<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/NCT03778138</url>
  </required_header>
  <id_info>
    <org_study_id>ALTER-L025</org_study_id>
    <nct_id>NCT03778138</nct_id>
  </id_info>
  <brief_title>Study of Anlotinib Combined With Pemetrexed in Patients With Advanced Nonsquamous NSCLC</brief_title>
  <acronym>ALTER-L025</acronym>
  <official_title>Study of Anlotinib Combined With Pemetrexed as the Second-line Treatment in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancer (ALTER-L025)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Henan Provincial People's Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Chia Tai Tianqing Pharmaceutical Group Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Henan Provincial People's Hospital</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>
      In recent years, with the progress in the treatment field, NSCLC has become the most&#xD;
      successful cancer species in precision medicine. Patients with positive driving genes such as&#xD;
      EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to&#xD;
      patients.However, about 50% of patients still lack a clear driving gene target, which has&#xD;
      become the focus of current research.In the field of wild-type NSCLC with negative driver&#xD;
      genes, the classic first-line treatment regimen is the two-drug regimen containing&#xD;
      platinum.he phase II clinical study of pemetrexed in the second-line treatment of advanced&#xD;
      non-small cell lung cancer patients with pemetrexed versus carboplatin pemetrexed showed that&#xD;
      the median PFS time in the pemetrexed group was 3.5 months.&#xD;
&#xD;
      Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and&#xD;
      development.In the phase Ⅲ study, patients who failed at least two kinds of systemic&#xD;
      chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or&#xD;
      placebo, the anlotinib group PFS and OS were 5.37 months and 9.63 months, the placebo group&#xD;
      PFS and OS were 1.4 months and 6.3 months.&#xD;
&#xD;
      The efficacy and safety of anrotinib combined with pemetrexed in the second-line treatment of&#xD;
      advanced non-squamous and non-small cell patients deserve further exploration.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicentre single arm clinical trial conducted in China,the purpose of this study&#xD;
      is to evaluate and observe Anlotinib (12mg QD PO d1-14, 21 days per cycle) Combined With&#xD;
      Pemetrexed(500mg/m2,IV,d1,21 days per cycle) as the second-line Treatment in Patients With&#xD;
      Advanced nonsquamous Non-Small-Cell Lung Cancer.As the report,The median PFS of advanced&#xD;
      NSCLC treated by Pemetrexed as second-line was 3-3.5 months.We expect the median PFS of&#xD;
      Anlotinib combined with Pemetrexed as the second-line Treatment in Patients With Advanced&#xD;
      nonsquamous NSCLC was 6 months.Using PASS15, we calculated the sample size of this study was&#xD;
      46(α=0.025、β=0.1), according to 10% censoring,the expected sample size is 51.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Anticipated">January 1, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2020</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2019</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>Anlotinib and Pemetrexed</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Progress free survival (PFS) based on investigator assessment</measure>
    <time_frame>each 42 days up to PD or death(up to 24 months)</time_frame>
    <description>PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective Response Rate based on investigator assessment</measure>
    <time_frame>each 42 days up to intolerance the toxicity or PD (up to 24 months)</time_frame>
    <description>ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate（DCR）</measure>
    <time_frame>each 42 days up to intolerance the toxicity or PD (up to 24 months)</time_frame>
    <description>Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival（OS）</measure>
    <time_frame>each 42 days up to intolerance the toxicity or PD (up to 24 months) .</time_frame>
    <description>Defined as the time until death due to any cause.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety(Number of Participants with Adverse Events and Clinical laboratory numerical evaluation as a Measure of Safety)</measure>
    <time_frame>each 42 days up to intolerance the toxicity or PD (up to 24 months) .</time_frame>
    <description>Number of Participants with Adverse Events and Clinical laboratory numerical evaluation as a Measure of Safety</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">51</enrollment>
  <condition>Non-squamous Cell Non-Small Cell Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Anlotinib plus Pemetrexed</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Anlotinib(12mg QD PO d1-14, 21 days per cycle) plus Pemetrexed (500mg/m2 IV d1)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Anlotinib plus Pemetrexed</intervention_name>
    <description>Anlotinib(12mg QD PO d1-14, 21 days per cycle) plus Pemetrexed (500mg/m2 IV d1)</description>
    <arm_group_label>Anlotinib plus Pemetrexed</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed the informed consent form prior to patient entry;&#xD;
&#xD;
          -  Male or female patients aged 18-75 years old；&#xD;
&#xD;
          -  Diagnosed with advanced NSCLC (phase IIIB/IV) through pathology, Neoadjuvant&#xD;
             chemotherapy, or postoperative adjuvant chemotherapy or neoadjuvant chemotherapy&#xD;
             combined with postoperative adjuvant chemotherapy or targeted chemoradiotherapy for&#xD;
             local advanced disease recurrence within 6 months after completion;&#xD;
&#xD;
          -  Patients with negative driver genes who had previously only received first-line&#xD;
             platinum double-drug therapy progression or intolerance;&#xD;
&#xD;
          -  In the past 3 months at least one target lesion that had not previously been&#xD;
             irradiated,and at least one direction with the longest diameter at baseline greater&#xD;
             than 10 mm (shorter diameter required not less than 15 mm if lymph nodes are&#xD;
             involved)could be imaged by CT scan or MRI;&#xD;
&#xD;
          -  Expected Survival Time: Over 6 months;&#xD;
&#xD;
          -  had an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 or 1&#xD;
             (on a 5-point scale, with higher scores indicating increasing disability);&#xD;
&#xD;
          -  If there is central nervous system metastases,they must be asymptomatic central&#xD;
             nervous system metastases;&#xD;
&#xD;
          -  The main organs function are normally, the following criteria are met:(1)Blood routine&#xD;
             examination criteria should be met (no blood transfusion and blood products within 14&#xD;
             days, no correction by G-CSF and other hematopoietic stimuli): HB≥90 g/L; ANC ≥&#xD;
             1.5×10^9/L; PLT ≥80×10^9/L;(2)Biochemical examinations must meet the following&#xD;
             criteria: TBIL&lt;1.5×ULN; ALT and AST &lt; 2.5×ULN, and for patients with liver metastases&#xD;
             &lt; 5×ULN; Serum Cr ≤ 1.25×ULN or endogenous creatinine clearance &gt; 60 ml/min&#xD;
             (Cockcroft-Gault formula);&#xD;
&#xD;
          -  Women of child-bearing age should take appropriate contraceptive measures and should&#xD;
             not breastfeed from screening to 3 months after stopping the study and&#xD;
             treatment.Before starting administration, the pregnancy test was negative, or one of&#xD;
             the following criteria was met to prove that there was no risk of pregnancy:&#xD;
&#xD;
               1. Postmenopause is defined as amenorrhea at least 12 months after age 50 and&#xD;
                  cessation of all exogenous hormone replacement therapy;&#xD;
&#xD;
               2. Postmenopausal women under the age of 50 May also be considered postmenopausal if&#xD;
                  their amenorrhea is 12 months or more after the cessation of all exogenous&#xD;
                  hormone therapy and their luteinizing hormone (LH) and follicle-stimulating&#xD;
                  hormone (FSH) levels are within the reference value range of laboratory&#xD;
                  postmenopausal;&#xD;
&#xD;
               3. has undergone irreversible sterilization surgery, including hysterectomy,&#xD;
                  bilateral ovectomy or bilateral salpingectomy, except for bilateral tubal&#xD;
                  ligation. For men, consent is required to use appropriate methods of&#xD;
                  contraception or to be surgically sterilized during the trial and 8 weeks after&#xD;
                  the last administration of the trial drug.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Small cell lung cancer (including lung cancer mixed with small cell lung cancer and&#xD;
             non-small cell lung cancer),Lung sarcomatoid carcinoma;&#xD;
&#xD;
          -  Had histologically confirmed lung squamous cell carcinoma, or adenosquamous carcinoma;&#xD;
&#xD;
          -  EGFR、ALK mutation-positive by genetic testing technology (pathological examination&#xD;
             results of other hospitals are acceptable) and who receive EGFR-TKI and ALK-TKI&#xD;
             targeted drug therapy,except EGFR/ALK status cannot be determined for various reasons;&#xD;
&#xD;
          -  Imaging (CT or MRI) shows that the distance between tumor lesion and the large blood&#xD;
             vessel is ≤ 5 mm, or there is a central tumor that invades the local large blood&#xD;
             vessel; or there is a significant pulmonary cavity or necrotizing tumor;&#xD;
&#xD;
          -  have used Pemetrexed before and progressed;&#xD;
&#xD;
          -  Patients with uncontrolled pleural effusion need to be treated with other chemotherapy&#xD;
             drugs;&#xD;
&#xD;
          -  Significant weight loss (more than 10% weight loss in the previous 6 weeks);&#xD;
&#xD;
          -  Medical history and combined history：&#xD;
&#xD;
               1. Had clinically symptomatic central nervous system metastasis(a patient with brain&#xD;
                  metastases who have completed treatment and stable symptoms in 28 days before&#xD;
                  enrollment may be enrolled, but should be confirmed by brain MRI, CT or&#xD;
                  venography evaluation as no cerebral hemorrhage symptoms or metastases in&#xD;
                  midbrain, pons, cerebellum, medulla oblongata, or spinal cord);&#xD;
&#xD;
               2. The patient is participating in other clinical studies or completing the previous&#xD;
                  clinical study in less than 4 weeks;&#xD;
&#xD;
               3. Had malignant tumors except NSCLC within 5 years before enrollment(except for&#xD;
                  patients with cervical carcinoma in situ , basal cell or squamous cell skin&#xD;
                  cancer who have undergone a curative treatment, local prostate cancer after&#xD;
                  radical resection, ductal carcinoma in situ or papillary thyroid cancer after&#xD;
                  radical resection);&#xD;
&#xD;
               4. Patients with previous anti-tumor treatment-related adverse reactions (excluding&#xD;
                  hair loss) who have not recovered to NCI-CTCAE ≤1;&#xD;
&#xD;
               5. Abnormal blood coagulation (INR &gt; 1.5 or prothrombin time (PT) &gt; ULN + 4 seconds&#xD;
                  or APTT &gt; 1.5 ULN), with bleeding tendency or undergoing thrombolytic or&#xD;
                  anticoagulant therapy;Note: Under the premise of prothrombin time international&#xD;
                  normalized ratio (INR) ≤ 1.5, low-dose heparin (adult daily dose of 0.6 million&#xD;
                  to 12,000 U) or low-dose aspirin (daily dosage ≤ 100 mg) is allowed for&#xD;
                  preventive purposes;&#xD;
&#xD;
               6. Renal insufficiency: urine routine indicates urinary protein ≥ ++, or confirmed&#xD;
                  24-hour urine protein ≥ 1.0g;&#xD;
&#xD;
               7. The effects of surgery or trauma have been eliminated for less than 14 days&#xD;
                  before enrollment in subjects who have undergone major surgery or have severe&#xD;
                  trauma;&#xD;
&#xD;
               8. Severe acute or chronic infections requiring systemic treatment;&#xD;
&#xD;
               9. Suffering from severe cardiovascular disease: myocardial ischemia or myocardial&#xD;
                  infarction above grade II, poorly controlled arrhythmias (including men with QTc&#xD;
                  interval ≥ 450 ms, women ≥ 470 ms); according to NYHA criteria, grades III to IV&#xD;
                  Insufficient function, or cardiac color Doppler ultrasound examination indicates&#xD;
                  left ventricular ejection fraction (LVEF) &lt;50%;&#xD;
&#xD;
              10. There is currently a peripheral neuropathy of ≥CTCAE 2 degrees, except for&#xD;
                  trauma;&#xD;
&#xD;
              11. Respiratory syndrome (≥CTC AE grade 2 dyspnea), serous effusion (including&#xD;
                  pleural effusion, ascites, pericardial effusion) requiring surgical treatment;&#xD;
&#xD;
              12. Long-term unhealed wounds or fractures;&#xD;
&#xD;
              13. Decompensated diabetes or other ailments treated with high doses of&#xD;
                  glucocorticoids;&#xD;
&#xD;
              14. Factors that have a significant impact on oral drug absorption, such as inability&#xD;
                  to swallow, chronic diarrhea, and intestinal obstruction;&#xD;
&#xD;
              15. Clinically significant hemoptysis (daily hemoptysis greater than 2.5ml) within 3&#xD;
                  months prior to enrollment; or significant clinically significant bleeding&#xD;
                  symptoms or defined bleeding tendency, such as gastrointestinal bleeding,&#xD;
                  hemorrhagic gastric ulcer, baseline fecal occult blood ++ and above, or suffering&#xD;
                  from vasculitis;&#xD;
&#xD;
              16. Events of venous/venous thrombosis occurring within the first 12 months prior to&#xD;
                  enrollment, such as cerebrovascular accidents (including transient ischemic&#xD;
                  attacks, cerebral hemorrhage, cerebral infarction), deep vein thrombosis, and&#xD;
                  pulmonary embolism;&#xD;
&#xD;
              17. Participated in clinical trials of other antitumor drugs within 4 weeks before&#xD;
                  enrollment or planned systemic antitumor treatment within 4 weeks before grouping&#xD;
                  or prior to receiving the test drug including cytotoxic therapy, signal&#xD;
                  transduction inhibitors, immunotherapy( or use mitomycin C within 6 weeks prior&#xD;
                  to receiving the test drug).Radiation-rehabilitation radiotherapy (EF-RT) was&#xD;
                  performed within 4 weeks before grouping or limited-field radiotherapy to be&#xD;
                  evaluated for tumor lesions within 2 weeks before grouping.&#xD;
&#xD;
          -  Physical examination and laboratory findings&#xD;
&#xD;
               1. a known history of HIV testing positive or acquired immunodeficiency syndrome&#xD;
                  (AIDS);&#xD;
&#xD;
               2. untreated active hepatitis (hepatitis b: HBsAg positive and HBV DNA more than 1 x&#xD;
                  103 copy /ml; Hepatitis c: HCV RNA is positive and liver function is abnormal);&#xD;
                  Combined with hepatitis b and hepatitis c infection;&#xD;
&#xD;
               3. serious diseases that endanger patients' safety or affect patients' completion of&#xD;
                  research,according to the researchers' judgment.&#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_official>
    <last_name>Cang Shundong, doctor</last_name>
    <role>Principal Investigator</role>
    <affiliation>Henan Provincial People's Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Cang Shundong, doctor</last_name>
    <phone>0086-13592675836</phone>
    <email>cangshundong@163.com</email>
  </overall_contact>
  <location>
    <facility>
      <name>Henan Provincial People's Hospital</name>
      <address>
        <city>Zhengzhou</city>
        <state>Henan</state>
        <zip>450000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Cang Shundong, doctor</last_name>
      <phone>0086-13592675836</phone>
      <email>cangshundong@163.com</email>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 14, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>December 14, 2018</last_update_submitted>
  <last_update_submitted_qc>December 14, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 19, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Advanced nonsquamous Non-Small Cell Lung Cancer</keyword>
  <keyword>Anlotinib Combined With Pemetrexed</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <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>Pemetrexed</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/NCT03778138
org study id: ALTER-L025
nct id: NCT03778138
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
In recent years, with the progress in the treatment field, NSCLC has become the most
      successful cancer species in precision medicine. Patients with positive driving genes such as
      EGFR, ALK, ROS1, BRAF and so on have clearly targeted drugs, which bring survival benefits to
      patients.However, about 50% of patients still lack a clear driving gene target, which has
      become the focus of current research.In the field of wild-type NSCLC with negative driver
      genes, the classic first-line treatment regimen is the two-drug regimen containing
      platinum.he phase II clinical study of pemetrexed in the second-line treatment of advanced
      non-small cell lung cancer patients with pemetrexed versus carboplatin pemetrexed showed that
      the median PFS time in the pemetrexed group was 3.5 months.

      Anlotinib is a multi-target receptor tyrosine kinase inhibitor in domestic research and
      development.In the phase Ⅲ study, patients who failed at least two kinds of systemic
      chemotherapy (third line or beyond) or drug intolerance were treated with anlotinib or
      placebo, the anlotinib group PFS and OS were 5.37 months and 9.63 months, the placebo group
      PFS and OS were 1.4 months and 6.3 months.

      The efficacy and safety of anrotinib combined with pemetrexed in the second-line treatment of
      advanced non-squamous and non-small cell patients deserve further exploration.
This is a multicentre single arm clinical trial conducted in China,the purpose of this study
      is to evaluate and observe Anlotinib (12mg QD PO d1-14, 21 days per cycle) Combined With
      Pemetrexed(500mg/m2,IV,d1,21 days per cycle) as the second-line Treatment in Patients With
      Advanced nonsquamous Non-Small-Cell Lung Cancer.As the report,The median PFS of advanced
      NSCLC treated by Pemetrexed as second-line was 3-3.5 months.We expect the median PFS of
      Anlotinib combined with Pemetrexed as the second-line Treatment in Patients With Advanced
      nonsquamous NSCLC was 6 months.Using PASS15, we calculated the sample size of this study was
      46(α=0.025、β=0.1), according to 10% censoring,the expected sample size is 51.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Anlotinib and Pemetrexed
primary purpose: Treatment
masking: None (Open Label)
measure: Progress free survival (PFS) based on investigator assessment
time frame: each 42 days up to PD or death(up to 24 months)
description: PFS defined as the time from first dose of study treatment until the first date of either objective disease progression or death due to any cause.
measure: Objective Response Rate based on investigator assessment
time frame: each 42 days up to intolerance the toxicity or PD (up to 24 months)
description: ORR is defined as the percentage of subjects with evidence of a confirmed complete response (CR) or partial response (PR) as per Response Evaluation Criteria In Solid Tumors (RECIST) Version 1.1.prior to progression or any further therapy.
measure: Disease Control Rate（DCR）
time frame: each 42 days up to intolerance the toxicity or PD (up to 24 months)
description: Defined as the proportion of patients with a documented complete response, partial response, and stable disease (CR + PR + SD) based on RECIST 1.1.
measure: Overall Survival（OS）
time frame: each 42 days up to intolerance the toxicity or PD (up to 24 months) .
description: Defined as the time until death due to any cause.
measure: Safety(Number of Participants with Adverse Events and Clinical laboratory numerical evaluation as a Measure of Safety)
time frame: each 42 days up to intolerance the toxicity or PD (up to 24 months) .
description: Number of Participants with Adverse Events and Clinical laboratory numerical evaluation as a Measure of Safety
arm group label: Anlotinib plus Pemetrexed
arm group type: Experimental
description: Anlotinib(12mg QD PO d1-14, 21 days per cycle) plus Pemetrexed (500mg/m2 IV d1)
intervention type: Drug
intervention name: Anlotinib plus Pemetrexed
description: Anlotinib(12mg QD PO d1-14, 21 days per cycle) plus Pemetrexed (500mg/m2 IV d1)
arm group label: Anlotinib plus Pemetrexed
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Cang Shundong, doctor
role: Principal Investigator
affiliation: Henan Provincial People's Hospital
last name: Cang Shundong, doctor
phone: 0086-13592675836
email: cangshundong@163.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Pemetrexed
sharing ipd: No