xml: <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/NCT05962502</url>
    </required_header>
    <id_info>
      <org_study_id>NEORAS-SYSUCC</org_study_id>
      <nct_id>NCT05962502</nct_id>
    </id_info>
    <brief_title>Cetuximab Plus Irinotecan in Patients With NeoRAS Wild-type Metastatic Colorectal Cancer In Third-line Therapy</brief_title>
    <official_title>A Single-arm, Open-label, Phase II Clinical Study of Cetuximab Plus Irinotecan in Patients With NeoRAS Wild-type Metastatic Colorectal Cancer In Third-line Therapy</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>Sun Yat-sen University</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
    </sponsors>
    <source>Sun Yat-sen University</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>
        This is a single-arm, open-label, phase II clinical trial. The goal of this study is to&#xD;
        evaluate the efficacy and safety of cetuximab plus irinotecan in patients with NeoRAS&#xD;
        wild-type primary left-sided mCRC in third-line therapy.&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        At present, the third-line therapy in China includes 3 anti-angiogenic small molecule&#xD;
        tyrosine kinase (TKI) inhibitors, namely regorafenib, fruquintinib and oral chemotherapeutic&#xD;
        agent TAS-102.There are high-level evidences for the above 3 drugs, but their therapeutic&#xD;
        effects are still unsatisfactory with the progression-free survival (PFS) of only 2-4 months.&#xD;
        As a result, more effective regimens need to be explored. The BOND study found that in mCRC&#xD;
        patients with RAS wild-type and irinotecan resistance, cetuximab combined with irinotecan as&#xD;
        the third-line therapy could effectively reverse irinotecan resistance with an ORR of 22.9%.&#xD;
        The CRIKET study assessed the effect of cetuximab combined with irinotecan in later-line&#xD;
        setting for advanced CRC; the result showed that the cetuximab combined with irinotecan&#xD;
        therapy achieved an objective response rate (ORR) of 21% (95% CI, 10-40%). In the subgroup&#xD;
        analysis, compared with patients with mutations, patients with RAS wild-type confirmed by&#xD;
        circulating tumor DNA (ctDNA) had longer PFS benefit (4.0 months vs 1.9 months), which&#xD;
        suggested that patients with RAS wild-type mCRC might still benefit from cetuximab plus&#xD;
        irinotecan re-challenge in third-line setting after cetuximab treatment. However, third-line&#xD;
        therapy options are still limited for another 35% to 40% patients with RAS wide-type mCRC and&#xD;
        the prognosis for these patients is relatively poor. More studies are needed to explore other&#xD;
        effective regimens.&#xD;
  &#xD;
        ctDNA, or liquid biopsy technology, can detect DNA released from tumor cells into the blood.&#xD;
        Moreover, it has some detecting advantages, such as real-time, dynamic, comprehensive and&#xD;
        noninvasive. More and more studies have shown that this technology is promising and can be&#xD;
        widely applied in the whole disease management course of CRC patients, such as early&#xD;
        diagnosis, therapeutic target detection, minimal residual disease (MRD) detection and&#xD;
        efficacy monitoring. One of previous studies of our team found that the status of RAS and&#xD;
        BRAF genes detected by ctDNA in advanced CRC patients would change along with treatment. The&#xD;
        study dynamically monitored ctDNA in 171 patients with unresectable mCRC. The results showed&#xD;
        that 42.6% of patients with initial RAS mutation were converted to RAS wild-type mCRC after&#xD;
        the standard first-line treatment, and such patients were called NeoRAS wild-type mCRC&#xD;
        patients. Other studies have also found similar phenomena, but the frequency of NeoRAS&#xD;
        wild-type conversion varies among studies (2%-45%), which might be related to several factors&#xD;
        such as patients' treatment stage, early treatment regimen, and ctDNA detection method.&#xD;
        Therefore, in order to optimize treatment strategies, RAS status should be retested during&#xD;
        overall management of patients with RAS mutant mCRC.&#xD;
  &#xD;
        The target population for this study is patients with RAS/BRAF wild-type primary left-sided&#xD;
        mCRC by blood-based ctDNA testing before third-line therapy, who are initial RAS mutant and&#xD;
        BRAF wild-type CRC patients, who have disease progression after first- and second-line&#xD;
        therapy (previously treated with fluorouracil compounds, oxaliplatin and irinotecan) and who&#xD;
        have tumor progression, during or within 3 months after irinotecan-containing regimen. This&#xD;
        population will receive third-line therapy with cetuximab plus irinotecan bi-weekly until&#xD;
        disease progression. The primary study endpoint is ORR, and the secondary study endpoints are&#xD;
        PFS, OS and drug safety.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Recruiting</overall_status>
    <start_date type="Actual">August 24, 2023</start_date>
    <completion_date type="Anticipated">December 30, 2026</completion_date>
    <primary_completion_date type="Anticipated">March 30, 2025</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>Objective response rate (ORR)</measure>
      <time_frame>Up to 1 year</time_frame>
      <description>Based on RECIST 1.1</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Progression free survival (PFS)</measure>
      <time_frame>Up to 2 years</time_frame>
      <description>Based on RECIST 1.1</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Overall survival (OS)</measure>
      <time_frame>Up to 3 years</time_frame>
      <description>Based on RECIST 1.1</description>
    </secondary_outcome>
    <secondary_outcome>
      <measure>Drug-related adverse reactions</measure>
      <time_frame>Up to 3 years</time_frame>
      <description>Based on NCI-CTCAE v5.0 criteria</description>
    </secondary_outcome>
    <number_of_arms>1</number_of_arms>
    <enrollment type="Anticipated">54</enrollment>
    <condition>Metastatic Colorectal Cancer</condition>
    <arm_group>
      <arm_group_label>cetuximab plus irinotecan</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Cetuximab 500 mg/m2 iv drip 90 min d1, Irinotecan 180 mg/m2 iv drip d1 (For patients with UGT*28 7/7 or UGT*6 A/A or UGT*28 6/7 plus UGT*6 A/G, irinotecan 150 mg/m2 is used) The above regimen is repeated every 2 weeks</description>
    </arm_group>
    <intervention>
      <intervention_type>Drug</intervention_type>
      <intervention_name>Cetuximab and irinotecan</intervention_name>
      <description>chemotherapy plus targeted therapy</description>
      <arm_group_label>cetuximab plus irinotecan</arm_group_label>
      <other_name>ERBITUX</other_name>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            1. Age ≥ 18 years.&#xD;
  &#xD;
            2. Histologically confirmed colorectal adenocarcinoma.&#xD;
  &#xD;
            3. Patients with initial RAS mutant, BRAF wild-type left-sided mCRC.&#xD;
  &#xD;
            4. Progression after standard first-line and second-line therapy (previously treated with&#xD;
               fluorouracil compounds, oxaliplatin and irinotecan).&#xD;
  &#xD;
            5. Tumor progression within 3 months during or after irinotecan-containing regimen.&#xD;
  &#xD;
            6. Blood-based ctDNA testing shows that both RAS and BRAF genes are wild-type after&#xD;
               second-line therapy progression .&#xD;
  &#xD;
            7. There are objectively measurable lesions according to RECIST v1.1 criteria.&#xD;
  &#xD;
            8. Normal hematologic function (platelets &gt; 90 × 109/L; leukocytes &gt; 3 × 109/L;&#xD;
               neutrophils &gt; 1.5 × 109/L; hemoglobin &gt; 8.0g/100ml).&#xD;
  &#xD;
            9. Serum bilirubin ≤ 1.5 x the upper limit of normal (ULN) and transaminases ≤ 5 x ULN.&#xD;
  &#xD;
           10. Normal coagulation function, albumin ≥ 35 g/L.&#xD;
  &#xD;
           11. Liver function: Child-Push score: Class A.&#xD;
  &#xD;
           12. Serum creatinine &lt; 1.5 x ULN, or calculated creatinine clearance ≥ 50 ml/min (using&#xD;
               the Cockcroft Gault formula).&#xD;
  &#xD;
           13. ECOG PS score 0-2.&#xD;
  &#xD;
           14. Life expectancy &gt; 3 months.&#xD;
  &#xD;
           15. Sign written informed consent.&#xD;
  &#xD;
           16. Willing and able to be followed up until death or end of study or study termination.&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            1. Primary right-sided mCRC.&#xD;
  &#xD;
            2. dMMR/MSI-H mCRC.&#xD;
  &#xD;
            3. Patients with initial RAS wild-type or BRAF mutant mCRC.&#xD;
  &#xD;
            4. ctDNA testing shows that RAS or BRAF gene is mutant mCRC after second-line therapy.&#xD;
  &#xD;
            5. Serious arterial embolism or ascites.&#xD;
  &#xD;
            6. Serious bleeding tendency or coagulation disorder.&#xD;
  &#xD;
            7. Serious uncontrolled systemic complications such as infection or diabetes.&#xD;
  &#xD;
            8. Clinically significant cardiovascular disease such as cerebrovascular accident (within&#xD;
               6 months prior to enrollment), myocardial infarction (within 6 months prior to&#xD;
               enrollment), uncontrolled hypertension despite appropriate medical treatment. Unstable&#xD;
               angina, congestive heart failure (NYHA class 2-4), cardiac arrhythmia requiring&#xD;
               medication.&#xD;
  &#xD;
            9. History or physical evidence of central nervous system disease (e.g., primary brain&#xD;
               tumor, epilepsy uncontrolled by standard of care, any history of brain metastases or&#xD;
               stroke).&#xD;
  &#xD;
           10. Other malignancies (except cutaneous basal cell carcinoma and/or cervical carcinoma in&#xD;
               situ of the cervix and/or thyroid carcinoma after radical surgery) within the past 5&#xD;
               years.&#xD;
  &#xD;
           11. Hypersensitivity to any drug in the study.&#xD;
  &#xD;
           12. Pregnant and lactating women.&#xD;
  &#xD;
           13. Women of childbearing age (&lt; 2 years after last menstruation) or men of fertile&#xD;
               potential who are not using or refuse to use effective non-hormonal contraception&#xD;
               (intrauterine contraceptive ring, barrier contraceptives combined with spermicidal&#xD;
               gel, or surgical sterilization).&#xD;
  &#xD;
           14. Unable or unwilling to comply with the study protocol.&#xD;
  &#xD;
           15. Patients with any other diseases, dysfunction caused by metastatic lesions, or&#xD;
               suspected disease found by physical examination, indicating possible contraindications&#xD;
               to the use of the investigational drug or putting the patients at high risk of&#xD;
               treatment-related complications.&#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>Ruihua Xu, MD, PhD</last_name>
      <role>Principal Investigator</role>
      <affiliation>Sun Yat-sen University</affiliation>
    </overall_official>
    <overall_contact>
      <last_name>Ruihua Xu, MD, PhD</last_name>
      <phone>+86 13922206676</phone>
      <email>xurh@sysucc.org.cn</email>
    </overall_contact>
    <location>
      <facility>
        <name>Cancer center of Sun Yat-sen University</name>
        <address>
          <city>Guangzhou</city>
          <state>Guangdong</state>
          <zip>510060</zip>
          <country>China</country>
        </address>
      </facility>
      <status>Recruiting</status>
      <contact>
        <last_name>Zhi-da Lv, BS</last_name>
        <phone>+862087342635</phone>
        <email>lvzd@sysucc.org.cn</email>
      </contact>
    </location>
    <location_countries>
      <country>China</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>July 17, 2023</study_first_submitted>
    <study_first_submitted_qc>July 26, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">July 27, 2023</study_first_posted>
    <last_update_submitted>August 30, 2023</last_update_submitted>
    <last_update_submitted_qc>August 30, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 31, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>Sun Yat-sen University</investigator_affiliation>
      <investigator_full_name>Rui-hua Xu, MD, PhD</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>NeoRAS wild-type</keyword>
    <keyword>mCRC</keyword>
    <keyword>Cetuximab</keyword>
    <keyword>Third-line therapy</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Colorectal Neoplasms</mesh_term>
    </condition_browse>
    <intervention_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Irinotecan</mesh_term>
      <mesh_term>Cetuximab</mesh_term>
    </intervention_browse>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: 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/NCT05962502
  org study id: NEORAS-SYSUCC
  nct id: NCT05962502
  lead sponsor: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  This is a single-arm, open-label, phase II clinical trial. The goal of this study is to
        evaluate the efficacy and safety of cetuximab plus irinotecan in patients with NeoRAS
        wild-type primary left-sided mCRC in third-line therapy.
  At present, the third-line therapy in China includes 3 anti-angiogenic small molecule
        tyrosine kinase (TKI) inhibitors, namely regorafenib, fruquintinib and oral chemotherapeutic
        agent TAS-102.There are high-level evidences for the above 3 drugs, but their therapeutic
        effects are still unsatisfactory with the progression-free survival (PFS) of only 2-4 months.
        As a result, more effective regimens need to be explored. The BOND study found that in mCRC
        patients with RAS wild-type and irinotecan resistance, cetuximab combined with irinotecan as
        the third-line therapy could effectively reverse irinotecan resistance with an ORR of 22.9%.
        The CRIKET study assessed the effect of cetuximab combined with irinotecan in later-line
        setting for advanced CRC; the result showed that the cetuximab combined with irinotecan
        therapy achieved an objective response rate (ORR) of 21% (95% CI, 10-40%). In the subgroup
        analysis, compared with patients with mutations, patients with RAS wild-type confirmed by
        circulating tumor DNA (ctDNA) had longer PFS benefit (4.0 months vs 1.9 months), which
        suggested that patients with RAS wild-type mCRC might still benefit from cetuximab plus
        irinotecan re-challenge in third-line setting after cetuximab treatment. However, third-line
        therapy options are still limited for another 35% to 40% patients with RAS wide-type mCRC and
        the prognosis for these patients is relatively poor. More studies are needed to explore other
        effective regimens.
  
        ctDNA, or liquid biopsy technology, can detect DNA released from tumor cells into the blood.
        Moreover, it has some detecting advantages, such as real-time, dynamic, comprehensive and
        noninvasive. More and more studies have shown that this technology is promising and can be
        widely applied in the whole disease management course of CRC patients, such as early
        diagnosis, therapeutic target detection, minimal residual disease (MRD) detection and
        efficacy monitoring. One of previous studies of our team found that the status of RAS and
        BRAF genes detected by ctDNA in advanced CRC patients would change along with treatment. The
        study dynamically monitored ctDNA in 171 patients with unresectable mCRC. The results showed
        that 42.6% of patients with initial RAS mutation were converted to RAS wild-type mCRC after
        the standard first-line treatment, and such patients were called NeoRAS wild-type mCRC
        patients. Other studies have also found similar phenomena, but the frequency of NeoRAS
        wild-type conversion varies among studies (2%-45%), which might be related to several factors
        such as patients' treatment stage, early treatment regimen, and ctDNA detection method.
        Therefore, in order to optimize treatment strategies, RAS status should be retested during
        overall management of patients with RAS mutant mCRC.
  
        The target population for this study is patients with RAS/BRAF wild-type primary left-sided
        mCRC by blood-based ctDNA testing before third-line therapy, who are initial RAS mutant and
        BRAF wild-type CRC patients, who have disease progression after first- and second-line
        therapy (previously treated with fluorouracil compounds, oxaliplatin and irinotecan) and who
        have tumor progression, during or within 3 months after irinotecan-containing regimen. This
        population will receive third-line therapy with cetuximab plus irinotecan bi-weekly until
        disease progression. The primary study endpoint is ORR, and the secondary study endpoints are
        PFS, OS and drug safety.
  allocation: N/A
  intervention model: Single Group Assignment
  primary purpose: Treatment
  masking: None (Open Label)
  measure: Objective response rate (ORR)
  time frame: Up to 1 year
  description: Based on RECIST 1.1
  measure: Progression free survival (PFS)
  time frame: Up to 2 years
  description: Based on RECIST 1.1
  measure: Overall survival (OS)
  time frame: Up to 3 years
  description: Based on RECIST 1.1
  measure: Drug-related adverse reactions
  time frame: Up to 3 years
  description: Based on NCI-CTCAE v5.0 criteria
  arm group label: cetuximab plus irinotecan
  arm group type: Experimental
  description: Cetuximab 500 mg/m2 iv drip 90 min d1, Irinotecan 180 mg/m2 iv drip d1 (For patients with UGT*28 7/7 or UGT*6 A/A or UGT*28 6/7 plus UGT*6 A/G, irinotecan 150 mg/m2 is used) The above regimen is repeated every 2 weeks
  intervention type: Drug
  intervention name: Cetuximab and irinotecan
  description: chemotherapy plus targeted therapy
  arm group label: cetuximab plus irinotecan
  other name: ERBITUX
  criteria: 
  gender: All
  minimum age: 18 Years
  maximum age: N/A
  healthy volunteers: No
  last name: Ruihua Xu, MD, PhD
  role: Principal Investigator
  affiliation: Sun Yat-sen University
  last name: Ruihua Xu, MD, PhD
  phone: +86 13922206676
  email: xurh@sysucc.org.cn
  facility: 
  status: Recruiting
  contact: 
  country: China
  responsible party type: Principal Investigator
  investigator affiliation: Sun Yat-sen University
  investigator full name: Rui-hua Xu, MD, PhD
  investigator title: Professor
  mesh term: Colorectal Neoplasms
  mesh term: Irinotecan
  mesh term: Cetuximab