<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/NCT04488107</url>
  </required_header>
  <id_info>
    <org_study_id>AH150201</org_study_id>
    <nct_id>NCT04488107</nct_id>
  </id_info>
  <brief_title>Safety, Tolerability, Pharmacokinetics and Antitumor Activity of FCN-437c</brief_title>
  <official_title>A Multicenter, Open, Single Arm Dose-escalation and Dose-expansion Study: to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of FCN-437c Alone or in Combination With Letrozole in ER+/ HER2- Advanced Breast Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ahon Pharmaceutical Co., Ltd.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Fudan University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Zhejiang Cancer Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Sir Run Run Shaw Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Ahon Pharmaceutical Co., Ltd.</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 multicenter, open, single arm dose escalation and dose expansion clinical study to&#xD;
      evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of FCN-437c alone&#xD;
      or in combination with letrozole in women with ER +/ HER2 - advanced breast cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a multicenter, open, single arm clinical study to evaluate the safety, tolerability,&#xD;
      and antitumor activity of FCN-437c in combination with letrozole in postmenopausal women with&#xD;
      ER + / HER2 - advanced breast cancer, and to evaluate the PK characteristics of FCN-437c&#xD;
      monotherapy and combined therapy.&#xD;
&#xD;
      The single drug administration period (7 days) . The continuous administration period made up&#xD;
      of 21 days of continuous administration, followed by 7 days of withdrawal, which made up of&#xD;
      28 days as a treatment cycle. The evaluation was conducted every 8 weeks until one of the&#xD;
      following happened, disease progression, intolerable toxicity, death, the researcher's&#xD;
      decision or the patients' voluntary withdrawal from the study. The follow-up visit was&#xD;
      conducted 30 days after the last administration. The telephone follow-up was conducted once&#xD;
      every 3 months until the end of the study to record the survival period.&#xD;
&#xD;
      In the expansion period, FCN-437c was continuous administration per day for 21 days, followed&#xD;
      by 7 days of withdrawal, making a treatment cycle of 28 days during which letrozole was&#xD;
      continuously administrated 2.5 mg QD. Evaluation was conducted every 8 weeks until one of the&#xD;
      following occurred, disease progression, intolerable toxicity, death, decision of the&#xD;
      researcher or patients' voluntary withdrawal of the study. Follow up visit was conducted 30&#xD;
      days after the last administration, followed by the survival period telephone follow-up every&#xD;
      3 months until the end of the study.&#xD;
&#xD;
      End of of the study was defined as the last patient in the dose expansion stage took the&#xD;
      treatment for more than one year, or terminated the treatment (depending on which occurred&#xD;
      earlier.&#xD;
&#xD;
      At the end of the study, patients with no disease progression were determined to continue&#xD;
      taking FCN-437c according to the clinical benefits.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 14, 2019</start_date>
  <completion_date type="Anticipated">June 30, 2022</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This study plans to start dose escalating from 50 mg, followed by 100, 200, 300, 450, and 600 mg as tentatively designated escalating dose groups. After the initial dose group, it is allowed to adjust the subsequent dose level according to the test data, but it will not exceed 100% dose increment. After the completion of DLT observation in each group, the next dose group and the number of cases were determined according to the safety, efficacy and PK data of the dose group. The traditional &quot;3+3&quot; method was used in the design of dose escalating stage, and the improved Fibonacci series was used for the dose increasing stage.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>DLT within 7 days of FCN-437c monotherapy</measure>
    <time_frame>7 days</time_frame>
    <description>The incidence of DLT occurred within 7 days of FCN-437c monotherapy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>DLT within 28 days of FCN-437c monotherapy</measure>
    <time_frame>28 days</time_frame>
    <description>The incidence of DLT occurred within 28 days of FCN-437c monotherapy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>DLT within 28 days of FCN-437c combined therapy</measure>
    <time_frame>28 days</time_frame>
    <description>The incidence of DLT occurred within 28 days of the letrozole-combined treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Adverse events until the last followup</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>The types and frequencies of adverse events (AEs) evaluated according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Serious and significant adverse events</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Serious adverse events (SAE) and toxic reactions leading to permanent drug withdrawal occurred during the treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of Deaths</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>The frequency and causes of deaths during the treatment.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of abnormal laboratory results</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Abnormal laboratory results of safety concerns such as ALT, AST, Cr and BUN, et al according to NCI-CTCAE 5.0 classification.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of ECGs from baselines</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Changes of ECGs from baselines, such as QT interval。</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Anti-tumor efficacy of monotherapy</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Objective response rate (ORR) of FCN-437c monotherapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anti-tumor efficacy of combined treatment</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Objective response rate (ORR) of FCN-437c and letrozole-combined treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>FPS</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Progression free survival (PFS) during the treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>OS</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>overall survival (OS) during the treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>survival rate</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>1-year OS rate during the 1st year of treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DOR</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>duration of response (DOR) during the treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CBR</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>clinical benefit response (CBR) during the treatment.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of FCN-437c in monotherapy</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Maximal plasma concentration of FCN-437c in monotherapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC of FCN-437c in monotherapy</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Entire exposure of FCN-437c in monotherapy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cmax of FCN-437c in combined treatment</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Maximal plasma concentration of FCN-437c combined with letrozole.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC of FCN-437c in combined treatment</measure>
    <time_frame>through study completion, assessed up to 24 months</time_frame>
    <description>Entire exposure of FCN-437c combined with letrozole.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">78</enrollment>
  <condition>Breast Neoplasms</condition>
  <arm_group>
    <arm_group_label>Dose escalation cohort of FCN-437c</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>This study plans to start escalating from 50 mg QD, through 100 mg, 200 mg, 300 mg, 450 mg, to 600 mg.&#xD;
Participants will receive FCN-437c in sequential 28-day cycles which are made up of monotherapy QD for 21 days followed by a 7 day rest period.&#xD;
Participants must be histologically or cytologically diagnosed with ER+/ HER2- advanced breast cancer.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose expansion cohort of FCN-437c + letrozole</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The dose expansion stage will be initiated after escalating to MTD.&#xD;
Six patients will be treated with FCN-437c combined with letrozole.&#xD;
DLT assessment and PK blood collection will be completed in the first 28-day cycle.&#xD;
If DLT does not occur in the first three patients, 15 additional patients were enrolled to complete the expansion study of MTD group.&#xD;
If one DLT occurs in the first three patients, three additional patients will be enrolled onal patients were enrolled and completed the MTD group.&#xD;
Patients will be evaluated every 8 weeks until disease progression, intolerable toxicity, death, investigator's decision or patient's voluntary withdrawal from the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>FCN-437c</intervention_name>
    <description>- FCN-437c is a selective and potent CDK4/6 dual inhibitor, with broad antitumor activity in preclinical pharmacology models, favorable physical and pharmacokinetic (PK) properties, and acceptable toxicity profile in nonclinical studies.</description>
    <arm_group_label>Dose escalation cohort of FCN-437c</arm_group_label>
    <arm_group_label>Dose expansion cohort of FCN-437c + letrozole</arm_group_label>
    <other_name>Dose-escalation and expansion</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Letrozole 2.5mg</intervention_name>
    <description>Letrozole is the latest generation of aromatase inhibitor. Letrozole lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body.&#xD;
Letrozole is used to treat breast cancer in postmenopausal women. It is often given to women who have been taking tamoxifen (Nolvadex, Soltamox) for 5 years.</description>
    <arm_group_label>Dose expansion cohort of FCN-437c + letrozole</arm_group_label>
    <other_name>Dose-escalation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adult (&gt;= 18 years old) patients diagnosed as ER +/ HER2 - advanced breast cancer,&#xD;
             without standard treatment or unable to receive standard treatment;&#xD;
&#xD;
          -  The eastern cooperative oncology group (ECOG) score is 0 or 1;&#xD;
&#xD;
          -  According to RECIST version 1.1, there was at least one measurable lesion or only bone&#xD;
             metastasis;&#xD;
&#xD;
          -  The expected survival period is at least 12 weeks;&#xD;
&#xD;
          -  Patients have sufficient bone marrow and organ function;&#xD;
&#xD;
          -  Patients is willing and able to follow the planned visit, treatment plan, laboratory&#xD;
             examination and other test procedures;&#xD;
&#xD;
          -  Patients fully understand the study and are willing to sign the informed consent form&#xD;
             (ICF);&#xD;
&#xD;
          -  The inclusion criteria specific for the dose expansion stage are as follows.&#xD;
&#xD;
          -  The postmenopausal patients (&gt;= 18 years old) diagnosed as ER +/ HER2 - breast cancer&#xD;
             have evidence of local recurrence or metastasis, and are not suitable for surgical&#xD;
             resection or radiotherapy for the purpose of cure;&#xD;
&#xD;
          -  There was neither history of systematic treatment nor clinical indication for&#xD;
             chemotherapy for patients in the dose expansion stage;&#xD;
&#xD;
          -  The patients in the dose expansion stage should neither have received neoadjuvant or&#xD;
             adjuvant endocrine therapy previously, nor have progression free survival during or&#xD;
             after the neoadjuvant or adjuvant endocrine therapy was shorter than 12 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  HER2 + breast cancer, either defined as by fluorescence hybridization (FISH) or&#xD;
             detected by standard immunohistochemistry (IHC);&#xD;
&#xD;
          -  History of previous CDK4 / 6 inhibitors treatment;&#xD;
&#xD;
          -  Received anti-tumor chemotherapy, major surgery, radiotherapy, biological drug therapy&#xD;
             or other research drug treatment within 28 days before enrollment;&#xD;
&#xD;
          -  The toxicity of previous anti-tumor therapy has not recovered (&gt;= grade 2 according to&#xD;
             NCI CTCAE version 5.0), except for hair loss; the neurotoxicity of patients who have&#xD;
             received chemotherapy before should be restored to grade 2 or below based on NCI CTCAE&#xD;
             version 5.0;&#xD;
&#xD;
          -  The patient used CYP3A strong inhibitor or CYP3A inducer 14 days before the first dose&#xD;
             administration;&#xD;
&#xD;
          -  Cardiac dysfunction or disease are consistent with one of the following conditions&#xD;
             such as arrhythmia with clinical significance, any risk factors increasing risk of QTc&#xD;
             interval prolongation, or congestive heart failure (CHF) with grade ≥ 3 according to&#xD;
             NYHA ;&#xD;
&#xD;
          -  Dysphagia, active digestive system disease, major gastrointestinal surgery,&#xD;
             malabsorption syndrome, or other conditions that may impair the absorption of&#xD;
             FCN-437c;&#xD;
&#xD;
          -  Known allergy to letrozole, FNC-437c or any other excipients;&#xD;
&#xD;
          -  Uncontrolled central system metastasis;&#xD;
&#xD;
          -  Active infection, including HBV, HCV, HIV, et al;&#xD;
&#xD;
          -  Any other disease or condition of clinical significance (e.g., uncontrolled diabetes,&#xD;
             active or uncontrollable infection) that the researchers believe may affect protocol&#xD;
             compliance or affect patients' signing of ICF;&#xD;
&#xD;
          -  The exclusion criteria specific for the dose expansion stage was as follows.&#xD;
&#xD;
          -  Postmenopausal women with advanced breast cancer who have received neoadjuvant /&#xD;
             adjuvant endocrine therapy and progressed less than 12 months after treatment;&#xD;
&#xD;
          -  Patients with advanced breast cancer who had received systemic anti-tumor therapy&#xD;
             including endocrine and chemotherapy (patients with ER + and HER2 - who had received&#xD;
             aromatase inhibitors for no more than 14 days were allowed to be enrolled) ;&#xD;
&#xD;
          -  Other exclusion criteria are the same as those of the dose escalation stage.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Women with breast cancer,</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Xichun Hu, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Fudan University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Xichun Hu, M.D.</last_name>
    <phone>13816110335</phone>
    <email>xchu2009@hotmail.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jian Zhang, M.D.</last_name>
    <email>syner2000@163.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Fudan University Shanghai Cancer Center</name>
      <address>
        <city>Shanghai</city>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Xichun Hu, M.D.</last_name>
      <phone>13816110335</phone>
      <email>xchu2009@hotmail.com</email>
    </contact>
    <contact_backup>
      <last_name>Jian zhang, M.D.</last_name>
      <email>syner2000@163.com</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Curigliano G, Gomez Pardo P, Meric-Bernstam F, Conte P, Lolkema MP, Beck JT, Bardia A, Martinez Garcia M, Penault-Llorca F, Dhuria S, Tang Z, Solovieff N, Miller M, Di Tomaso E, Hurvitz SA. Ribociclib plus letrozole in early breast cancer: A presurgical, window-of-opportunity study. Breast. 2016 Aug;28:191-8. doi: 10.1016/j.breast.2016.06.008. Epub 2016 Jun 20.</citation>
    <PMID>27336726</PMID>
  </reference>
  <reference>
    <citation>Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson JR, Crystal AS, Parasuraman S, Shapiro GI. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res. 2016 Dec 1;22(23):5696-5705. doi: 10.1158/1078-0432.CCR-16-1248. Epub 2016 Aug 19.</citation>
    <PMID>27542767</PMID>
  </reference>
  <reference>
    <citation>Tamura K, Mukai H, Naito Y, Yonemori K, Kodaira M, Tanabe Y, Yamamoto N, Osera S, Sasaki M, Mori Y, Hashigaki S, Nagasawa T, Umeyama Y, Yoshino T. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016 Jun;107(6):755-63. doi: 10.1111/cas.12932. Epub 2016 May 11.</citation>
    <PMID>26991823</PMID>
  </reference>
  <reference>
    <citation>Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.</citation>
    <PMID>19097774</PMID>
  </reference>
  <reference>
    <citation>Elsasser A, Regnstrom J, Vetter T, Koenig F, Hemmings RJ, Greco M, Papaluca-Amati M, Posch M. Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency. Trials. 2014 Oct 2;15:383. doi: 10.1186/1745-6215-15-383.</citation>
    <PMID>25278265</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 13, 2020</study_first_submitted>
  <study_first_submitted_qc>July 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>July 23, 2020</last_update_submitted>
  <last_update_submitted_qc>July 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ER-Positive</keyword>
  <keyword>HER2-Negative</keyword>
  <keyword>Breast Neoplasms</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Letrozole</mesh_term>
  </intervention_browse>
  <study_docs>
    <study_doc>
      <doc_id>ICH topic S9</doc_id>
      <doc_type>ICH topic S9 - nonclinical evaluation for anticancer pharmaceuticals. 2009</doc_type>
      <doc_url>https://database.ich.org/sites/default/files/S9_Guideline.pdf</doc_url>
    </study_doc>
    <study_doc>
      <doc_id>IBRANCE® (palbociclib) capsule</doc_id>
      <doc_type>label for IBRANCE® (palbociclib) capsules</doc_type>
      <doc_url>https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207103s000lbl.pdf</doc_url>
    </study_doc>
    <study_doc>
      <doc_id>IBRANCE® (palbociclib) tablets</doc_id>
      <doc_type>label for IBRANCE® (palbociclib) tablets,</doc_type>
      <doc_url>https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212436lbl.pdf</doc_url>
    </study_doc>
    <study_doc>
      <doc_id>KISQALI® (ribociclib) tablets</doc_id>
      <doc_type>Label for KISQALI® (ribociclib) tablets</doc_type>
      <doc_url>https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209092s005lbl.pdf</doc_url>
    </study_doc>
    <study_doc>
      <doc_id>ICH Topic E6 (R1)</doc_id>
      <doc_type>ICH Topic E6 (R1) Guideline for Good Clinical Practice</doc_type>
      <doc_url>https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e6-r1-guideline-good-clinical-practice_en.pdf</doc_url>
    </study_doc>
    <study_doc>
      <doc_id>ICH Topic E9</doc_id>
      <doc_type>ICH Topic E9 Statistical Principles for Clinical Trials</doc_type>
      <doc_url>https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-9-statistical-principles-clinical-trials-step-5_en.pdf</doc_url>
    </study_doc>
  </study_docs>
  <!-- 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/NCT04488107
org study id: AH150201
nct id: NCT04488107
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This is a multicenter, open, single arm dose escalation and dose expansion clinical study to
      evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of FCN-437c alone
      or in combination with letrozole in women with ER +/ HER2 - advanced breast cancer.
This is a multicenter, open, single arm clinical study to evaluate the safety, tolerability,
      and antitumor activity of FCN-437c in combination with letrozole in postmenopausal women with
      ER + / HER2 - advanced breast cancer, and to evaluate the PK characteristics of FCN-437c
      monotherapy and combined therapy.

      The single drug administration period (7 days) . The continuous administration period made up
      of 21 days of continuous administration, followed by 7 days of withdrawal, which made up of
      28 days as a treatment cycle. The evaluation was conducted every 8 weeks until one of the
      following happened, disease progression, intolerable toxicity, death, the researcher's
      decision or the patients' voluntary withdrawal from the study. The follow-up visit was
      conducted 30 days after the last administration. The telephone follow-up was conducted once
      every 3 months until the end of the study to record the survival period.

      In the expansion period, FCN-437c was continuous administration per day for 21 days, followed
      by 7 days of withdrawal, making a treatment cycle of 28 days during which letrozole was
      continuously administrated 2.5 mg QD. Evaluation was conducted every 8 weeks until one of the
      following occurred, disease progression, intolerable toxicity, death, decision of the
      researcher or patients' voluntary withdrawal of the study. Follow up visit was conducted 30
      days after the last administration, followed by the survival period telephone follow-up every
      3 months until the end of the study.

      End of of the study was defined as the last patient in the dose expansion stage took the
      treatment for more than one year, or terminated the treatment (depending on which occurred
      earlier.

      At the end of the study, patients with no disease progression were determined to continue
      taking FCN-437c according to the clinical benefits.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This study plans to start dose escalating from 50 mg, followed by 100, 200, 300, 450, and 600 mg as tentatively designated escalating dose groups. After the initial dose group, it is allowed to adjust the subsequent dose level according to the test data, but it will not exceed 100% dose increment. After the completion of DLT observation in each group, the next dose group and the number of cases were determined according to the safety, efficacy and PK data of the dose group. The traditional "3+3" method was used in the design of dose escalating stage, and the improved Fibonacci series was used for the dose increasing stage.
primary purpose: Treatment
masking: None (Open Label)
measure: DLT within 7 days of FCN-437c monotherapy
time frame: 7 days
description: The incidence of DLT occurred within 7 days of FCN-437c monotherapy
measure: DLT within 28 days of FCN-437c monotherapy
time frame: 28 days
description: The incidence of DLT occurred within 28 days of FCN-437c monotherapy
measure: DLT within 28 days of FCN-437c combined therapy
time frame: 28 days
description: The incidence of DLT occurred within 28 days of the letrozole-combined treatment.
measure: Adverse events until the last followup
time frame: through study completion, assessed up to 24 months
description: The types and frequencies of adverse events (AEs) evaluated according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0.
measure: Serious and significant adverse events
time frame: through study completion, assessed up to 24 months
description: Serious adverse events (SAE) and toxic reactions leading to permanent drug withdrawal occurred during the treatment.
measure: Incidence of Deaths
time frame: through study completion, assessed up to 24 months
description: The frequency and causes of deaths during the treatment.
measure: Incidence of abnormal laboratory results
time frame: through study completion, assessed up to 24 months
description: Abnormal laboratory results of safety concerns such as ALT, AST, Cr and BUN, et al according to NCI-CTCAE 5.0 classification.
measure: Changes of ECGs from baselines
time frame: through study completion, assessed up to 24 months
description: Changes of ECGs from baselines, such as QT interval。
measure: Anti-tumor efficacy of monotherapy
time frame: through study completion, assessed up to 24 months
description: Objective response rate (ORR) of FCN-437c monotherapy.
measure: Anti-tumor efficacy of combined treatment
time frame: through study completion, assessed up to 24 months
description: Objective response rate (ORR) of FCN-437c and letrozole-combined treatment.
measure: FPS
time frame: through study completion, assessed up to 24 months
description: Progression free survival (PFS) during the treatment.
measure: OS
time frame: through study completion, assessed up to 24 months
description: overall survival (OS) during the treatment.
measure: survival rate
time frame: through study completion, assessed up to 24 months
description: 1-year OS rate during the 1st year of treatment.
measure: DOR
time frame: through study completion, assessed up to 24 months
description: duration of response (DOR) during the treatment.
measure: CBR
time frame: through study completion, assessed up to 24 months
description: clinical benefit response (CBR) during the treatment.
measure: Cmax of FCN-437c in monotherapy
time frame: through study completion, assessed up to 24 months
description: Maximal plasma concentration of FCN-437c in monotherapy.
measure: AUC of FCN-437c in monotherapy
time frame: through study completion, assessed up to 24 months
description: Entire exposure of FCN-437c in monotherapy.
measure: Cmax of FCN-437c in combined treatment
time frame: through study completion, assessed up to 24 months
description: Maximal plasma concentration of FCN-437c combined with letrozole.
measure: AUC of FCN-437c in combined treatment
time frame: through study completion, assessed up to 24 months
description: Entire exposure of FCN-437c combined with letrozole.
arm group label: Dose escalation cohort of FCN-437c
arm group type: Experimental
description: This study plans to start escalating from 50 mg QD, through 100 mg, 200 mg, 300 mg, 450 mg, to 600 mg.
Participants will receive FCN-437c in sequential 28-day cycles which are made up of monotherapy QD for 21 days followed by a 7 day rest period.
Participants must be histologically or cytologically diagnosed with ER+/ HER2- advanced breast cancer.
arm group label: Dose expansion cohort of FCN-437c + letrozole
arm group type: Experimental
description: The dose expansion stage will be initiated after escalating to MTD.
Six patients will be treated with FCN-437c combined with letrozole.
DLT assessment and PK blood collection will be completed in the first 28-day cycle.
If DLT does not occur in the first three patients, 15 additional patients were enrolled to complete the expansion study of MTD group.
If one DLT occurs in the first three patients, three additional patients will be enrolled onal patients were enrolled and completed the MTD group.
Patients will be evaluated every 8 weeks until disease progression, intolerable toxicity, death, investigator's decision or patient's voluntary withdrawal from the study.
intervention type: Drug
intervention name: FCN-437c
description: - FCN-437c is a selective and potent CDK4/6 dual inhibitor, with broad antitumor activity in preclinical pharmacology models, favorable physical and pharmacokinetic (PK) properties, and acceptable toxicity profile in nonclinical studies.
arm group label: Dose escalation cohort of FCN-437c
arm group label: Dose expansion cohort of FCN-437c + letrozole
other name: Dose-escalation and expansion
intervention type: Drug
intervention name: Letrozole 2.5mg
description: Letrozole is the latest generation of aromatase inhibitor. Letrozole lowers estrogen levels in postmenopausal women, which may slow the growth of certain types of breast tumors that need estrogen to grow in the body.
Letrozole is used to treat breast cancer in postmenopausal women. It is often given to women who have been taking tamoxifen (Nolvadex, Soltamox) for 5 years.
arm group label: Dose expansion cohort of FCN-437c + letrozole
other name: Dose-escalation
criteria: 
gender: Female
gender based: Yes
gender description: Women with breast cancer,
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Xichun Hu, M.D.
role: Principal Investigator
affiliation: Fudan University
last name: Xichun Hu, M.D.
phone: 13816110335
email: xchu2009@hotmail.com
last name: Jian Zhang, M.D.
email: syner2000@163.com
facility: 
status: Recruiting
contact: 
contact backup: 
country: China
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PMID: 27336726
citation: Infante JR, Cassier PA, Gerecitano JF, Witteveen PO, Chugh R, Ribrag V, Chakraborty A, Matano A, Dobson JR, Crystal AS, Parasuraman S, Shapiro GI. A Phase I Study of the Cyclin-Dependent Kinase 4/6 Inhibitor Ribociclib (LEE011) in Patients with Advanced Solid Tumors and Lymphomas. Clin Cancer Res. 2016 Dec 1;22(23):5696-5705. doi: 10.1158/1078-0432.CCR-16-1248. Epub 2016 Aug 19.
PMID: 27542767
citation: Tamura K, Mukai H, Naito Y, Yonemori K, Kodaira M, Tanabe Y, Yamamoto N, Osera S, Sasaki M, Mori Y, Hashigaki S, Nagasawa T, Umeyama Y, Yoshino T. Phase I study of palbociclib, a cyclin-dependent kinase 4/6 inhibitor, in Japanese patients. Cancer Sci. 2016 Jun;107(6):755-63. doi: 10.1111/cas.12932. Epub 2016 May 11.
PMID: 26991823
citation: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
PMID: 19097774
citation: Elsasser A, Regnstrom J, Vetter T, Koenig F, Hemmings RJ, Greco M, Papaluca-Amati M, Posch M. Adaptive clinical trial designs for European marketing authorization: a survey of scientific advice letters from the European Medicines Agency. Trials. 2014 Oct 2;15:383. doi: 10.1186/1745-6215-15-383.
PMID: 25278265
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Letrozole
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