<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/NCT04504747</url>
  </required_header>
  <id_info>
    <org_study_id>NEO-R-IPC 2019-041</org_study_id>
    <nct_id>NCT04504747</nct_id>
  </id_info>
  <brief_title>Real Time Molecular Analysis of Breast Cancer Receiving Neo-adjuvant Chemotherapy</brief_title>
  <acronym>NEO-R</acronym>
  <official_title>Real Time Molecular Analysis of Breast Cancer Receiving Neo-adjuvant Chemotherapy: Identification of Preclinical Models Predictive for Therapeutic Resistance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut Paoli-Calmettes</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut Paoli-Calmettes</source>
  <oversight_info>
    <has_dmc>No</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>
      The present project aims at identifying robust candidates for drug resistance in BC patients&#xD;
      eligible for NAC. Its originality lies upon the combination of three different and&#xD;
      complementary prospective approaches: from the molecular analyses of biopsies sampled before&#xD;
      and after NAC, from in vitro BC Patient-Derived Organoids (PDO) mimicking patient's response&#xD;
      to NAC, and from Circulating Tumor Cells (CTCs) isolated before/during/after NAC.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Breast cancer (BC) is a major public health problem in France, with an increasing incidence,&#xD;
      estimated at ~60,000 new cases in 2017 and 12,000 deaths. Despite survival improvement in the&#xD;
      recent years, resistance to chemotherapy (CT) remains a paramount challenge in BC: the&#xD;
      molecular mechanisms remain poorly known and the current interventions are inadequate to&#xD;
      target chemoresistance. Neo-adjuvant chimiotherapy (NAC) is now used increasingly in women&#xD;
      with operable but aggressive BC such as triple-negative (TN) or HER2+ tumor (Pusztai et al,&#xD;
      Lancet Oncol 2019). It provides at least three advantages: i) tumor debulking authorizing&#xD;
      conservative surgery, ii) tailoring of adjuvant systemic therapy according to the&#xD;
      pathological response, with delivery of capecitabine in TN patients (Masuda N. et al, N Engl&#xD;
      J Med. 2017) and T-DM1 in HER2+ patients (von Minckwitz G et al., N Engl J Med. 2019) in the&#xD;
      absence of pathological complete response (pCR), and iii) providing resources for&#xD;
      investigating the molecular mechanisms of chemoresistance. The current standard NAC regimen&#xD;
      is based on a sequential association of anthracycline and taxane (and trastuzumab if HER2+)&#xD;
      (Huober &amp; von Minckwitz, Breast Care 2011), and the achievement of pCR, defined as the&#xD;
      absence of residual invasive cancer on pathological evaluation of the operative specimen&#xD;
      (resected breast specimen and sampled ipsilateral lymph nodes (i.e., ypT0/Tis ypN0 in the&#xD;
      AJCC staging system), is a good-prognosis feature; the patients without pCR being at high&#xD;
      relapse risk (≈50% of the TN and HER2+ subtypes).&#xD;
&#xD;
      The major bottleneck in improving treatment efficiency for these patients is the&#xD;
      identification of candidates effectively involved in the resistance to NAC, their validation&#xD;
      in relevant and predictive models, and their detection from surrogate markers. Of course, the&#xD;
      search for molecular alterations differentially represented in the pre-NAC samples between&#xD;
      the resistant (no pCR) versus sensitive (pCR) patients, or between the paired post- versus&#xD;
      pre-NAC samples may reveal candidates involved in resistance (&quot;innate&quot; and &quot;acquired stable&quot;&#xD;
      respectively), but ignores the alterations that occur during the NAC that may be reversible&#xD;
      (&quot;acquired reversible&quot;) and not identified in the resected specimen (Echeverria GV, Sci&#xD;
      Transl Med 2019), but only identifiable by analysis of serial samples during NAC regimen,&#xD;
      difficult and traumatic in clinical practice.&#xD;
&#xD;
      The present project aims at identifying robust candidates for drug resistance in BC patients&#xD;
      eligible for NAC. Its originality lies upon the combination of three different and&#xD;
      complementary prospective approaches: from the molecular analyses of biopsies sampled before&#xD;
      and after NAC, from in vitro BC Patient-Derived Organoids (PDO) mimicking patient's response&#xD;
      to NAC, and from Circulating Tumor Cells (CTCs) isolated before/during/after NAC. This&#xD;
      project will combine the most advanced technologies (RNA and DNA-sequencing from small amount&#xD;
      of biologic material, rare subsets/single-cell isolation, and multi-omics analyses) with&#xD;
      innovative models (drug testing on breast PDO, identification of reversible drug-induced&#xD;
      changes) and clever combination of robust markers involved in drug resistance that have all&#xD;
      been established and are running in the laboratory (cf Part B). The last two points have only&#xD;
      recently become feasible thanks to two recent technological advances: breast cancer PDO&#xD;
      cultures (Sachs N, et al. Cell. 2018) and CTCs isolation and characterization (Gkountela S,&#xD;
      et al. Cell. 2019). Briefly, the investigators will use serial tumor biopsies and blood&#xD;
      samples from a cohort of BC patients treated with NAC (Figure 1). Tumor biopsies will be&#xD;
      collected before and after NAC. They will be analyzed by RNA-seq and targeted-NGS (exome)&#xD;
      approaches to capture the differences resulting from NAC in patients with different&#xD;
      pathological response. They will also be used to generate BC PDO models. The PDO models&#xD;
      predictive for NAC response will be exploited as relevant models to investigate NAC&#xD;
      resistance. Specifically, investigators will use these models to look at in vitro &quot;acquired&#xD;
      reversible&quot; drug-induced resistance mechanisms (i.e only detectable during the drug&#xD;
      exposure). Blood samples will be collected before, during, and after NAC to analyze CTCs, and&#xD;
      aim at identifying &quot;acquired reversible&quot; drug-induced resistance mechanisms ex vivo, which&#xD;
      the investigators might fail to detect with the before/after NAC samples only.&#xD;
&#xD;
      To our knowledge, this is the first time that these three innovative approaches will be used&#xD;
      together to investigate in depth the topic of &quot;resistance&quot; in patients receiving NAC. The&#xD;
      strength of this combination is to anticipate different - not mutually exclusive - situations&#xD;
      that might occur (&quot;innate&quot;, &quot;acquired stable&quot; and/or &quot;reversible&quot; drug-induced resistance).&#xD;
      Each approach will provide original, precise and specific information that will contribute to&#xD;
      build a more complete answer to this question than the scattered and incomplete data&#xD;
      currently available in the literature.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">November 3, 2022</start_date>
  <completion_date type="Anticipated">January 2030</completion_date>
  <primary_completion_date type="Anticipated">January 2025</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>Identify robust candidates - &quot;innate, &quot;acquired stable&quot; and/or reversible&quot;</measure>
    <time_frame>5 years</time_frame>
    <description>comparison of pre and/or post NAC molecular profiles in tumors, PDO models and CTCs - will be targeted with a drug in relevant models</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>public repertoire of whole transcriptome and targeted-NGS</measure>
    <time_frame>5 years</time_frame>
    <description>NAC&quot; database will be constructed from well documented RNAseq and targeted-NGS profiles established from serial HER2+ and TN tumors before/after NAC treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identify molecular signatures associated with response to NAC</measure>
    <time_frame>5 years</time_frame>
    <description>Comparison of serial molecular profiles</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Establish PDO samples exposed to NAC</measure>
    <time_frame>5 years</time_frame>
    <description>Percentage of PDO exposed to NAC that will parallel the patient's clinical response to NAC</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of CTCs features</measure>
    <time_frame>5 years</time_frame>
    <description>phenotype, RNA-seq-based transcriptome</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">150</enrollment>
  <condition>Breast Cancer Female</condition>
  <arm_group>
    <arm_group_label>RH+</arm_group_label>
    <description>Prospective blood and biopsie analyses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HER2+</arm_group_label>
    <description>Prospective blood and biopsie analyses</description>
  </arm_group>
  <arm_group>
    <arm_group_label>TN</arm_group_label>
    <description>Prospective blood and biopsie analyses</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>molecular analysis of blood and tumor</intervention_name>
    <description>RNAseq, DNAseq, CTCs</description>
    <arm_group_label>HER2+</arm_group_label>
    <arm_group_label>RH+</arm_group_label>
    <arm_group_label>TN</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Bllod and tumor tissue&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Brest cancer females with a non metastatic cancer&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Woman over 18&#xD;
&#xD;
          2. Signed consent to participate&#xD;
&#xD;
          3. Invasive mammary adenocarcinoma proven histologically and / or cytologically&#xD;
&#xD;
          4. Indication of CNA retention by the referring clinical team.&#xD;
&#xD;
          5. No contraindication to CNA.&#xD;
&#xD;
          6. Selected indication of the post-CNA surgery sequence, then radiotherapy&#xD;
&#xD;
          7. Performance index ≤ 1 (WHO).&#xD;
&#xD;
          8. Affiliation to a social security scheme, or beneficiary of such a scheme&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Planned therapeutic sequence: CNA, followed by neoadjuvant radiotherapy (HIST-RIC&#xD;
             clinical trial for example) before surgery&#xD;
&#xD;
          2. Metastatic disease at diagnosis&#xD;
&#xD;
          3. Patient relapsed from breast cancer precede&#xD;
&#xD;
          4. Other malignant disease in the previous 3 years, with the exception of cervical&#xD;
             carcinoma in situ or skin basal cell carcinoma and any other cancerous pathology&#xD;
             considered to have been properly treated and at low risk of relapse.&#xD;
&#xD;
          5. Woman pregnant or likely to be (without effective contraception) or breastfeeding&#xD;
&#xD;
          6. Person in an emergency situation, adult person subject to a legal protection measure&#xD;
             (adult under guardianship, guardianship or legal protection), or unable to express&#xD;
             consent.&#xD;
&#xD;
          7. Inability to undergo medical monitoring of the trial for geographical, social or&#xD;
             psychological reasons&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>François BERTUCCI, Pr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut Paoli-Calmettes</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dominique GENRE, Dr</last_name>
    <phone>0491223778</phone>
    <email>drci.up@ipc.unicancer.fr</email>
  </overall_contact>
  <location>
    <facility>
      <name>Institut Paoli-Calmettes</name>
      <address>
        <city>Marseille</city>
        <zip>13009</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Dominique GENRE, Dr</last_name>
      <phone>0491223778</phone>
      <email>drci.up@ipc.unicancer.fr</email>
    </contact>
    <investigator>
      <last_name>François BERTUCCI, Pr</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>August 5, 2020</study_first_submitted>
  <study_first_submitted_qc>August 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2020</study_first_posted>
  <last_update_submitted>February 28, 2023</last_update_submitted>
  <last_update_submitted_qc>February 28, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 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>Breast Neoplasms</mesh_term>
  </condition_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/NCT04504747
org study id: NEO-R-IPC 2019-041
nct id: NCT04504747
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The present project aims at identifying robust candidates for drug resistance in BC patients
      eligible for NAC. Its originality lies upon the combination of three different and
      complementary prospective approaches: from the molecular analyses of biopsies sampled before
      and after NAC, from in vitro BC Patient-Derived Organoids (PDO) mimicking patient's response
      to NAC, and from Circulating Tumor Cells (CTCs) isolated before/during/after NAC.
Breast cancer (BC) is a major public health problem in France, with an increasing incidence,
      estimated at ~60,000 new cases in 2017 and 12,000 deaths. Despite survival improvement in the
      recent years, resistance to chemotherapy (CT) remains a paramount challenge in BC: the
      molecular mechanisms remain poorly known and the current interventions are inadequate to
      target chemoresistance. Neo-adjuvant chimiotherapy (NAC) is now used increasingly in women
      with operable but aggressive BC such as triple-negative (TN) or HER2+ tumor (Pusztai et al,
      Lancet Oncol 2019). It provides at least three advantages: i) tumor debulking authorizing
      conservative surgery, ii) tailoring of adjuvant systemic therapy according to the
      pathological response, with delivery of capecitabine in TN patients (Masuda N. et al, N Engl
      J Med. 2017) and T-DM1 in HER2+ patients (von Minckwitz G et al., N Engl J Med. 2019) in the
      absence of pathological complete response (pCR), and iii) providing resources for
      investigating the molecular mechanisms of chemoresistance. The current standard NAC regimen
      is based on a sequential association of anthracycline and taxane (and trastuzumab if HER2+)
      (Huober & von Minckwitz, Breast Care 2011), and the achievement of pCR, defined as the
      absence of residual invasive cancer on pathological evaluation of the operative specimen
      (resected breast specimen and sampled ipsilateral lymph nodes (i.e., ypT0/Tis ypN0 in the
      AJCC staging system), is a good-prognosis feature; the patients without pCR being at high
      relapse risk (≈50% of the TN and HER2+ subtypes).

      The major bottleneck in improving treatment efficiency for these patients is the
      identification of candidates effectively involved in the resistance to NAC, their validation
      in relevant and predictive models, and their detection from surrogate markers. Of course, the
      search for molecular alterations differentially represented in the pre-NAC samples between
      the resistant (no pCR) versus sensitive (pCR) patients, or between the paired post- versus
      pre-NAC samples may reveal candidates involved in resistance ("innate" and "acquired stable"
      respectively), but ignores the alterations that occur during the NAC that may be reversible
      ("acquired reversible") and not identified in the resected specimen (Echeverria GV, Sci
      Transl Med 2019), but only identifiable by analysis of serial samples during NAC regimen,
      difficult and traumatic in clinical practice.

      The present project aims at identifying robust candidates for drug resistance in BC patients
      eligible for NAC. Its originality lies upon the combination of three different and
      complementary prospective approaches: from the molecular analyses of biopsies sampled before
      and after NAC, from in vitro BC Patient-Derived Organoids (PDO) mimicking patient's response
      to NAC, and from Circulating Tumor Cells (CTCs) isolated before/during/after NAC. This
      project will combine the most advanced technologies (RNA and DNA-sequencing from small amount
      of biologic material, rare subsets/single-cell isolation, and multi-omics analyses) with
      innovative models (drug testing on breast PDO, identification of reversible drug-induced
      changes) and clever combination of robust markers involved in drug resistance that have all
      been established and are running in the laboratory (cf Part B). The last two points have only
      recently become feasible thanks to two recent technological advances: breast cancer PDO
      cultures (Sachs N, et al. Cell. 2018) and CTCs isolation and characterization (Gkountela S,
      et al. Cell. 2019). Briefly, the investigators will use serial tumor biopsies and blood
      samples from a cohort of BC patients treated with NAC (Figure 1). Tumor biopsies will be
      collected before and after NAC. They will be analyzed by RNA-seq and targeted-NGS (exome)
      approaches to capture the differences resulting from NAC in patients with different
      pathological response. They will also be used to generate BC PDO models. The PDO models
      predictive for NAC response will be exploited as relevant models to investigate NAC
      resistance. Specifically, investigators will use these models to look at in vitro "acquired
      reversible" drug-induced resistance mechanisms (i.e only detectable during the drug
      exposure). Blood samples will be collected before, during, and after NAC to analyze CTCs, and
      aim at identifying "acquired reversible" drug-induced resistance mechanisms ex vivo, which
      the investigators might fail to detect with the before/after NAC samples only.

      To our knowledge, this is the first time that these three innovative approaches will be used
      together to investigate in depth the topic of "resistance" in patients receiving NAC. The
      strength of this combination is to anticipate different - not mutually exclusive - situations
      that might occur ("innate", "acquired stable" and/or "reversible" drug-induced resistance).
      Each approach will provide original, precise and specific information that will contribute to
      build a more complete answer to this question than the scattered and incomplete data
      currently available in the literature.
observational model: Cohort
time perspective: Prospective
measure: Identify robust candidates - "innate, "acquired stable" and/or reversible"
time frame: 5 years
description: comparison of pre and/or post NAC molecular profiles in tumors, PDO models and CTCs - will be targeted with a drug in relevant models
measure: public repertoire of whole transcriptome and targeted-NGS
time frame: 5 years
description: NAC" database will be constructed from well documented RNAseq and targeted-NGS profiles established from serial HER2+ and TN tumors before/after NAC treatment
measure: Identify molecular signatures associated with response to NAC
time frame: 5 years
description: Comparison of serial molecular profiles
measure: Establish PDO samples exposed to NAC
time frame: 5 years
description: Percentage of PDO exposed to NAC that will parallel the patient's clinical response to NAC
measure: Evaluation of CTCs features
time frame: 5 years
description: phenotype, RNA-seq-based transcriptome
arm group label: RH+
description: Prospective blood and biopsie analyses
arm group label: HER2+
description: Prospective blood and biopsie analyses
arm group label: TN
description: Prospective blood and biopsie analyses
intervention type: Other
intervention name: molecular analysis of blood and tumor
description: RNAseq, DNAseq, CTCs
arm group label: HER2+
arm group label: RH+
arm group label: TN
Bllod and tumor tissue
study pop: 
sampling method: Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: François BERTUCCI, Pr
role: Principal Investigator
affiliation: Institut Paoli-Calmettes
last name: Dominique GENRE, Dr
phone: 0491223778
email: drci.up@ipc.unicancer.fr
facility: 
status: Recruiting
contact: 
investigator: 
country: France
responsible party type: Sponsor
mesh term: Breast Neoplasms
sharing ipd: No