<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/NCT03010722</url>
  </required_header>
  <id_info>
    <org_study_id>4164</org_study_id>
    <nct_id>NCT03010722</nct_id>
  </id_info>
  <brief_title>Prospective Translational Study Investigating Molecular Predictors of Resistance and Response to Regorafenib Monotherapy</brief_title>
  <acronym>PROSPECT-R</acronym>
  <official_title>A Prospective Translational Study Investigating Molecular Predictors of Resistance and Response to Regorafenib Monotherapy in RAS Mutant Metastatic Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Royal Marsden NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bayer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Royal Marsden NHS Foundation Trust</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a single centre prospective biological translational research study involving the&#xD;
      collection of tumour tissue, blood samples and clinical data from patients being treated with&#xD;
      regorafenib for metastatic Colorectal Cancer (mCRC) at the Royal Marsden Hospital. Patients&#xD;
      will be eligible for the study if they have a histological diagnosis of CRC, are refractory&#xD;
      to standard available therapies with palliative intent for mCRC, have received prior&#xD;
      treatment with at least one anti-VEGF antibody and chemotherapy drugs including fluorouracil&#xD;
      (5FU) or capecitabine, oxaliplatin and irinotecan, and patients have RAS mutant tumours.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an exploratory translational research study to obtain research biopsies of RAS mutant&#xD;
      metastatic colorectal cancer (mCRC) tumour tissue prior to commencement of regorafenib&#xD;
      multi-tyrosine kinase inhibitor (MKI) treatment targeting vascular endothelial growth factor&#xD;
      receptor (VEGFR), tumour microenvironment and oncogenic driver alterations, and again at&#xD;
      development of resistance. Candidate markers of resistance will be identified in tissue&#xD;
      biopsies through genetic and other molecular analysis and parallel collection of serial blood&#xD;
      specimens will facilitate the identification of resistance markers and the tracking of&#xD;
      resistance evolution in circulating nucleic acids. Early dynamic contrast enhanced MRI&#xD;
      (DCE-MRI) along with diffusion weighted (DW)-MRI imaging at the beginning, and on day 15+/-7&#xD;
      post treatment will be performed. Additionally, dual contrast enhanced CT (DECT) will be&#xD;
      performed according to routine clinical evaluation time points before drug administration and&#xD;
      at 8 weeks after drug administration. Disease will be monitored with serial CT scans of the&#xD;
      chest abdomen and pelvis (CT-CAP) every eight weeks, until progression. The aim of the study&#xD;
      is to identify novel predictive biomarkers of resistance and response to this targeted&#xD;
      therapy in mCRC previously treated with oxaliplatin, fluoropyrimidines and irinotecan, using&#xD;
      genetic, epigenetic, transcriptomics, proteomic and live tissue culture methods. These&#xD;
      molecular analyses will be performed on metastatic tumour tissue samples taken firstly before&#xD;
      commencement of regorafenib, and secondly on progression of disease, and thirdly from&#xD;
      archival primary or metastatic tumour tissue. There is an additional biopsy at 8 weeks in&#xD;
      patients with response or stable disease, as determined by Response Evaluation Criteria in&#xD;
      Solid Tumours (RECIST) 1.1 criteria.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2015</start_date>
  <completion_date type="Actual">July 2017</completion_date>
  <primary_completion_date type="Actual">January 2017</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>disease control rate (DCR), measured in months</measure>
    <time_frame>12 months</time_frame>
    <description>DCR will be defined as complete response (CR)/partial response (PR)/ stable disease (SD) using RECIST v1.1. Chi2 or Fisher's exact tests will be employed to explore whether there is an association between low or high mutations and DCR. Logistic regression will be employed to produce odds ratios (ORs) and 95% confidence intervals (CIs).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>progression free survival (PFS), measured in months</measure>
    <time_frame>12 months</time_frame>
    <description>PFS will be measured from start of treatment to date of progression or death from any cause.Logistic regression will be employed to produce odds ratios (ORs) and 95% confidence intervals (CIs). The PFS will be estimated using the Kaplan-Meier method and survival curves will be generated for each group. The log-rank test will be used to compare the survival curves and a Cox proportional hazards model will be fitted to obtain hazard ratios (HRs) and 95% CIs. The proportional hazards assumption will be tested with the use of Schoenfeld residuals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>overall survival (OS), measured in months</measure>
    <time_frame>12 months</time_frame>
    <description>OS will be defined as time from start of treatment to death of any cause. Logistic regression will be employed to produce odds ratios (ORs) and 95% confidence intervals (CIs). The OS will be estimated using the Kaplan-Meier method and survival curves will be generated for each group. The log-rank test will be used to compare the survival curves and a Cox proportional hazards model will be fitted to obtain hazard ratios (HRs) and 95% CIs. The proportional hazards assumption will be tested with the use of Schoenfeld residuals</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Median values of volume transfer constant (Ktrans) and enhancing fraction (EF) and their product KEF (product of summarised median values of Ktrans x EF/100) will be compared at baseline and on day 15</measure>
    <time_frame>15 days</time_frame>
    <description>Dynamic contrast enhance magnetic resonance imaging (DCE-MRI) will be performed pre-treatment and at day 15. KEF changes of more than 70% between the two time points will be considered significant and patients will be thus stratified in two groups, i.e. A) drop in KEF of &gt;70% and B) less than 70% drop in KEF.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">49</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Regorafenib</arm_group_label>
    <description>160 mg orally (po) od for 3 weeks of every 4-week cycle&#xD;
All patients will be required to have pre-treatment dynamic contrast enhance computed tomography (DECT) scan pre-treatment and at 8 weeks. Suitable patients will also be required to have dynamic contrast enhanced magnetic resonance imaging (DEC-MRI) and diffusion weighted (DW)-MRI, pre-treatment and at 2 weeks. All patients will also be required to have an Ultrasound (USS) or CT-guided biopsy of suitable metastatic lesion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Regorafenib</intervention_name>
    <description>Patients meeting all of the inclusion criteria and none of the exclusion criteria will receive regorafenib 160 mg orally (po) od for 3 weeks of every 4-week cycle. Each cycle will comprise 3 weeks of treatment followed by 1 week without treatment, hereafter described as &quot;3 weeks on/1 week off&quot;. Each 160-mg dose will include four regorafenib 40-mg tablets.</description>
    <arm_group_label>Regorafenib</arm_group_label>
    <other_name>Stivarga</other_name>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Tissue and plasma samples will be retained for a maximum period of 20 years, according to UK&#xD;
      regulatory approval policy and study protocol.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients will be selected from the clinics and multi-disciplinary meetings, so long that&#xD;
        they meet all the inclusion criteria and no exclusion criteria.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients with RAS mutant (MT) metastatic colorectal cancer (mCRC) who have been at&#xD;
             least once treated with available therapies including fluoropyrimidine-based&#xD;
             chemotherapy, oxaliplatin, irinotecan and an anti-angiogenic agent, except for&#xD;
             patients who have not been treated with oxaliplatin due to previous documented&#xD;
             peripheral neuropathy in an adjuvant setting or in those patients where disease has&#xD;
             progressed within a short time from receiving adjuvant treatment (&lt;12 months).&#xD;
&#xD;
          2. Eligible to receive regorafenib within the context of PROSPECT-R trial at the Royal&#xD;
             Marsden Hospital&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
        A patient who meets any of the exclusion criteria will NOT be eligible for randomization.&#xD;
&#xD;
        A patient must NOT&#xD;
&#xD;
          1. have had prior treatment with regorafenib or any other VEGF-targeting kinase inhibitor&#xD;
&#xD;
          2. have had previous or concurrent cancer that is distinct in primary site or histology&#xD;
             from colorectal cancer within 5 years prior to randomization EXCEPT for curatively&#xD;
             treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder&#xD;
             tumors [Ta (Noninvasive tumor), Tis (Carcinoma in situ) and T1 (Tumor invades lamina&#xD;
             propria)].&#xD;
&#xD;
          3. Patients that are participating in another clinical trial involving an investigational&#xD;
             medicinal product, unless it is more than 14 days after they have ceased the&#xD;
             investigational medicinal product&#xD;
&#xD;
          4. Patients that are participating in another research study involving tumour tissue&#xD;
             biopsies planned to take place during the time that the patient is participating in&#xD;
             this study&#xD;
&#xD;
          5. Have had a major surgical procedure, open biopsy, or significant traumatic injury&#xD;
             within 28 days prior to initiation of study treatment&#xD;
&#xD;
          6. If female and of childbearing potential, be engaged in breast feeding&#xD;
&#xD;
          7. Be unable to swallow oral tablets (crushing of study treatment tablets is not allowed)&#xD;
&#xD;
          8. Arterial or venous thrombotic or embolic events such as cerebrovascular accident&#xD;
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism&#xD;
             within 6 month before the start of study medication (except for adequately treated&#xD;
             catheter-related venous thrombosis occurring more than one month before the start of&#xD;
             study medication)&#xD;
&#xD;
          9. Interstitial lung disease with ongoing signs and symptoms at the time of informed&#xD;
             consent.&#xD;
&#xD;
         10. Ongoing infection &gt; Grade 2 NCI Common Toxicity Criterial for Adverse Effects (CTCAE).&#xD;
&#xD;
         11. Uncontrolled hypertension (Systolic blood pressure &gt; 140 mmHg or diastolic pressure &gt;&#xD;
             90 mmHg) despite optimal medical management&#xD;
&#xD;
         12. Have congestive heart failure classified as New York Heart Association Class 2 or&#xD;
             higher&#xD;
&#xD;
         13. Have had unstable angina (angina symptoms at rest) or new-onset angina &lt; 3 months&#xD;
             prior to screening&#xD;
&#xD;
         14. Have had a myocardial infarction &lt; 6 months prior to initiation of study treatment&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>The Royal Marsden NHS Foundation Trust London and Surrey</name>
      <address>
        <city>Carshalton</city>
        <state>Surrey</state>
        <zip>SM2 5PT</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>January 6, 2015</study_first_submitted>
  <study_first_submitted_qc>January 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 5, 2017</study_first_posted>
  <last_update_submitted>April 30, 2021</last_update_submitted>
  <last_update_submitted_qc>April 30, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 3, 2021</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>Colorectal 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/NCT03010722
org study id: 4164
nct id: NCT03010722
lead sponsor: 
collaborator: 
has dmc: Yes
This is a single centre prospective biological translational research study involving the
      collection of tumour tissue, blood samples and clinical data from patients being treated with
      regorafenib for metastatic Colorectal Cancer (mCRC) at the Royal Marsden Hospital. Patients
      will be eligible for the study if they have a histological diagnosis of CRC, are refractory
      to standard available therapies with palliative intent for mCRC, have received prior
      treatment with at least one anti-VEGF antibody and chemotherapy drugs including fluorouracil
      (5FU) or capecitabine, oxaliplatin and irinotecan, and patients have RAS mutant tumours.
This is an exploratory translational research study to obtain research biopsies of RAS mutant
      metastatic colorectal cancer (mCRC) tumour tissue prior to commencement of regorafenib
      multi-tyrosine kinase inhibitor (MKI) treatment targeting vascular endothelial growth factor
      receptor (VEGFR), tumour microenvironment and oncogenic driver alterations, and again at
      development of resistance. Candidate markers of resistance will be identified in tissue
      biopsies through genetic and other molecular analysis and parallel collection of serial blood
      specimens will facilitate the identification of resistance markers and the tracking of
      resistance evolution in circulating nucleic acids. Early dynamic contrast enhanced MRI
      (DCE-MRI) along with diffusion weighted (DW)-MRI imaging at the beginning, and on day 15+/-7
      post treatment will be performed. Additionally, dual contrast enhanced CT (DECT) will be
      performed according to routine clinical evaluation time points before drug administration and
      at 8 weeks after drug administration. Disease will be monitored with serial CT scans of the
      chest abdomen and pelvis (CT-CAP) every eight weeks, until progression. The aim of the study
      is to identify novel predictive biomarkers of resistance and response to this targeted
      therapy in mCRC previously treated with oxaliplatin, fluoropyrimidines and irinotecan, using
      genetic, epigenetic, transcriptomics, proteomic and live tissue culture methods. These
      molecular analyses will be performed on metastatic tumour tissue samples taken firstly before
      commencement of regorafenib, and secondly on progression of disease, and thirdly from
      archival primary or metastatic tumour tissue. There is an additional biopsy at 8 weeks in
      patients with response or stable disease, as determined by Response Evaluation Criteria in
      Solid Tumours (RECIST) 1.1 criteria.
observational model: Cohort
time perspective: Prospective
measure: disease control rate (DCR), measured in months
time frame: 12 months
description: DCR will be defined as complete response (CR)/partial response (PR)/ stable disease (SD) using RECIST v1.1. Chi2 or Fisher's exact tests will be employed to explore whether there is an association between low or high mutations and DCR. Logistic regression will be employed to produce odds ratios (ORs) and 95% confidence intervals (CIs).
measure: progression free survival (PFS), measured in months
time frame: 12 months
description: PFS will be measured from start of treatment to date of progression or death from any cause.Logistic regression will be employed to produce odds ratios (ORs) and 95% confidence intervals (CIs). The PFS will be estimated using the Kaplan-Meier method and survival curves will be generated for each group. The log-rank test will be used to compare the survival curves and a Cox proportional hazards model will be fitted to obtain hazard ratios (HRs) and 95% CIs. The proportional hazards assumption will be tested with the use of Schoenfeld residuals
measure: overall survival (OS), measured in months
time frame: 12 months
description: OS will be defined as time from start of treatment to death of any cause. Logistic regression will be employed to produce odds ratios (ORs) and 95% confidence intervals (CIs). The OS will be estimated using the Kaplan-Meier method and survival curves will be generated for each group. The log-rank test will be used to compare the survival curves and a Cox proportional hazards model will be fitted to obtain hazard ratios (HRs) and 95% CIs. The proportional hazards assumption will be tested with the use of Schoenfeld residuals
measure: Median values of volume transfer constant (Ktrans) and enhancing fraction (EF) and their product KEF (product of summarised median values of Ktrans x EF/100) will be compared at baseline and on day 15
time frame: 15 days
description: Dynamic contrast enhance magnetic resonance imaging (DCE-MRI) will be performed pre-treatment and at day 15. KEF changes of more than 70% between the two time points will be considered significant and patients will be thus stratified in two groups, i.e. A) drop in KEF of >70% and B) less than 70% drop in KEF.
arm group label: Regorafenib
description: 160 mg orally (po) od for 3 weeks of every 4-week cycle
All patients will be required to have pre-treatment dynamic contrast enhance computed tomography (DECT) scan pre-treatment and at 8 weeks. Suitable patients will also be required to have dynamic contrast enhanced magnetic resonance imaging (DEC-MRI) and diffusion weighted (DW)-MRI, pre-treatment and at 2 weeks. All patients will also be required to have an Ultrasound (USS) or CT-guided biopsy of suitable metastatic lesion.
intervention type: Drug
intervention name: Regorafenib
description: Patients meeting all of the inclusion criteria and none of the exclusion criteria will receive regorafenib 160 mg orally (po) od for 3 weeks of every 4-week cycle. Each cycle will comprise 3 weeks of treatment followed by 1 week without treatment, hereafter described as "3 weeks on/1 week off". Each 160-mg dose will include four regorafenib 40-mg tablets.
arm group label: Regorafenib
other name: Stivarga
Tissue and plasma samples will be retained for a maximum period of 20 years, according to UK
      regulatory approval policy and study protocol.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Colorectal Neoplasms