<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/NCT03299660</url>
  </required_header>
  <id_info>
    <org_study_id>AveRec</org_study_id>
    <nct_id>NCT03299660</nct_id>
  </id_info>
  <brief_title>Avelumab With Chemoradiation in Locally Advanced Rectal Cancer</brief_title>
  <official_title>Phase II Trial PD-L1/PD-1 Blockade Avelumab (MSB0010718C) With Chemoradiotherapy for Locally Advanced Resectable Rectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Peter MacCallum Cancer Centre, Australia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Peter MacCallum Cancer Centre, Australia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This trial is investigating the inclusion of avelumab post long-course chemo-radiotherapy in&#xD;
      patients with resectable locally advanced rectal cancer. It is hypothesised that this may&#xD;
      enhance the pathological and imaging response rates whilst potentially reducing the relapse&#xD;
      rates. Participants will receive standard long course chemoradiotherapy (LCCRT) treatment&#xD;
      with radiotherapy and 5-fluorouracil (5 FU)/Capecitabine for 6 weeks, this then followed by 4&#xD;
      cycles of Avelumab and then surgical resection. The trial will measure disease response just&#xD;
      prior to surgery and participants will be followed up for a minimum of 18 months (from study&#xD;
      entry) and up to 42 months.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 30, 2018</start_date>
  <completion_date type="Actual">February 28, 2023</completion_date>
  <primary_completion_date type="Actual">February 28, 2023</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>
    <intervention_model_description>All participants will receive standard LCCRT treatment followed by 4 cycles of Avelumab followed by surgical resection</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pathological Response rate</measure>
    <time_frame>At time of resection i.e.16 -18 weeks post commencement of treatment</time_frame>
    <description>To investigate the role of PD-L1 blockade for rectal cancer following neoadjuvant LCCRT, prior to definitive surgical resection, in terms pathological response rates. Assessed by tumour regression grade in resected rectal cancers post LCCRT at the time of definitive surgery: according to Ryan et al</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response as per structural imaging</measure>
    <time_frame>At 8 weeks post LCCRT</time_frame>
    <description>Describe radiological response rate based on Pelvic MRI post PD-L1 blockade as per RECIST 1.1</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall FDG PET response</measure>
    <time_frame>At 8 weeks post LCCRT</time_frame>
    <description>Describe FDG-PET response rate post PDL1 blockade as per PERCIST</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Define toxicity during administration of PDL1 inhibitor and post-surgery</measure>
    <time_frame>From consent until 4 weeks post surgery</time_frame>
    <description>Worst grade AE's and SAE's CTCAE version 4.03</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determine rate of downstaging</measure>
    <time_frame>At time of surgical resection</time_frame>
    <description>Patients will be considered downstaged if the pathologic T or N stage at surgery assessment is lower than the initial radiological stage.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">37</enrollment>
  <condition>Rectal Cancer</condition>
  <arm_group>
    <arm_group_label>Avelumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Long course chemoradiotherapy (LCCRT) comprised of 50.4 Gy radiotherapy in conjunction with 5FU (225mg/m2/day continuous infusion)/Capecitabine (825 mg/m2 BID on RT days) over 5. 5 weeks, followed by 4 cycles of Avelumab. This is then followed up with surgical resection</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Avelumab</intervention_name>
    <description>Avelumab 10 mg/Kg every 2 weeks for 4 cycles post LCCRT</description>
    <arm_group_label>Avelumab</arm_group_label>
    <other_name>MSB0010718C</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>5 Fluorouracil</intervention_name>
    <description>5FU continuous infusion 225mg/m2/day during radiotherapy</description>
    <arm_group_label>Avelumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Capecitabine Pill</intervention_name>
    <description>Can be administered in place of 5FU infusion. Dose = 825 mg/m2 twice a day on each day of radiotherapy</description>
    <arm_group_label>Avelumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Radiation</intervention_type>
    <intervention_name>Radiotherapy</intervention_name>
    <description>50.4 Gy in 28 fractions delivered over 5.5 weeks as 5 fractions/week</description>
    <arm_group_label>Avelumab</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Surgical Resection</intervention_name>
    <description>Surgical resection of tumour mass post radiotherapy and chemotherapy</description>
    <arm_group_label>Avelumab</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female aged ≥ 18 years at screening&#xD;
&#xD;
          2. Patients with histologically confirmed rectal adenocarcinoma clinical stage&#xD;
             T3bN1-N2M0, T3c/dN0-N2M0, T4N0-N2M0 (see Appendix 1),1 as defined by pelvic MRI&#xD;
&#xD;
          3. Planned to receive neoadjuvant long course chemoradiotherapy (50.4 Gy, with infusional&#xD;
             5FU or capecitabine) followed by curative total mesorectal excision plus&#xD;
             abdomino-perineal resection or anterior resection&#xD;
&#xD;
          4. Lower border of tumour must be within 12 cm from anal verge&#xD;
&#xD;
          5. Measurable disease by RECIST1.12&#xD;
&#xD;
          6. ECOG Performance Status 0-1&#xD;
&#xD;
          7. Patients must be willing to provide fresh (where possible) and archival tumour tissue&#xD;
             samples for translational studies at specified time points&#xD;
&#xD;
          8. Adequate organ function&#xD;
&#xD;
               1. Absolute neutrophil count ≥1.5 x 109/L&#xD;
&#xD;
               2. Platelet count ≥100 x 109/L&#xD;
&#xD;
               3. Haemoglobin ≥ 90 g/L (may have been transfused)&#xD;
&#xD;
               4. Creatinine ≤ 1.5 x upper normal limit OR measured creatinine clearance ≥ 50&#xD;
                  mL/minute&#xD;
&#xD;
               5. Total bilirubin ≤ 1.5 x upper normal limit&#xD;
&#xD;
               6. AST/ALT ≤ 2.5 x upper normal limit&#xD;
&#xD;
          9. Female patients of childbearing potential must have a negative urine or serum&#xD;
             pregnancy test at screening&#xD;
&#xD;
         10. Both male and female patients should be willing to use highly effective contraception&#xD;
             (that is, methods with a failure rate of less than 1% per year) if the risk of&#xD;
             conception exists&#xD;
&#xD;
         11. Has provided written informed consent for the trial&#xD;
&#xD;
         12. Agrees to comply with trial therapy or trial-related investigations and evaluations&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients with disease outside the pelvis&#xD;
&#xD;
          2. Prior pelvic radiotherapy&#xD;
&#xD;
          3. Participation in another interventional clinical trial within 30 days of registration&#xD;
             (participation in observational studies are permitted)&#xD;
&#xD;
          4. Concurrent anti-cancer treatment&#xD;
&#xD;
          5. Concurrent treatment with a non-permitted drug (Section 8.3.2)&#xD;
&#xD;
          6. Major surgery for any reason within 4 weeks of registration (except defunctioning&#xD;
             stoma creation with the patient having fully recovered from this procedure)&#xD;
&#xD;
          7. Current use of immunosuppressive medication. Except for the following: (a) intranasal,&#xD;
             inhaled, topical steroids, or local steroid injection (e.g., intra-articular&#xD;
             injection); (b). Systemic corticosteroids at physiologic doses ≤ 10 mg/day of&#xD;
             prednisone or equivalent; (c). Steroids as premedication for hypersensitivity&#xD;
             reactions (e.g., CT scan premedication); (d) Short-term administration of systemic&#xD;
             steroids (that is, for allergic reactions or the management of irAEs) is allowed while&#xD;
             on study.&#xD;
&#xD;
             Note: Patients receiving bisphosphonate or denosumab are eligible&#xD;
&#xD;
          8. Active autoimmune disease that might deteriorate when receiving an immunostimulatory&#xD;
             agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid&#xD;
             diseases not requiring immunosuppressive treatment are eligible&#xD;
&#xD;
          9. Active or history of immunodeficiencies&#xD;
&#xD;
         10. Has received prior therapy with an anti-PD1, anti-PDL1, anti-PDL2 or anti-CTLA-4&#xD;
             agents&#xD;
&#xD;
         11. Has clinically significant (that is, active) cardiovascular disease: cerebral vascular&#xD;
             accident / stroke (&lt; 6 months prior to registration), myocardial infarction (&lt; 6&#xD;
             months prior to registration), unstable angina, congestive heart failure (New York&#xD;
             Heart Association Classification Class ≥ II), or serious cardiac arrhythmia requiring&#xD;
             medication.&#xD;
&#xD;
         12. Has an active infection requiring systemic therapy&#xD;
&#xD;
         13. Other severe acute or chronic medical conditions including immune colitis,&#xD;
             inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric&#xD;
             conditions including recent (within the past year) or active suicidal ideation or&#xD;
             behaviour; or laboratory abnormalities that may increase the risk associated with&#xD;
             study participation or study treatment administration or may interfere with the&#xD;
             interpretation of study results and, in the judgment of the investigator, would make&#xD;
             the patient inappropriate for entry into this study&#xD;
&#xD;
         14. Prior malignancies within 3 years of registration (with the exception of non-&#xD;
             melanomatous skin cancer)&#xD;
&#xD;
         15. Prior organ transplantation, including allogeneic stem-cell transplantation&#xD;
&#xD;
         16. A known history of testing positive for HIV or known acquired immunodeficiency&#xD;
             syndrome (AIDS)&#xD;
&#xD;
         17. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive&#xD;
             HBV surface antigen or HCV RNA if anti-HCV antibody screening test is positive)&#xD;
&#xD;
         18. Known prior severe hypersensitivity to investigational product or any component in its&#xD;
             formulations, including known severe hypersensitivity reactions to monoclonal&#xD;
             antibodies (CTCAE v4.03 grade ≥ 3)&#xD;
&#xD;
         19. Is pregnant or lactating&#xD;
&#xD;
         20. Vaccination within 4 weeks of registration and while on trials is prohibited except&#xD;
             for administration of inactivated vaccines&#xD;
&#xD;
         21. Known deficiency of dihydropyrimidine dehydrogenase&#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>Michael Michael, A/Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Peter MacCallum Cancer Centre, Australia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Prince of Wales Hospital</name>
      <address>
        <city>Randwick</city>
        <state>New South Wales</state>
        <zip>2031</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Royal North Shore</name>
      <address>
        <city>St Leonards</city>
        <state>New South Wales</state>
        <zip>2065</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Box Hill Hospital</name>
      <address>
        <city>Box hill</city>
        <state>Victoria</state>
        <zip>3128</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cabrini Hospital</name>
      <address>
        <city>Malvern</city>
        <state>Victoria</state>
        <zip>3144</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peter MacCallum Cancer Centre</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3002</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Monash Health</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alfred Hospital</name>
      <address>
        <city>Prahran</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>September 24, 2017</study_first_submitted>
  <study_first_submitted_qc>October 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 3, 2017</study_first_posted>
  <last_update_submitted>March 14, 2023</last_update_submitted>
  <last_update_submitted_qc>March 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fluorouracil</mesh_term>
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Avelumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03299660
org study id: AveRec
nct id: NCT03299660
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This trial is investigating the inclusion of avelumab post long-course chemo-radiotherapy in
      patients with resectable locally advanced rectal cancer. It is hypothesised that this may
      enhance the pathological and imaging response rates whilst potentially reducing the relapse
      rates. Participants will receive standard long course chemoradiotherapy (LCCRT) treatment
      with radiotherapy and 5-fluorouracil (5 FU)/Capecitabine for 6 weeks, this then followed by 4
      cycles of Avelumab and then surgical resection. The trial will measure disease response just
      prior to surgery and participants will be followed up for a minimum of 18 months (from study
      entry) and up to 42 months.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: All participants will receive standard LCCRT treatment followed by 4 cycles of Avelumab followed by surgical resection
primary purpose: Treatment
masking: None (Open Label)
measure: Pathological Response rate
time frame: At time of resection i.e.16 -18 weeks post commencement of treatment
description: To investigate the role of PD-L1 blockade for rectal cancer following neoadjuvant LCCRT, prior to definitive surgical resection, in terms pathological response rates. Assessed by tumour regression grade in resected rectal cancers post LCCRT at the time of definitive surgery: according to Ryan et al
measure: Response as per structural imaging
time frame: At 8 weeks post LCCRT
description: Describe radiological response rate based on Pelvic MRI post PD-L1 blockade as per RECIST 1.1
measure: Overall FDG PET response
time frame: At 8 weeks post LCCRT
description: Describe FDG-PET response rate post PDL1 blockade as per PERCIST
measure: Define toxicity during administration of PDL1 inhibitor and post-surgery
time frame: From consent until 4 weeks post surgery
description: Worst grade AE's and SAE's CTCAE version 4.03
measure: Determine rate of downstaging
time frame: At time of surgical resection
description: Patients will be considered downstaged if the pathologic T or N stage at surgery assessment is lower than the initial radiological stage.
arm group label: Avelumab
arm group type: Experimental
description: Long course chemoradiotherapy (LCCRT) comprised of 50.4 Gy radiotherapy in conjunction with 5FU (225mg/m2/day continuous infusion)/Capecitabine (825 mg/m2 BID on RT days) over 5. 5 weeks, followed by 4 cycles of Avelumab. This is then followed up with surgical resection
intervention type: Drug
intervention name: Avelumab
description: Avelumab 10 mg/Kg every 2 weeks for 4 cycles post LCCRT
arm group label: Avelumab
other name: MSB0010718C
intervention type: Drug
intervention name: 5 Fluorouracil
description: 5FU continuous infusion 225mg/m2/day during radiotherapy
arm group label: Avelumab
intervention type: Drug
intervention name: Capecitabine Pill
description: Can be administered in place of 5FU infusion. Dose = 825 mg/m2 twice a day on each day of radiotherapy
arm group label: Avelumab
intervention type: Radiation
intervention name: Radiotherapy
description: 50.4 Gy in 28 fractions delivered over 5.5 weeks as 5 fractions/week
arm group label: Avelumab
intervention type: Procedure
intervention name: Surgical Resection
description: Surgical resection of tumour mass post radiotherapy and chemotherapy
arm group label: Avelumab
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Michael Michael, A/Prof
role: Principal Investigator
affiliation: Peter MacCallum Cancer Centre, Australia
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
responsible party type: Sponsor
mesh term: Rectal Neoplasms
mesh term: Fluorouracil
mesh term: Capecitabine
mesh term: Avelumab
sharing ipd: No