<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/NCT02240212</url>
  </required_header>
  <id_info>
    <org_study_id>201050</org_study_id>
    <nct_id>NCT02240212</nct_id>
  </id_info>
  <brief_title>Study of Afuresertib Combined With Paclitaxel in Gastric Cancer</brief_title>
  <official_title>Phase Ib Study of Afuresertib Combined With Paclitaxel in Pre-treated HER2-negative Advanced Gastric Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase Ib, open-label, dose-escalation study to determine the Maximal tolerated dose&#xD;
      (MTD) and the recommended Phase 2 dose (RP2D) for the combination of afuresertib and&#xD;
      paclitaxel in subjects with recurrent HER2-negative gastric cancer, and further assess safety&#xD;
      and preliminary efficacy of combination at the RP2D. Afuresertib had showed synergistic&#xD;
      activity when combined with paclitaxel in vitro and in vivo models of gastric cancer. Dose&#xD;
      escalation will continue until the MTD is established. The dose schedule is once daily (QD)&#xD;
      dosing for afuresertib and intravenous (IV) infusion for paclitaxel Dose escalation in Part 1&#xD;
      will follow the 3 + 3 cohort design. A sequential approach will be conducted to explore the&#xD;
      optimal paclitaxel regimen (weekly or 3weekly schedule) when combined with afuresertib. The&#xD;
      dose escalation will be started from Cohort A (afuresertib combined with weekly paclitaxel&#xD;
      regimen at 80 milligram (mg)/meter (m)^2 day1, 8,15, every 4 weeks (q4w). The starting dose&#xD;
      in Cohort A will be 125 mg afuresertib QD. Once its MTD is identified, and then the study&#xD;
      will move to dosing Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175&#xD;
      mg/m^2 day1, every 3 week (q3w). The starting daily dose of Cohort B will be 25 mg less than&#xD;
      the MTD dose from Cohort A for afuresertib. If it is tolerated, then the dose escalation&#xD;
      schedule will be followed in Cohort B until the MTD in this Cohort is reached. If the&#xD;
      starting dose is not tolerated, then dose de-escalation will be explored until the MTD in&#xD;
      this Cohort is reached. Once two dimensions of the MTD are achieved, then the optimal regimen&#xD;
      for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile&#xD;
      will be identified. The combination regimen at the RP2D selected following Part I will be&#xD;
      further investigated in its efficacy and safety in the Part II Expansion Cohort. Once a&#xD;
      combination dose regimen for Part 2 has been determined, at least 20 and up to 40 subjects&#xD;
      will be enrolled at the dose regimen selected following Part I. Overall response rate (ORR)&#xD;
      will be evaluated using a Green-Dahlberg design. The design consists with one interim&#xD;
      analysis. If less than 3 responses are observed in the initial 20 subjects, enrollment will&#xD;
      be terminated due to futility; otherwise, the study will continue to meet the planned sample&#xD;
      size of 40 subjects.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 2014</start_date>
  <completion_date type="Actual">February 7, 2017</completion_date>
  <primary_completion_date type="Actual">February 7, 2017</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of subjects with any serious adverse event (SAE), non-serious adverse event (AE) in Phase I Dose Escalation phase</measure>
    <time_frame>Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)</time_frame>
    <description>An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of changes in clinical laboratory tests in Phase I Dose Escalation phase</measure>
    <time_frame>Day 1 to Day 21 after the last dose of study treatment. (assessed up to 1 years)</time_frame>
    <description>Clinical laboratory tests included hematology, clinical chemistry, urinalysis</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of 12-lead electrocardiogram (ECG) findings in Phase I Dose Escalation phase</measure>
    <time_frame>Screening and Day 22</time_frame>
    <description>Heart rate, pulse rate (PR), QRS, QT, and Electrocardiogram QT interval corrected for heart rate using Fridericia's formula (QTcF intervals) will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-recumbent or supine position after 5 minutes rest</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of Echocardiograms (ECHOs) in Phase I Dose Escalation phase</measure>
    <time_frame>Every 9 weeks (for 3 weekly paclitaxel regimen) and every 8 weeks (for weekly paclitaxel regimen) until day 21 after last dose of study treatment (assessed up to 1 years)</time_frame>
    <description>The cardiac ejection fraction and cardiac valve morphology will be assessed by ECHOs. The evaluation of the echocardiographer should include an evaluation for left ventricular ejection fraction (LVEF)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of blood pressure (vital signs) in Phase I Dose Escalation</measure>
    <time_frame>Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)</time_frame>
    <description>Vital signs will include measurement of systolic and diastolic blood pressure. Vital signs should be measured after resting for at least 5minutes in a semi-supine position</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of preliminary clinical efficacy in Phase II dose expansion</measure>
    <time_frame>Every 6 weeks for 3 weekly paclitaxel regimen or every 8 weeks for weekly paclitaxel regimen (assessed up to 1 years)</time_frame>
    <description>Tumor response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST 1.1), the ORR will be based on confirmed responses by investigator-based assessment for gastric cancer</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of respiration rate (vital signs) in Phase I Dose Escalation</measure>
    <time_frame>Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)]</time_frame>
    <description>Vital signs will include measurement of respiration rate. Vital signs should be measured after resting for at least 5minutes in a semi-supine position.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of PR (vital signs) in Phase I Dose Escalation</measure>
    <time_frame>Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)]</time_frame>
    <description>Vital signs will include measurement of PR. Vital signs should be measured after resting for at least 5minutes in a semi-supine position.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Composite of pharmacokinetics parameters of afuresertib and paclitaxel combination regimen in dose escalation cohort</measure>
    <time_frame>Day 1 (pre-dose, 1 to 3 hour [h]), Day 22 (pre-dose, 1 to 3 h and 6-8 h) for 3 weekly dose Paclitaxel regimen</time_frame>
    <description>Afuresertib pharmacokinetic parameters following single and repeat dose administration, including Area under the concentration-time curve (AUC), Maximum observed concentration (Cmax) and paclitaxel Pre-dose (trough) concentration at the end of the dosing interval (Ctrough), Cmax after repeat dose administration, time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluation of the progression free survival (PFS) in expansion cohort</measure>
    <time_frame>Day 1and the earliest date of disease progression or death due to any cause; up to 6 months</time_frame>
    <description>PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause by investigator assessment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of subjects with any SAE, AE in expansion cohort</measure>
    <time_frame>Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years).</time_frame>
    <description>An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of changes in clinical laboratory tests in expansion cohort</measure>
    <time_frame>Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)</time_frame>
    <description>Clinical laboratory tests included hematology, clinical chemistry, urinalysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of 12-lead ECG findings in expansion cohort</measure>
    <time_frame>Screening and Day 22</time_frame>
    <description>Heart rate, PR, QRS, QT, and Electrocardiogram QT interval corrected for heart rate using QTcF intervals will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-recumbent or supine position after 5 minutes rest</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of ECHOs in expansion cohort</measure>
    <time_frame>Every 9 weeks (for 3 weekly paclitaxel regimen) or every 8 weeks (for weekly paclitaxel regimen) to day 21 after last dose of study treatment (assessed up to 1 years)</time_frame>
    <description>The cardiac ejection fraction and cardiac valve morphology will be assessed by ECHOs The evaluation of the echocardiographer should include an evaluation LVEF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of composite pharmacokinetics of afuresertib and paclitaxel in expansion cohort</measure>
    <time_frame>Day 1 (pre-dose, 1 to 3 hour [h]), Day 22 (pre-dose, 1 to 3 h and 6-8 h) for 3 weekly dose Paclitaxel regimen Day 1 (pre-dose, 1 to 3 h), Day 15 (pre-dose, 1 to 3 h and 6-8 h) for weekly dose Paclitaxel regimen</time_frame>
    <description>Afuresertib concentration following single and repeat dose administration and Paclitaxel Ctrough and Cmax after repeat dose administration</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Cancer</condition>
  <arm_group>
    <arm_group_label>Part 1: Dose-escalation (weekly paclitaxel)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The dose escalation will be started from Cohort A (afuresertib combined with weekly paclitaxel regimen at 80 mg/m^2 d1, 8,15, q4w). The starting dose in Cohort A will be 125 mg afuresertib QD to indentify MTD</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 1: Dose-escalation (3 weeks Paclitaxel)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Once its MTD is identified, and then the study will move to dosing Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m^2 d1, q3w. Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m^2 d1, q3w). The starting daily dose of Cohort B will be 25 mg less than the MTD dose from Cohort A for afuresertib. If it is tolerated, then the dose escalation schedule will be followed in Cohort B until the MTD in this Cohort is reached. If the starting dose is not tolerated, then dose de-escalation will be explored until the MTD in this Cohort is reached. Once two dimensions of the MTD are achieved, then the optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be identified</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part 2: Experimental Cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be administered</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afuresertib</intervention_name>
    <description>The unit dose strength is 50mg/75mg tablet. Afuresertib will be taken orally once daily continuously during trail.</description>
    <arm_group_label>Part 1: Dose-escalation (3 weeks Paclitaxel)</arm_group_label>
    <arm_group_label>Part 1: Dose-escalation (weekly paclitaxel)</arm_group_label>
    <arm_group_label>Part 2: Experimental Cohort</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Paclitaxel</intervention_name>
    <description>Paclitaxel sourced locally will be administered IV</description>
    <arm_group_label>Part 1: Dose-escalation (3 weeks Paclitaxel)</arm_group_label>
    <arm_group_label>Part 1: Dose-escalation (weekly paclitaxel)</arm_group_label>
    <arm_group_label>Part 2: Experimental Cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Provided signed written informed consent&#xD;
&#xD;
          -  Male or female &gt;=18 years of age with a diagnosis of Performance Status score of 0 or&#xD;
             1 according to the Eastern Cooperative Oncology at the time of signing the informed&#xD;
             consent&#xD;
&#xD;
          -  Able to swallow and retain orally administered study treatment&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test within 7&#xD;
             days prior to the first dose of study treatment and agree to use effective&#xD;
             contraception during the study. Men with a female partner of childbearing potential&#xD;
             must have either had a prior vasectomy or agree to use effective contraception (Condom&#xD;
             [during non-vaginal intercourse with any partner - male or female] OR Double-barrier&#xD;
             method: condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal&#xD;
             agent (foam/gel/film/cream/suppository) [during sexual intercourse with a female].&#xD;
             Abstinence, defined as sexual inactivity consistent with the preferred and usual&#xD;
             lifestyle of the subject. Periodic abstinence (e.g. calendar, ovulation,&#xD;
             symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
             contraception.&#xD;
&#xD;
          -  Adequate organ system functions at screening as Hematologic system (Absolute&#xD;
             neutrophil count &gt;=1.5 x 10^9/Litre (L), Hemoglobin &gt;=9.0 gram (g)/deci (d)L,&#xD;
             Platelets &gt;=100 x 10^9/microL without transfusion in the past 7 days, prothrombin&#xD;
             time/ international normalized ratio (PT/INR) and partial thromboplastin time (PTT)&#xD;
             &lt;=1.5 x Upper limit of normal [ULN]), Hepatic system (Total bilirubin &lt;=1.0x ULN,&#xD;
             Aspartate aminotransferase (AST) and Alanine aminotransferase (ALT) &lt;=2.5x ULN),&#xD;
             Metabolic system (Fasting Serum Glucose &lt; 126 milli (m)g/dL [7 millimol/L], Hemoglobin&#xD;
             A1C&lt;=8%) and Renal system (Serum creatinine &lt;= ULN, 24-hour urine creatinine clearance&#xD;
             &gt;=60 mL/minute [min])&#xD;
&#xD;
          -  Histologically confirmed from the stomach or gastroeosophageal (GE) junction cancer&#xD;
             with documented HER2-negative (defined as immunohistochemistry (IHC) 0-1+ or IHC2+&#xD;
             with a negative fluorescent in situ hybridization (FISH) test assessed by local or&#xD;
             designated central lab) in primary or metastatic tumor tissue.&#xD;
&#xD;
          -  Metastatic or locally advanced, unresectable disease.&#xD;
&#xD;
          -  Subjects must have received first-line platinum/fluoropyrimidine doublet regimen for&#xD;
             advanced gastric cancer and now exhibit progressive disease (PD), and must have&#xD;
             recovered from any treatment-related toxicity. Note: prior XELOX, XP, FOLFOX, or SP&#xD;
             (S-1+cisplatin)) treatment could be eligible, but prior-taxane are ineligible. Note:&#xD;
             if patient is refractory or disease progression within 6 months of adjuvant treatment,&#xD;
             then his previous treatment would be considered as first line treatment rather than&#xD;
             adjuvant treatment, and then this patient could be enrolled into this study if other&#xD;
             inclusion/exclusion criterion meets.&#xD;
&#xD;
          -  Subjects shall have at least one measurable disease (i.e., present with at least one&#xD;
             measurable lesion) by RECIST version1.1&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of another malignancy. Exception: Subjects who have been disease-free for 3&#xD;
             years, or subjects with a history of completely resected non-melanoma skin cancer or&#xD;
             successfully treated in situ carcinoma are eligible.&#xD;
&#xD;
          -  Prior PI3K-AKT- mammalian target of rapamycin (mTOR) pathway targeted therapy will not&#xD;
             be eligible. (Note: prior vaccine and immunotherapy is allowed but must end at least 8&#xD;
             weeks prior to study treatment).&#xD;
&#xD;
          -  Unresolved toxicity (Grade &lt;=1) from prior chemotherapy with the exception of alopecia&#xD;
             or anemia (Hemoglobin &gt;9 g/dL).&#xD;
&#xD;
          -  Subjects with uncontrolled brain metastases or spinal cord compression.&#xD;
&#xD;
          -  Current use of warfarin for therapeutic anticoagulation (Note: low molecular weight&#xD;
             heparin is permitted).&#xD;
&#xD;
          -  Presence of an active gastrointestinal disease (not including gastric cancer), or&#xD;
             other condition known to interfere significantly with the absorption, distribution,&#xD;
             metabolism, or excretion of drugs. Prior gastrectomy is allowed.&#xD;
&#xD;
          -  History of myocardial infarction, acute coronary syndromes (including unstable&#xD;
             angina), coronary angioplasty, or stenting or bypass grafting within six months of&#xD;
             Screening.&#xD;
&#xD;
          -  Pregnant or lactating female.&#xD;
&#xD;
          -  Any serious and/or unstable pre-existing medical, psychiatric disorder or other&#xD;
             conditions that could interfere with subject's safety, obtaining informed consent or&#xD;
             compliance to the study procedures.&#xD;
&#xD;
          -  Any prohibited medication(s) as Co-administration of afuresertib and medications which&#xD;
             are a sensitive substrate of CYP3A4, OATP1B1 and BCRP with a low therapeutic index&#xD;
             will be prohibited. Coadministration of afuresertib and medications which are a&#xD;
             sensitive substrate of CYP2C8 with a low therapeutic index will be used with caution.&#xD;
&#xD;
          -  History of Type 1 diabetes&#xD;
&#xD;
          -  Any major surgery within the last four weeks.&#xD;
&#xD;
          -  QTcF interval &gt;=470 milliseconds (msec)s.&#xD;
&#xD;
          -  known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to&#xD;
             drugs similar or related to afuresertib and taxanes.&#xD;
&#xD;
          -  Any contraindications (as identified by the investigator) to the doses of paclitaxel&#xD;
             defined in the protocol.&#xD;
&#xD;
          -  Any history of reduction in standard of care paclitaxel dose for peripheral&#xD;
             neuropathy.&#xD;
&#xD;
          -  Known Human Immunodeficiency Virus (HIV) infection or active hepatitis B or C. (Note:&#xD;
             active Hepatitis B virus (HBV) infection is defined as ALT/AST is above or equal to&#xD;
             normal range or HBV deoxyribonucleic acid (DNA) &gt;=2×10^3-4 international unit (IU)/mL;&#xD;
             active Hepatitis C virus (HCV) infection is defined as HCV ribonucleic acid (RNA)+ and&#xD;
             ALT/AST is above normal range). Antiviral therapy should be initiated before study&#xD;
             treatment, and maintain during study treatment in patients with inactive HBV&#xD;
             infection. Prophylaxis against HBV reactivation is recommended in accordance with&#xD;
             established guidelines: the Asian-Pacific census statement on HBV in 2012 and Taiwan&#xD;
             health insurance guidance in 2013.&#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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>110-774</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>120/752</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>135-710</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Taipei</city>
        <zip>100</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Taipei</city>
        <zip>112</zip>
        <country>Taiwan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Korea, Republic of</country>
    <country>Taiwan</country>
  </location_countries>
  <verification_date>April 2017</verification_date>
  <study_first_submitted>September 11, 2014</study_first_submitted>
  <study_first_submitted_qc>September 11, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 15, 2014</study_first_posted>
  <last_update_submitted>April 7, 2017</last_update_submitted>
  <last_update_submitted_qc>April 7, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">April 11, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>second line treatment</keyword>
  <keyword>oncology</keyword>
  <keyword>AKT inhibitor</keyword>
  <keyword>paclitaxel</keyword>
  <keyword>HER2 (ErbB2) negative advanced gastric cancer</keyword>
  <keyword>Afuresertib</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Stomach Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</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/NCT02240212
org study id: 201050
nct id: NCT02240212
lead sponsor: 
has dmc: No
This is a Phase Ib, open-label, dose-escalation study to determine the Maximal tolerated dose
      (MTD) and the recommended Phase 2 dose (RP2D) for the combination of afuresertib and
      paclitaxel in subjects with recurrent HER2-negative gastric cancer, and further assess safety
      and preliminary efficacy of combination at the RP2D. Afuresertib had showed synergistic
      activity when combined with paclitaxel in vitro and in vivo models of gastric cancer. Dose
      escalation will continue until the MTD is established. The dose schedule is once daily (QD)
      dosing for afuresertib and intravenous (IV) infusion for paclitaxel Dose escalation in Part 1
      will follow the 3 + 3 cohort design. A sequential approach will be conducted to explore the
      optimal paclitaxel regimen (weekly or 3weekly schedule) when combined with afuresertib. The
      dose escalation will be started from Cohort A (afuresertib combined with weekly paclitaxel
      regimen at 80 milligram (mg)/meter (m)^2 day1, 8,15, every 4 weeks (q4w). The starting dose
      in Cohort A will be 125 mg afuresertib QD. Once its MTD is identified, and then the study
      will move to dosing Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175
      mg/m^2 day1, every 3 week (q3w). The starting daily dose of Cohort B will be 25 mg less than
      the MTD dose from Cohort A for afuresertib. If it is tolerated, then the dose escalation
      schedule will be followed in Cohort B until the MTD in this Cohort is reached. If the
      starting dose is not tolerated, then dose de-escalation will be explored until the MTD in
      this Cohort is reached. Once two dimensions of the MTD are achieved, then the optimal regimen
      for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile
      will be identified. The combination regimen at the RP2D selected following Part I will be
      further investigated in its efficacy and safety in the Part II Expansion Cohort. Once a
      combination dose regimen for Part 2 has been determined, at least 20 and up to 40 subjects
      will be enrolled at the dose regimen selected following Part I. Overall response rate (ORR)
      will be evaluated using a Green-Dahlberg design. The design consists with one interim
      analysis. If less than 3 responses are observed in the initial 20 subjects, enrollment will
      be terminated due to futility; otherwise, the study will continue to meet the planned sample
      size of 40 subjects.
allocation: Non-Randomized
primary purpose: Treatment
masking: None (Open Label)
measure: Number of subjects with any serious adverse event (SAE), non-serious adverse event (AE) in Phase I Dose Escalation phase
time frame: Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)
description: An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect
measure: Assessment of changes in clinical laboratory tests in Phase I Dose Escalation phase
time frame: Day 1 to Day 21 after the last dose of study treatment. (assessed up to 1 years)
description: Clinical laboratory tests included hematology, clinical chemistry, urinalysis
measure: Assessment of 12-lead electrocardiogram (ECG) findings in Phase I Dose Escalation phase
time frame: Screening and Day 22
description: Heart rate, pulse rate (PR), QRS, QT, and Electrocardiogram QT interval corrected for heart rate using Fridericia's formula (QTcF intervals) will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-recumbent or supine position after 5 minutes rest
measure: Assessment of Echocardiograms (ECHOs) in Phase I Dose Escalation phase
time frame: Every 9 weeks (for 3 weekly paclitaxel regimen) and every 8 weeks (for weekly paclitaxel regimen) until day 21 after last dose of study treatment (assessed up to 1 years)
description: The cardiac ejection fraction and cardiac valve morphology will be assessed by ECHOs. The evaluation of the echocardiographer should include an evaluation for left ventricular ejection fraction (LVEF)
measure: Assessment of blood pressure (vital signs) in Phase I Dose Escalation
time frame: Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)
description: Vital signs will include measurement of systolic and diastolic blood pressure. Vital signs should be measured after resting for at least 5minutes in a semi-supine position
measure: Assessment of preliminary clinical efficacy in Phase II dose expansion
time frame: Every 6 weeks for 3 weekly paclitaxel regimen or every 8 weeks for weekly paclitaxel regimen (assessed up to 1 years)
description: Tumor response will be measured by Response Evaluation Criteria In Solid Tumors (RECIST 1.1), the ORR will be based on confirmed responses by investigator-based assessment for gastric cancer
measure: Assessment of respiration rate (vital signs) in Phase I Dose Escalation
time frame: Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)]
description: Vital signs will include measurement of respiration rate. Vital signs should be measured after resting for at least 5minutes in a semi-supine position.
measure: Assessment of PR (vital signs) in Phase I Dose Escalation
time frame: Screening to Day 21 after the last dose of study treatment (assessed up to 1 years)]
description: Vital signs will include measurement of PR. Vital signs should be measured after resting for at least 5minutes in a semi-supine position.
measure: Composite of pharmacokinetics parameters of afuresertib and paclitaxel combination regimen in dose escalation cohort
time frame: Day 1 (pre-dose, 1 to 3 hour [h]), Day 22 (pre-dose, 1 to 3 h and 6-8 h) for 3 weekly dose Paclitaxel regimen
description: Afuresertib pharmacokinetic parameters following single and repeat dose administration, including Area under the concentration-time curve (AUC), Maximum observed concentration (Cmax) and paclitaxel Pre-dose (trough) concentration at the end of the dosing interval (Ctrough), Cmax after repeat dose administration, time of occurrence of Cmax (tmax), and terminal phase half-life (t1/2)
measure: Evaluation of the progression free survival (PFS) in expansion cohort
time frame: Day 1and the earliest date of disease progression or death due to any cause; up to 6 months
description: PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause by investigator assessment
measure: Number of subjects with any SAE, AE in expansion cohort
time frame: Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years).
description: An AE is defined as any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, or is a congenital anomaly/birth defect
measure: Assessment of changes in clinical laboratory tests in expansion cohort
time frame: Day 1 to Day 21 after the last dose of study treatment (assessed up to 1 years)
description: Clinical laboratory tests included hematology, clinical chemistry, urinalysis
measure: Assessment of 12-lead ECG findings in expansion cohort
time frame: Screening and Day 22
description: Heart rate, PR, QRS, QT, and Electrocardiogram QT interval corrected for heart rate using QTcF intervals will be recorded by measuring triplicate 12-lead ECGs, obtained in semi-recumbent or supine position after 5 minutes rest
measure: Assessment of ECHOs in expansion cohort
time frame: Every 9 weeks (for 3 weekly paclitaxel regimen) or every 8 weeks (for weekly paclitaxel regimen) to day 21 after last dose of study treatment (assessed up to 1 years)
description: The cardiac ejection fraction and cardiac valve morphology will be assessed by ECHOs The evaluation of the echocardiographer should include an evaluation LVEF
measure: Assessment of composite pharmacokinetics of afuresertib and paclitaxel in expansion cohort
time frame: Day 1 (pre-dose, 1 to 3 hour [h]), Day 22 (pre-dose, 1 to 3 h and 6-8 h) for 3 weekly dose Paclitaxel regimen Day 1 (pre-dose, 1 to 3 h), Day 15 (pre-dose, 1 to 3 h and 6-8 h) for weekly dose Paclitaxel regimen
description: Afuresertib concentration following single and repeat dose administration and Paclitaxel Ctrough and Cmax after repeat dose administration
arm group label: Part 1: Dose-escalation (weekly paclitaxel)
arm group type: Experimental
description: The dose escalation will be started from Cohort A (afuresertib combined with weekly paclitaxel regimen at 80 mg/m^2 d1, 8,15, q4w). The starting dose in Cohort A will be 125 mg afuresertib QD to indentify MTD
arm group label: Part 1: Dose-escalation (3 weeks Paclitaxel)
arm group type: Experimental
description: Once its MTD is identified, and then the study will move to dosing Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m^2 d1, q3w. Cohort B (afuresertib combined with 3 weekly paclitaxel regimen at 175 mg/m^2 d1, q3w). The starting daily dose of Cohort B will be 25 mg less than the MTD dose from Cohort A for afuresertib. If it is tolerated, then the dose escalation schedule will be followed in Cohort B until the MTD in this Cohort is reached. If the starting dose is not tolerated, then dose de-escalation will be explored until the MTD in this Cohort is reached. Once two dimensions of the MTD are achieved, then the optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be identified
arm group label: Part 2: Experimental Cohort
arm group type: Experimental
description: The optimal regimen for paclitaxel and MTD for afuresertib combined with paclitaxel based on the toxicity profile will be administered
intervention type: Drug
intervention name: Afuresertib
description: The unit dose strength is 50mg/75mg tablet. Afuresertib will be taken orally once daily continuously during trail.
arm group label: Part 1: Dose-escalation (3 weeks Paclitaxel)
arm group label: Part 1: Dose-escalation (weekly paclitaxel)
arm group label: Part 2: Experimental Cohort
intervention type: Drug
intervention name: Paclitaxel
description: Paclitaxel sourced locally will be administered IV
arm group label: Part 1: Dose-escalation (3 weeks Paclitaxel)
arm group label: Part 1: Dose-escalation (weekly paclitaxel)
arm group label: Part 2: Experimental Cohort
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
facility: 
facility: 
facility: 
facility: 
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country: Korea, Republic of
country: Taiwan
responsible party type: Sponsor
mesh term: Stomach Neoplasms
mesh term: Paclitaxel