the end of the trial</time_frame>
    <description>Recurrence free survival (RFS) will be calculated from the date of CRS/HIPEC to the date of documented disease recurrence. Events for the RFS endpoint include clinical, radiological (CT, PET), serological (CEA, CA-19-9, CA-125) and/or surgical exploration.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <condition>Peritoneal Carcinomatosis</condition>
  <condition>Colon Adenocarcinoma</condition>
  <arm_group>
    <arm_group_label>PIPAC arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Together with neoadjuvant systemic therpay PIPAC will be performed twice and regional chemotherpay will be administered before planned CRS/HIPEC</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)</intervention_name>
    <description>Pressurized Intraperitoneal Aerosol Chemotherapy will be delivered to the abdominal cavity by means of laparoscopy.</description>
    <arm_group_label>PIPAC arm</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of signed and dated informed consent form&#xD;
&#xD;
          2. Stated willingness to comply with all study procedures and availability for the&#xD;
             duration of the study and must be willing to return for follow-up&#xD;
&#xD;
          3. 18 years of age or older.&#xD;
&#xD;
          4. Biopsy (histopathology or cytology) diagnosis of colorectal cancer as defined by the&#xD;
             WHO or by cross-sectional imaging reviewed by a board-certified radiologist.&#xD;
&#xD;
          5. Good performance status (ECOG &lt; 2), Karnofski &gt;60.&#xD;
&#xD;
          6. Patients with low or acceptable surgical risk (American Society of Anesthesiology&#xD;
             (ASA) score of 3 or less.&#xD;
&#xD;
          7. Patient is a candidate for CRS and HIPEC as discussed and recommended by the&#xD;
             institutional disease management team (DMT, Tumor Board)&#xD;
&#xD;
          8. Patient receiving systemic chemotherapy for up to a maximum of 6 months from&#xD;
             peritoneal diagnosis management with stable or responsive disease are eligible for the&#xD;
             trial.&#xD;
&#xD;
          9. Absolute neutrophil count (ANC) exceeds 1200/mm3, white blood cell count exceeds&#xD;
             4000/mm3 and platelet count is greater than 100,000/mm3&#xD;
&#xD;
         10. An international normalized ratio (INR) ≤ 1.5 (patients who are therapeutically&#xD;
             anticoagulated for non-related medical conditions such as atrial fibrillation and&#xD;
             whose anti-thrombotic treatment can be withheld for operation will be eligible&#xD;
&#xD;
         11. Adequate hepatic function must be met as evidenced by total serum bilirubin ≤ 1.5&#xD;
             mg/dl (patients with total bilirubin &gt; 1.5 mg/dL eligible only with Gilbert's&#xD;
             syndrome); alkaline phosphatase &lt; 2.5 times the upper limit of normal; and, AST less&#xD;
             than 1.5 times upper limit of normal [alkaline phosphatase and AST cannot both exceed&#xD;
             the upper limit of normal&#xD;
&#xD;
         12. Serum renal functional parameters, BUN and creatinine are within normal limits&#xD;
&#xD;
         13. For females of reproductive potential: use of highly effective contraception for at&#xD;
             least 1 month prior to screening or with negative pregnancy test at screening.&#xD;
&#xD;
         14. Life expectancy of at least six months&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with unresectable (not eligible for CRS/HIPEC) tumors as decided by a&#xD;
             multidisciplinary disease management team&#xD;
&#xD;
          2. Patients that already received multiple cycles of systemic chemotherapy of more than 6&#xD;
             months and or show progression of disease on systemic therapy.&#xD;
&#xD;
          3. Patients with extraperitoneal disease.&#xD;
&#xD;
          4. Pregnancy or lactation&#xD;
&#xD;
          5. Patients with low performance status (ECOG &gt; 2 or Karnofski &lt; 60%)&#xD;
&#xD;
          6. Any one or more of the following hematological abnormalities&#xD;
&#xD;
          7. Hgb &lt; 8gm/dl unable to be corrected with transfusion&#xD;
&#xD;
          8. Absolute Neutrophil Count &lt; 1200/mm3&#xD;
&#xD;
          9. White blood cell count &lt; 4000/mm3&#xD;
&#xD;
         10. Platelet count &lt; 100,000/mm3&#xD;
&#xD;
         11. INR &gt; 1.5 (except in patients who are therapeutically AST anticoagulated for&#xD;
             non-related medical conditions such as atrial fibrillation and whose anti-thrombotic&#xD;
             treatment cannot be withheld for operation will be eligible)&#xD;
&#xD;
         12. History of hepatic cirrhosis or present hepatic dysfunction&#xD;
&#xD;
         13. Alkaline phosphatase ≥ 2.5 times the upper limit of normal&#xD;
&#xD;
         14. ≥ 1.5 times upper limit of normal&#xD;
&#xD;
         15. Serum bilirubin &gt; 1.5 mg/dl (except for patients with Gilbert's syndrome who must have&#xD;
             direct bilirubin ≤ 1.0 mg/dl)&#xD;
&#xD;
         16. Alkaline phosphatase and AST both exceed the upper limit of normal&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Gal Levi, M.Sc</last_name>
    <phone>972-3-5307595</phone>
    <email>gal.levi@sheba.gov.il</email>
  </overall_contact>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 14, 2020</study_first_submitted>
  <study_first_submitted_qc>July 14, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 17, 2020</study_first_posted>
  <last_update_submitted>July 14, 2020</last_update_submitted>
  <last_update_submitted_qc>July 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 17, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Sheba Medical Center</investigator_affiliation>
    <investigator_full_name>Prof. Aviram Nissan</investigator_full_name>
    <investigator_title>Proffesor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Peritoneal Neoplasms</mesh_term>
    <mesh_term>Colonic Neoplasms</mesh_term>
  </condition_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/NCT04475159
org study id: 6881-20-SMC
nct id: NCT04475159
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a novel drug-delivery system
      developed to deliver, effectively and safely, small doses of cytotoxic agents into peritoneal
      tumor deposits. It is currently used for palliation and for down-staging of patients who are
      non-eligible for cytoreductive surgery (CRS) and hyperthermic intra-peritoneal chemotherapy
      (HIPEC).

      The aim of this study is to evaluate the efficacy of PIPAC used in neoadjuvant setting to
      enhance the response of patients with colorectal peritoneal metastasis when combined with
      neoadjuvant systemic therapy for patients eligible to CRS/HIPEC prior to planned surgery.
This is an open label, single arm, single center, phase II trial to study the added efficacy
      benefit of PIPAC administered in the neoadjuvant setting in combination with systemic therapy
      for patients eligible for CRS/HIPEC.

      the following procedures will be done to all study population. Visit 0 (Week #0) screening -
      Clinical evaluation and baseline cross-sectional imaging. Patients will be evaluated for
      their eligibility and recruited if found suitable.

      (Week #1) tumor board discussion to ensure eligibility and staging (Week #2-4) Initiation of
      systemic therapy, if not been already started (2 cycles): Systemic therapy will be
      administered and tailored by the treating oncologist as per patient tolerability. If already
      on chemotherapy at visit 0, patients will continue chemotherapy until first PIPAC.

      Visit 1 (Week #4) first PIPAC: Diagnostic laparoscopy, staging, PCI evaluation and biopsies
      will be taken as described earlier.

      Systemic therapy (2 cycles, Week #4-8): Systemic therapy will be administered and tailored by
      the treating oncologist as per patient tolerability.

      Visit 2 (Week #6) - post first PIPAC - Surgical Oncology Clinic: evaluation of PIPAC
      tolerability and possible side effects or complications. Cross sectional imaging to monitor
      progression prior to the upcoming second PIPAC.

      Visit 3 (Week #8) - second PIPAC: Diagnostic laparoscopy, staging, PCI evaluation and
      biopsies will be taken as described earlier.

      Systemic therapy (2 cycles, Week #8-12): Systemic therapy will be administered and tailored
      by the treating oncologist as per patient tolerability. Systemic therapy will be stopped at
      week#12 (2-4 weeks) prior to planned CRS/HIPEC Visit 4 (Week #10) - post second PIPAC -
      Surgical Oncology Clinic: evaluation of PIPAC tolerability, quality of life, and possible
      side effects or complications after PIPAC.

      Visit 5 (Week #12-14) - Surgical evaluation and cross-sectional imaging - Surgical Oncology
      Clinic: Planning for upcoming CRS/HIPEC Visit 6 (Week #14-16) - CRS/HIPEC: proper PCI
      evaluation, complete tumor cytoreduction and HIPEC will be targeted. The extent of surgery,
      technical difficulties including OR time and blood loss will be documented.

      Visit 7 follow up visit: will be conducted within 1 month after hospital discharge.
      Tolerability and possible complications post-surgery will be evaluated.

      Visit 8-11 follow up visits: Surgical Oncology Clinic evaluation: cross sectional imaging,
      Tumor markers and clinical evaluation will be conducted for any signs of possible recurrence
      on 3 monthly bases Visit 12-13 follow up: Surgical oncology clinic: cross sectional imaging,
      Tumor markers and clinical evaluation will be conducted for any signs of possible recurrence
      on 6 monthly bases. The follow up for the trial will be concluded at this stage (total of 3
      years follow up).

      To be noted that patient systemic chemotherapy would not be interrupted throughout the
      treatment protocol and PIPAC therapy will be delivered in-between chemotherapy cycles.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Best Overall Response Rates (BORR)
time frame: 12 months after last patient recruitment
description: Clinically, at time of laparoscopic exploration, tumor burden and distribution will be assessed. Peritoneal cancer index (PCI) will be documented. Final evaluation of tumor burden, PCI and clinical response will be evaluated at time of CRS/HIPEC. Radiologically, a baseline abdominal computed tomography (CT) scan will be acquired <4 weeks before the initiation of the treatment plan and will be repeated before CRS/HIPEC. Response will be evaluated by an independent radiologist as per RECIST criteria 1.1. Pathologically, biopsies from representative lesions will be taken. During the first procedure, before PIPAC delivery one sample from each abdominal quadrant and will be submitted to histopathology examination. Each biopsy site will be marked by a sliver clip for subsequent biopsies in the following PIPAC. Final pathological assessment will be done from specimens obtained at time of cytoreductive surgery .
measure: Recurrence free survival (RFS)
time frame: 3 years after the end of the trial
description: Recurrence free survival (RFS) will be calculated from the date of CRS/HIPEC to the date of documented disease recurrence. Events for the RFS endpoint include clinical, radiological (CT, PET), serological (CEA, CA-19-9, CA-125) and/or surgical exploration.
arm group label: PIPAC arm
arm group type: Experimental
description: Together with neoadjuvant systemic therpay PIPAC will be performed twice and regional chemotherpay will be administered before planned CRS/HIPEC
intervention type: Procedure
intervention name: Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC)
description: Pressurized Intraperitoneal Aerosol Chemotherapy will be delivered to the abdominal cavity by means of laparoscopy.
arm group label: PIPAC arm
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Gal Levi, M.Sc
phone: 972-3-5307595
email: gal.levi@sheba.gov.il
responsible party type: Sponsor-Investigator
investigator affiliation: Sheba Medical Center
investigator full name: Prof. Aviram Nissan
investigator title: Proffesor
mesh term: Carcinoma
mesh term: Peritoneal Neoplasms
mesh term: Colonic Neoplasms