<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/NCT04455594</url>
  </required_header>
  <id_info>
    <org_study_id>HS-LK-2020-005</org_study_id>
    <nct_id>NCT04455594</nct_id>
  </id_info>
  <brief_title>Almonertinib Vs. Erlotinib/Chemotherapy for Neo-adjuVant Treatment of Stage IIIA-N2 EGFR-mutated NSCLC</brief_title>
  <acronym>ANSWER</acronym>
  <official_title>Almonertinib Vs. Erlotinib/Chemotherapy for Neo-adjuVant Treatment of Stage IIIA-N2 EGFR-mutated NSCLC: a Multicenter, Open-label, Phase II Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The First Affiliated Hospital of Guangzhou Medical University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The First Affiliated Hospital of Guangzhou Medical University</source>
  <oversight_info>
    <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 multicenter, randomized, controlled, phase II study assessing the efficacy and&#xD;
      safety of Almonertinib compared Erlotinib or platinum doublet chemotherapy (carboplatin or&#xD;
      cisplatin + pemetrexed) as neoadjuvant therapy to EGFRm+ IIIA-N2 NSCLC patients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">October 2020</start_date>
  <completion_date type="Anticipated">October 2025</completion_date>
  <primary_completion_date type="Anticipated">January 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel 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>From date of randomization to an average of 6 weeks after the first dose</time_frame>
    <description>Objective Response Rate (ORR) is defined as participants who had complete response (CR) or partial response(PR) divided by the total number of patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pathological complete response (pCR)</measure>
    <time_frame>From date of randomization to an average of 12 weeks after the first dose</time_frame>
    <description>Defined as absence of any residual cancer cells in the surgical specimen assessed post-surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Major Pathological Response (MPR)</measure>
    <time_frame>From date of randomization to an average of 12 weeks after the first dose</time_frame>
    <description>Defined as ≤10% residual cancer cells in the surgical specimen, as assessed per central pathology laboratory post-surgery</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease free survival (DFS)</measure>
    <time_frame>From date of randomization up to approximately 18 months after date of resection</time_frame>
    <description>DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first.&#xD;
If there is residual disease after surgery (eg. positive margins), the DFS event is the date of surgery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>Up to approximately 5.5 years after the last patient is randomized</time_frame>
    <description>Patients will be followed up to approximately 5.5 years after they are randomized.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>R0 resection rate</measure>
    <time_frame>Up to 1 week after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Downstaging rate</measure>
    <time_frame>From date of randomization to an average of 12 weeks after the first dose</time_frame>
    <description>Measured using lymph node staging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Concordance of EGFRm status between plasma-derived ctDNA</measure>
    <time_frame>Baseline, up to 1 week before surgery and up to 1 week after surgery</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Adverse Events (AEs)</measure>
    <time_frame>Up to 80 weeks</time_frame>
    <description>According to CTCAE4.0</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">168</enrollment>
  <condition>Non-Small Cell Lung Cancer Stage IIIA</condition>
  <arm_group>
    <arm_group_label>Almonertinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Almonertinib 110mg QD</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Investigator-choice therapy (Erlotinib or Chemotherapy)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Erlotinib 150mg QD or Cisplatin(75mg/m2) or Carboplatin (AUC=5) to be administered with pemetrexed (500mg/m2) on Day 1 of every 3-week cycle for 3 cycles</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Almonertinib</intervention_name>
    <description>Oral, 110mg QD</description>
    <arm_group_label>Almonertinib</arm_group_label>
    <other_name>HS-10296</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erlotinib</intervention_name>
    <description>Oral, 150mg QD</description>
    <arm_group_label>Investigator-choice therapy (Erlotinib or Chemotherapy)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cisplatin</intervention_name>
    <description>Cisplatin(75mg/m2) be administered with pemetrexed (500mg/m2) on Day 1 of every 3-week cycle for 3 cycles</description>
    <arm_group_label>Investigator-choice therapy (Erlotinib or Chemotherapy)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Carboplatin (AUC=5) to be administered with pemetrexed (500mg/m2) on Day 1 of every 3-week cycle for 3 cycles</description>
    <arm_group_label>Investigator-choice therapy (Erlotinib or Chemotherapy)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pemetrexed</intervention_name>
    <description>Pemetrexed (500mg/m2) to be administered with Cisplatin(75mg/m2) or Carboplatin (AUC=5) on Day 1 of every 3-week cycle for 3 cycles</description>
    <arm_group_label>Investigator-choice therapy (Erlotinib or Chemotherapy)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female, age at least 18 years, no more than 75 years.&#xD;
&#xD;
          2. Previously untreated, histologically documented NSCLC with completely or potentially&#xD;
             resectable IIIA-N2 nonsquamous NSCLC(according to Version 8 of AJCC staging). N2 is&#xD;
             defined as as radiologically and pathologically confirmed, nonbulky metastases to&#xD;
             single-station mediastinal lymph nodes (lymph nodes &lt; 2 cm in short axis) that are&#xD;
             expected to be completely resectable.&#xD;
&#xD;
          3. Tumor tissue samples or blood samples are confirmed as EGFR sensitive mutations by&#xD;
             central laboratory tests (including Ex19del or L858R, both alone or with other EGFR&#xD;
             mutations). If the tumor tissue is accessible, the tumor tissue is recommended to be&#xD;
             submitted for examination. If tumor tissue is not accessible or patient cannot undergo&#xD;
             tissue biopsy, blood sample is also allowed.&#xD;
&#xD;
          4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no&#xD;
             deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.&#xD;
&#xD;
          5. At least 1 lesion that has not previously been irradiated, that has not been chosen&#xD;
             for biopsy during the study screening period, and that can be accurately measured at&#xD;
             Baseline as &gt;= 10 mm in the longest diameter (except lymph nodes, which must have&#xD;
             short axis &gt;= 15mm) with computerized tomography (CT) or magnetic resonance imaging&#xD;
             (MRI), whichever is suitable for accurately repeated measurements. If only one&#xD;
             measurable lesion exists, it is acceptable to be used (as a target lesion) as long as&#xD;
             it has not been previously irradiated and baseline tumour assessment scans are done at&#xD;
             least 14days afar the screening biopsy is performed.&#xD;
&#xD;
          6. Women of childbearing potential must use a contraception method during the study&#xD;
             treatment and for at least 3 months after the treatment is completed; must have a&#xD;
             negative pregnancy test prior to starting treatment or proved no risk of pregancy by&#xD;
             meeting one of the following criteria:&#xD;
&#xD;
               1. Postmenopausal defined as age more than 50 years and amenorrheic for at least 12&#xD;
                  months following cessation of all exogenous hormonal treatments.&#xD;
&#xD;
               2. Women under 50 years old would be considered postmenopausal if they have been&#xD;
                  amenorrheic for 12 months or more, following cessation of exogenous hormonal&#xD;
                  treatments, and with luteinizing hormone (LH) and follicle-stimulating hormone&#xD;
                  (FSH) levels in the postmenopausal range for the laboratory.&#xD;
&#xD;
               3. Documentation of irreversible surgical sterilization by hysterectomy, bilateral&#xD;
                  oophorectomy, or bilateral salpingectomy, but not by tubal ligation.&#xD;
&#xD;
          7. Male patients should be willing to use barrier contraception (i.e., condoms) during&#xD;
             the study treatment and for at least 3 months after the treatment is completed.&#xD;
&#xD;
          8. Signed and dated informed consent form.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Treatment with any of the following:&#xD;
&#xD;
               1. Prior surgical resection of lung cancer.&#xD;
&#xD;
               2. Prior treatment with any EGFR TKI.&#xD;
&#xD;
               3. Prior treatment with any chemotherapy for NSCLC&#xD;
&#xD;
               4. Prior treatment with any radiotherapy for NSCLC&#xD;
&#xD;
               5. Major surgery (excluding placement of vascular access) within 4 weeks of the&#xD;
                  first dose of study drug.&#xD;
&#xD;
               6. Medications that are predominantly CYP3A4 strong inhibitors or inducers or&#xD;
                  sensitive substrates of CYP3A4 with a narrow therapeutic range within 7 days of&#xD;
                  the first dose of study drug.&#xD;
&#xD;
          2. Any concurrent and/or other active malignancy that has required treatment within 2&#xD;
             years of first dose of study drug.&#xD;
&#xD;
          3. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria&#xD;
             for Adverse Events (CTCAE) Grade 1 at the time of starting study treatment, with the&#xD;
             exception of alopecia and Grade 2 prior platinum-therapy related neuropathy.&#xD;
&#xD;
          4. Patients with malignant pleural effusion. [only exception: pleural effusion on CT scan&#xD;
             (not visible on CXR) or considered too small and pericardial effusion]&#xD;
&#xD;
          5. Patients who received yellow-fever vaccine or other attenuated live vaccine during&#xD;
             pemetrexed treatment.&#xD;
&#xD;
          6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled&#xD;
             hypertension or active bleeding diatheses, which, in the Investigator's opinion, makes&#xD;
             it undesirable for the patient to participate in the trial OR which would jeopardize&#xD;
             compliance with the protocol such as active infection. Screening for chronic&#xD;
             conditions is not required.&#xD;
&#xD;
          7. Refractory nausea, vomiting, or chronic gastrointestinal diseases, inability to&#xD;
             swallow the study drug, or previous significant bowel resection that would preclude&#xD;
             adequate absorption of Almonertinib.&#xD;
&#xD;
          8. Any of the following cardiac criteria:&#xD;
&#xD;
               1. Mean resting corrected QT interval (QTc) &gt; 470 ms obtained from 3&#xD;
                  electrocardiograms (ECGs), using the screening clinic's ECG machine and&#xD;
                  Fridericia's formula for QT interval correction (QTcF).&#xD;
&#xD;
               2. Any clinically important abnormalities in rhythm, conduction, or morphology of&#xD;
                  the resting ECG (e.g., complete left bundle branch block, third-degree heart&#xD;
                  block, second-degree heart block, PR interval &gt; 250 ms).&#xD;
&#xD;
               3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic&#xD;
                  events, such as heart failure, hypokalemia, congenital long QT syndrome, family&#xD;
                  history of long QT syndrome, or unexplained sudden death under 40 years of age in&#xD;
                  first degree relatives or any concomitant medication known to prolong the QT&#xD;
                  interval.&#xD;
&#xD;
               4. Left ventricular ejection fraction (LVEF) &lt;= 40%.&#xD;
&#xD;
          9. History of interstitial lung disease, drug-induced interstitial lung disease,&#xD;
             radiation pneumonitis that required steroid treatment, or any evidence of clinically&#xD;
             active interstitial lung disease.&#xD;
&#xD;
         10. Inadequate bone marrow reserve or organ function, as demonstrated by any of the&#xD;
             following laboratory values:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) &lt; 1.5 x 10^9 / L;&#xD;
&#xD;
               2. Platelet count &lt;100 x 10^9 / L;&#xD;
&#xD;
               3. Hemoglobin &lt; 90 g/L (&lt;9 g/dL);&#xD;
&#xD;
               4. Alanine aminotransferase &gt; 2.5 x upper limit of normal (ULN).&#xD;
&#xD;
               5. Aspartate aminotransferase (AST) &gt; 2.5 x ULN.&#xD;
&#xD;
               6. Total bilirubin (TBL) &gt; 1.5 x ULN or &gt; 3 x ULN in the presence of documented&#xD;
                  Gilbert's Syndrome (unconjugated hyperbilirubinemia).&#xD;
&#xD;
               7. Creatinine &gt; 1.5 x ULN concurrent with creatinine clearance &lt; 50 mL/min (measured&#xD;
                  or calculated by the Cockcroft-Gault equation); confirmation of creatinine&#xD;
                  clearance is only required when creatinine is &gt; 1.5 x ULN.&#xD;
&#xD;
         11. Women at breastfeeding or have a negative serum or urine pregnancy test in the 3 days&#xD;
             prior to the start of the treatment..&#xD;
&#xD;
         12. History of hypersensitivity to any active or inactive ingredient of Almonertinib, or&#xD;
             to drugs with a similar chemical structure or class to Almonertinib.&#xD;
&#xD;
         13. History of hypersensitivity to any active or inactive ingredient of Erlotinib, or to&#xD;
             drugs with a similar chemical structure or class to Erlotinib.&#xD;
&#xD;
         14. With lactose in the tablets, patients with rare genetic disease like galactose&#xD;
             intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not use&#xD;
             use erlotinib.&#xD;
&#xD;
         15. Patients who are allergic to pemetrexed or any other component of the preparation,&#xD;
             carboplatin or cisplatin.&#xD;
&#xD;
         16. Patients with contraindications of pemetrexed and carboplatin or cisplatin.&#xD;
&#xD;
         17. Any severe and uncontrolled ocular disease that may, in the ophthalmologist's opinion,&#xD;
             present a specific risk to the patient's safety.&#xD;
&#xD;
         18. Judgment by the Investigator that the patient should not participate in the study if&#xD;
             the patient is unlikely to comply with study procedures, restrictions, and&#xD;
             requirements.&#xD;
&#xD;
         19. Any disease or condition that, in the opinion of the Investigator, would compromise&#xD;
             the safety of the patient or interfere with study assessments.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Wenhua Liang</last_name>
    <phone>13710249454</phone>
    <email>Liangwh1987@163.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>The First Affiliated Hospital of Guangzhou Medical University</name>
      <address>
        <city>Guangzhou</city>
        <country>China</country>
      </address>
    </facility>
    <contact>
      <last_name>Wenhua Liang</last_name>
      <phone>13710249454</phone>
      <email>Liangwh1987@163.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>June 2020</verification_date>
  <study_first_submitted>June 19, 2020</study_first_submitted>
  <study_first_submitted_qc>June 30, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 2, 2020</study_first_posted>
  <last_update_submitted>June 30, 2020</last_update_submitted>
  <last_update_submitted_qc>June 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 2, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The First Affiliated Hospital of Guangzhou Medical University</investigator_affiliation>
    <investigator_full_name>Jianxing He</investigator_full_name>
    <investigator_title>Chief Surgeon</investigator_title>
  </responsible_party>
  <keyword>resectable NSCLC, IIIA-N2 NSCLC</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Pemetrexed</mesh_term>
    <mesh_term>Erlotinib Hydrochloride</mesh_term>
  </intervention_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/NCT04455594
org study id: HS-LK-2020-005
nct id: NCT04455594
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
This is a multicenter, randomized, controlled, phase II study assessing the efficacy and
      safety of Almonertinib compared Erlotinib or platinum doublet chemotherapy (carboplatin or
      cisplatin + pemetrexed) as neoadjuvant therapy to EGFRm+ IIIA-N2 NSCLC patients.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective response rate (ORR)
time frame: From date of randomization to an average of 6 weeks after the first dose
description: Objective Response Rate (ORR) is defined as participants who had complete response (CR) or partial response(PR) divided by the total number of patients.
measure: Pathological complete response (pCR)
time frame: From date of randomization to an average of 12 weeks after the first dose
description: Defined as absence of any residual cancer cells in the surgical specimen assessed post-surgery
measure: Major Pathological Response (MPR)
time frame: From date of randomization to an average of 12 weeks after the first dose
description: Defined as ≤10% residual cancer cells in the surgical specimen, as assessed per central pathology laboratory post-surgery
measure: Disease free survival (DFS)
time frame: From date of randomization up to approximately 18 months after date of resection
description: DFS is defined as the time from the date of surgery until the first date of disease recurrence (local or distant) or date of death due to any cause, whichever occurs first.
If there is residual disease after surgery (eg. positive margins), the DFS event is the date of surgery.
measure: Overall Survival (OS)
time frame: Up to approximately 5.5 years after the last patient is randomized
description: Patients will be followed up to approximately 5.5 years after they are randomized.
measure: R0 resection rate
time frame: Up to 1 week after surgery
measure: Downstaging rate
time frame: From date of randomization to an average of 12 weeks after the first dose
description: Measured using lymph node staging
measure: Concordance of EGFRm status between plasma-derived ctDNA
time frame: Baseline, up to 1 week before surgery and up to 1 week after surgery
measure: Incidence of Adverse Events (AEs)
time frame: Up to 80 weeks
description: According to CTCAE4.0
arm group label: Almonertinib
arm group type: Experimental
description: Almonertinib 110mg QD
arm group label: Investigator-choice therapy (Erlotinib or Chemotherapy)
arm group type: Active Comparator
description: Erlotinib 150mg QD or Cisplatin(75mg/m2) or Carboplatin (AUC=5) to be administered with pemetrexed (500mg/m2) on Day 1 of every 3-week cycle for 3 cycles
intervention type: Drug
intervention name: Almonertinib
description: Oral, 110mg QD
arm group label: Almonertinib
other name: HS-10296
intervention type: Drug
intervention name: Erlotinib
description: Oral, 150mg QD
arm group label: Investigator-choice therapy (Erlotinib or Chemotherapy)
intervention type: Drug
intervention name: Cisplatin
description: Cisplatin(75mg/m2) be administered with pemetrexed (500mg/m2) on Day 1 of every 3-week cycle for 3 cycles
arm group label: Investigator-choice therapy (Erlotinib or Chemotherapy)
intervention type: Drug
intervention name: Carboplatin
description: Carboplatin (AUC=5) to be administered with pemetrexed (500mg/m2) on Day 1 of every 3-week cycle for 3 cycles
arm group label: Investigator-choice therapy (Erlotinib or Chemotherapy)
intervention type: Drug
intervention name: Pemetrexed
description: Pemetrexed (500mg/m2) to be administered with Cisplatin(75mg/m2) or Carboplatin (AUC=5) on Day 1 of every 3-week cycle for 3 cycles
arm group label: Investigator-choice therapy (Erlotinib or Chemotherapy)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Wenhua Liang
phone: 13710249454
email: Liangwh1987@163.com
facility: 
contact: 
country: China
responsible party type: Principal Investigator
investigator affiliation: The First Affiliated Hospital of Guangzhou Medical University
investigator full name: Jianxing He
investigator title: Chief Surgeon
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Carboplatin
mesh term: Pemetrexed
mesh term: Erlotinib Hydrochloride