<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/NCT04487236</url>
  </required_header>
  <id_info>
    <org_study_id>ZN-A-1041-101</org_study_id>
    <nct_id>NCT04487236</nct_id>
  </id_info>
  <brief_title>Trial of ZN-A-1041 Enteric Capsules in Patients With HER2-Positive Advanced Solid Tumors</brief_title>
  <official_title>A Phase 1 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of ZN-A-1041 Enteric Capsules as a Single Agent or in Combination in Patients With HER2-Positive Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Suzhou Zanrong Pharma Limited</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Suzhou Zanrong Pharma Limited</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability,&#xD;
      PK and efficacy of ZN-A-1041 as a monotherapy or in combination in patients with&#xD;
      HER2-positive advanced solid tumors.&#xD;
&#xD;
      The study will consist of three phases: phase 1a (dose escalation with ZN-A-1041&#xD;
      monotherapy), phase 1b (dose escalation with ZN-A-1041 in combination with Capecitabine and&#xD;
      Trastuzumab) and phase 1c (dose expansion with ZN-A-1041 in combination with Capecitabine and&#xD;
      Trastuzumab).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase 1a of the study will adopt the &quot;modified 3+3&quot; dose escalation design with a total of 7&#xD;
      planned dose levels. Patients with HER2-positive advanced solid tumor (including those with&#xD;
      brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041&#xD;
      followed by multiple-dose administration of ZN-A-1041.&#xD;
&#xD;
      Phase 1b of the study will adopt the &quot;traditional 3+3&quot; dose escalation design. In phase 1b,&#xD;
      patients with HER2-positive advanced breast cancer (including those with brain metastases)&#xD;
      will be enrolled to receive multiple doses of ZN-A-1041 in combination with Capecitabine and&#xD;
      Trastuzumab.&#xD;
&#xD;
      In phase 1c patients with HER2-positive breast cancer with brain metastases were planned to&#xD;
      be enrolled to receive ZN-A-1041 in combination with Capecitabine and Trastuzumab The dose&#xD;
      levels will be determined based on the recommended doses obtained from the Phase 1b study,&#xD;
      and the possible changes in the dosage form and the food effect study, which will be decided&#xD;
      by the sponsor and the investigator after discussion.&#xD;
&#xD;
      Each phase of the study includes a screening period, a treatment period and a follow-up&#xD;
      period. During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as&#xD;
      monotherapy and in combination with Capecitabine and Trastuzumab in the subjects will be&#xD;
      collected and analyzed, thereby providing RP2D for the subsequent clinical trials.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 15, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 30, 2023</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>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a</measure>
    <time_frame>23days</time_frame>
    <description>Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The safety/tolerability of ZN-A-1041 in combination with Capecitabine and Trastuzumab in Phase 1b</measure>
    <time_frame>21days</time_frame>
    <description>Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The safety of ZN-A-1041 in combination with Capecitabine and Trastuzumab in Phase 1c</measure>
    <time_frame>through study completion, an average of 3 year</time_frame>
    <description>To evaluate the safety of ZN-A-1041 in combination with Capecitabine in patients on the RP2D Dose</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c</measure>
    <time_frame>From baseline to Day 8</time_frame>
    <description>To assess the AUC of ZN-A-1041 and its major metabolites;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma Level of ZN-A-1041 and its major metabolites on Phase 1a,phase 1 b and 1c</measure>
    <time_frame>From baseline to Day 8</time_frame>
    <description>To assess the Cmax of ZN-A-1041 and its major metabolites;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c</measure>
    <time_frame>From baseline to Day 8</time_frame>
    <description>To assess the Tmax of ZN-A-1041 and its major metabolites;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c</measure>
    <time_frame>through study completion, an average of 3 year</time_frame>
    <description>overall Response Rate (ORR);Progression free survival(PFS)</description>
  </secondary_outcome>
  <number_of_arms>11</number_of_arms>
  <enrollment type="Anticipated">84</enrollment>
  <condition>Advanced Solid Tumors</condition>
  <condition>HER2-positive Breast Cancer</condition>
  <arm_group>
    <arm_group_label>ZN-A-1041 50mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 100mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 200mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 400mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 600mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 800mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 1000mg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1a:&#xD;
Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 level 1+Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1b:&#xD;
ZN-A-1041 Level 1 (The previous dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study.&#xD;
Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.&#xD;
Trastuzumab (8 mg/kg in cycle 1 followed by 6 mg/kg beginning in cycle 2, administered as an IV infusion.&#xD;
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 level 2+Capecitabine 1000 mg/m2+ Trastuzumab 8 mg/kg iv. First Cycle</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1b:&#xD;
ZN-A-1041 Level 2 ( dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study.&#xD;
Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.&#xD;
Trastuzumab (8 mg/kg in cycle 1 followed by 6 mg/kg beginning in cycle 2, administered as an IV infusion.&#xD;
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041 MAD+Capecitabine 1000 mg/m2+Trastuzumab 8 mg/kg iv. First Cycle</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1b:&#xD;
If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level (MAD) of ZN-A-1041 in Phase 1a will be used in Phase 1b study.&#xD;
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ZN-A-1041+Capecitabine+Trastuzumab</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Phase 1c:&#xD;
The combined dose of ZN-A-1041 is based on the recommended combined dose in the Phase 1b and the possible changes in the dosage form and the results of the food effect study, which will be decided by the sponsor and the investigator after discussion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 50mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 50mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 100mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 100mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 200mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 200mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 400mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 400mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 600mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 600mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 800mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 800mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 1000mg BID</intervention_name>
    <description>Orally 21days for one cycle</description>
    <arm_group_label>ZN-A-1041 1000mg</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 Level 1 +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle</intervention_name>
    <description>ZN-A-1041 level 1 BID; Capecitabine 1000 mg/m2 BID Trastuzumab 8 mg/kg iv. First Cycle</description>
    <arm_group_label>ZN-A-1041 level 1+Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 Level 2 +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle</intervention_name>
    <description>ZN-A-1041 level 2 BID; Capecitabine 1000 mg/m2 BID Trastuzumab 8 mg/kg iv. First Cycle</description>
    <arm_group_label>ZN-A-1041 level 2+Capecitabine 1000 mg/m2+ Trastuzumab 8 mg/kg iv. First Cycle</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041 MAD +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle</intervention_name>
    <description>ZN-A-1041 MAD BID; Capecitabine 1000 mg/m2 BID Trastuzumab 8 mg/kg iv. First Cycle</description>
    <arm_group_label>ZN-A-1041 MAD+Capecitabine 1000 mg/m2+Trastuzumab 8 mg/kg iv. First Cycle</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ZN-A-1041+Capecitabine + Trastuzumab 8 mg/kg iv. First Cycle</intervention_name>
    <description>Base on 1b ZN-A-1041 dose Base on 1b Capecitabine dose Base on 1b Trastuzumab dose</description>
    <arm_group_label>ZN-A-1041+Capecitabine+Trastuzumab</arm_group_label>
    <other_name>ZN-A-1041 Enteric Capsules</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Key inclusion criteria:&#xD;
&#xD;
        11. ECOG performance status of 0 to 1 2. HER2-positive is defined as Immunohistochemistry&#xD;
        (IHC) (++) and Fluorescence In Situ Hybridization (FISH) positive, or IHC (+++).&#xD;
&#xD;
        3. Phase 1a study will enroll patients with unresectable or metastatic HER2-positive&#xD;
        advanced solid tumor; Phase 1b study will enroll patients with unresectable&#xD;
        locally-advanced or metastatic HER2+ breast cancer.&#xD;
&#xD;
        i. For patients who have no brain metastases, the following criteria should be met:&#xD;
&#xD;
          1. Patients should be relapsed or refractory to existing therapy(ies) or have been&#xD;
             intolerant of such therapies&#xD;
&#xD;
          2. Have at least one extracranial measurable lesion by RECIST v1. 1 ii. For patients with&#xD;
             brain metastasis, the following criteria should be met:&#xD;
&#xD;
        1) Have received prior treatment or patient declined the above treatment; 2) Patients with&#xD;
        HER2-positive gastric cancer must have previously received Trastuzumab 3) Do not require&#xD;
        immediate local treatment during the trial period, and meet either of the following two&#xD;
        criteria:&#xD;
&#xD;
          1. For patients who have received previous local treatment (surgery, whole brain&#xD;
             radiotherapy (WBRT) and stereotactic radiosurgery (SRS)) for brain metastases, stable&#xD;
             or progression of intracranial lesions is required. Interval from prior local therapy&#xD;
             could be 3 weeks from WBRT and 2 weeks from SRS.&#xD;
&#xD;
          2. Symptomatic or not, patient has not received previous local treatment (surgery or&#xD;
             radiotherapy) for brain metastases as long as no local therapy is needed during the&#xD;
             trial period.&#xD;
&#xD;
        iii. In Phase 1a, for patients who have received previous tyrosine kinase inhibitor (TKI)&#xD;
        treatment, chemotherapy, antibody, or antibody-drug conjugate (ADC), the interval between&#xD;
        the last treatment and the first administration of the study drug in this trial should be&#xD;
        at least 2 weeks. In Phase 1b, for patients who have received previous trastuzumab or other&#xD;
        antibodies, the interval between the last treatment and the first administration of the&#xD;
        study drug in this trial should be at least 3 weeks.&#xD;
&#xD;
        4. Phase 1c study will enroll patients with unresectable locally-advanced or metastatic&#xD;
        HER2+ breast cancer with brain metastases.&#xD;
&#xD;
        i. For patients with brain metastasis, patients do not require immediate local treatment&#xD;
        during the trial period, and meet either of the following two criteria:&#xD;
&#xD;
          1. For patients who have received previous local treatment (surgery, whole brain&#xD;
             radiotherapy (WBRT) and stereotactic radiosurgery (SRS)) for brain metastases, stable&#xD;
             or progression of intracranial lesions is required. Interval from prior local therapy&#xD;
             could be 3 weeks from WBRT, 2 weeks from SRS and 4 weeks from surgery&#xD;
&#xD;
          2. Symptomatic or not, patient has not received previous local treatment (surgery or&#xD;
             radiotherapy) for brain metastases as long as no local therapy is needed during the&#xD;
             trial period&#xD;
&#xD;
          3. Have at least one measurable lesion and is suitable for accurate repeated assessable&#xD;
             by RECIST 1.1, and the patient has an imaging-diagnosable intracranial lesion;&#xD;
&#xD;
          4. Patients should not include suspected or confirmed meningeal metastases;&#xD;
&#xD;
          5. The patient had no disease progression with previous 12 weeks' capecitabine therapy;&#xD;
&#xD;
          6. No capecitabine therapy within 6 months;&#xD;
&#xD;
          7. Patient should not previously treat with a tyrosine kinase inhibitor (TKI). Previous&#xD;
             treatment with trastuzumab or other antibodies should be at least 3 weeks apart from&#xD;
             the first treatment&#xD;
&#xD;
        Key exclusion criteria:&#xD;
&#xD;
          1. Subjects who have participated in any clinical study or received any clinical study&#xD;
             drug within 4 weeks prior to the first administration&#xD;
&#xD;
          2. There is evidence that other primary tumors are present at the same time;&#xD;
&#xD;
          3. Previous cumulative dose of doxorubicin exceeds 360mg/m2 or its equivalent dose of&#xD;
             similar drugs;&#xD;
&#xD;
          4. CNS Exclusion - Based on screening brain MRI and clinical assessment&#xD;
&#xD;
               1. Progressive neurologic impairment or increased intracranial pressure (including&#xD;
                  nausea, vomiting, blurred vision, headache, epilepsy, etc.)&#xD;
&#xD;
               2. Any intracranial lesion thought to require immediate local therapy&#xD;
&#xD;
               3. Require antiepileptic treatment (except for these patients with stable seizures&#xD;
                  require continuous Levetiracetam therapy).&#xD;
&#xD;
               4. Ongoing use of systemic corticosteroids for control of symptoms of brain&#xD;
                  metastases at a total daily dose of &gt; 2 mg of dexamethasone (or equivalent)&#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>Fei Ma, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Fei Ma, MD</last_name>
    <phone>+861087788060</phone>
    <email>drmafei@126.com</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Qun Yi Li, MD</last_name>
    <phone>+861087788120</phone>
    <email>liyiqun_chcams@foxmail.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Cancer hospital Chinese academy of medical sciences</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100000</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Qun Yi LI, MD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>October 2022</verification_date>
  <study_first_submitted>July 10, 2020</study_first_submitted>
  <study_first_submitted_qc>July 22, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 27, 2020</study_first_posted>
  <last_update_submitted>July 30, 2023</last_update_submitted>
  <last_update_submitted_qc>July 30, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phase 1</keyword>
  <keyword>Advanced Solid Tumors</keyword>
  <keyword>HER2-Positive Breast Cancer</keyword>
  <keyword>Brain metastases</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Capecitabine</mesh_term>
    <mesh_term>Trastuzumab</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/NCT04487236
org study id: ZN-A-1041-101
nct id: NCT04487236
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
This will be a phase 1, multicenter, open-label trial to evaluate the safety, tolerability,
      PK and efficacy of ZN-A-1041 as a monotherapy or in combination in patients with
      HER2-positive advanced solid tumors.

      The study will consist of three phases: phase 1a (dose escalation with ZN-A-1041
      monotherapy), phase 1b (dose escalation with ZN-A-1041 in combination with Capecitabine and
      Trastuzumab) and phase 1c (dose expansion with ZN-A-1041 in combination with Capecitabine and
      Trastuzumab).
Phase 1a of the study will adopt the "modified 3+3" dose escalation design with a total of 7
      planned dose levels. Patients with HER2-positive advanced solid tumor (including those with
      brain metastases) will be enrolled to receive a single-dose administration of ZN-A-1041
      followed by multiple-dose administration of ZN-A-1041.

      Phase 1b of the study will adopt the "traditional 3+3" dose escalation design. In phase 1b,
      patients with HER2-positive advanced breast cancer (including those with brain metastases)
      will be enrolled to receive multiple doses of ZN-A-1041 in combination with Capecitabine and
      Trastuzumab.

      In phase 1c patients with HER2-positive breast cancer with brain metastases were planned to
      be enrolled to receive ZN-A-1041 in combination with Capecitabine and Trastuzumab The dose
      levels will be determined based on the recommended doses obtained from the Phase 1b study,
      and the possible changes in the dosage form and the food effect study, which will be decided
      by the sponsor and the investigator after discussion.

      Each phase of the study includes a screening period, a treatment period and a follow-up
      period. During the trial, the safety, tolerability, PK and efficacy data of ZN-A-1041 as
      monotherapy and in combination with Capecitabine and Trastuzumab in the subjects will be
      collected and analyzed, thereby providing RP2D for the subsequent clinical trials.
allocation: Non-Randomized
intervention model: Sequential Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The safety/tolerability of ZN-A-1041 as a monotherapy on Phase 1a
time frame: 23days
description: Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.
measure: The safety/tolerability of ZN-A-1041 in combination with Capecitabine and Trastuzumab in Phase 1b
time frame: 21days
description: Dose at which no more than one out of six patient at the same dose level experiences a probable drug-related dose limiting toxicity.
measure: The safety of ZN-A-1041 in combination with Capecitabine and Trastuzumab in Phase 1c
time frame: through study completion, an average of 3 year
description: To evaluate the safety of ZN-A-1041 in combination with Capecitabine in patients on the RP2D Dose
measure: Plasma Level of ZN-A-1041 and its major metabolites on phase 1a,phase 1b and 1c
time frame: From baseline to Day 8
description: To assess the AUC of ZN-A-1041 and its major metabolites;
measure: Plasma Level of ZN-A-1041 and its major metabolites on Phase 1a,phase 1 b and 1c
time frame: From baseline to Day 8
description: To assess the Cmax of ZN-A-1041 and its major metabolites;
measure: Plasma level of ZN-A-1041 and its main metabolites Phase 1a,phase 1b and 1c
time frame: From baseline to Day 8
description: To assess the Tmax of ZN-A-1041 and its major metabolites;
measure: The preliminary efficacy of ZN-A-1041 as a monotherapy or combination in Phase 1a,phase 1b and 1c
time frame: through study completion, an average of 3 year
description: overall Response Rate (ORR);Progression free survival(PFS)
arm group label: ZN-A-1041 50mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 50mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 100mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 100mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 200mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 200mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 400mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 400mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 600mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 600mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 800mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 800mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 1000mg
arm group type: Experimental
description: Phase 1a:
Subjects will be given ZN-A-1041 orally 1000mg Bid, for 21days as one cycle
arm group label: ZN-A-1041 level 1+Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle
arm group type: Experimental
description: Phase 1b:
ZN-A-1041 Level 1 (The previous dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study.
Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.
Trastuzumab (8 mg/kg in cycle 1 followed by 6 mg/kg beginning in cycle 2, administered as an IV infusion.
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration
arm group label: ZN-A-1041 level 2+Capecitabine 1000 mg/m2+ Trastuzumab 8 mg/kg iv. First Cycle
arm group type: Experimental
description: Phase 1b:
ZN-A-1041 Level 2 ( dose of MTD) to be used in the combination therapy will be determined based on the MTD identified in the Phase 1a study.
Capecitabine will be given at the dose of 1000 mg/m2, BID (2000 mg/m2/day), during the first 2 weeks of the 21-day treatment cycle.
Trastuzumab (8 mg/kg in cycle 1 followed by 6 mg/kg beginning in cycle 2, administered as an IV infusion.
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration
arm group label: ZN-A-1041 MAD+Capecitabine 1000 mg/m2+Trastuzumab 8 mg/kg iv. First Cycle
arm group type: Experimental
description: Phase 1b:
If the MTD is still not reached at the maximum dose level in Phase 1a study, the maximum dose level (MAD) of ZN-A-1041 in Phase 1a will be used in Phase 1b study.
If intolerance, reduce Capecitabine dose to 750 mg/m2 for exploration
arm group label: ZN-A-1041+Capecitabine+Trastuzumab
arm group type: Experimental
description: Phase 1c:
The combined dose of ZN-A-1041 is based on the recommended combined dose in the Phase 1b and the possible changes in the dosage form and the results of the food effect study, which will be decided by the sponsor and the investigator after discussion
intervention type: Drug
intervention name: ZN-A-1041 50mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 50mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 100mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 100mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 200mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 200mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 400mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 400mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 600mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 600mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 800mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 800mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 1000mg BID
description: Orally 21days for one cycle
arm group label: ZN-A-1041 1000mg
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 Level 1 +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle
description: ZN-A-1041 level 1 BID; Capecitabine 1000 mg/m2 BID Trastuzumab 8 mg/kg iv. First Cycle
arm group label: ZN-A-1041 level 1+Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 Level 2 +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle
description: ZN-A-1041 level 2 BID; Capecitabine 1000 mg/m2 BID Trastuzumab 8 mg/kg iv. First Cycle
arm group label: ZN-A-1041 level 2+Capecitabine 1000 mg/m2+ Trastuzumab 8 mg/kg iv. First Cycle
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041 MAD +Capecitabine 1000 mg/m2 + Trastuzumab 8 mg/kg iv. First Cycle
description: ZN-A-1041 MAD BID; Capecitabine 1000 mg/m2 BID Trastuzumab 8 mg/kg iv. First Cycle
arm group label: ZN-A-1041 MAD+Capecitabine 1000 mg/m2+Trastuzumab 8 mg/kg iv. First Cycle
other name: ZN-A-1041 Enteric Capsules
intervention type: Drug
intervention name: ZN-A-1041+Capecitabine + Trastuzumab 8 mg/kg iv. First Cycle
description: Base on 1b ZN-A-1041 dose Base on 1b Capecitabine dose Base on 1b Trastuzumab dose
arm group label: ZN-A-1041+Capecitabine+Trastuzumab
other name: ZN-A-1041 Enteric Capsules
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Fei Ma, MD
role: Principal Investigator
affiliation: Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College
last name: Fei Ma, MD
phone: +861087788060
email: drmafei@126.com
last name: Qun Yi Li, MD
phone: +861087788120
email: liyiqun_chcams@foxmail.com
facility: 
status: Recruiting
contact: 
country: China
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Capecitabine
mesh term: Trastuzumab