<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/NCT02260661</url>
  </required_header>
  <id_info>
    <org_study_id>D6140C00001</org_study_id>
    <nct_id>NCT02260661</nct_id>
  </id_info>
  <brief_title>Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours</brief_title>
  <official_title>A Phase I, Open-Label, Multicentre, Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AstraZeneca</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>AstraZeneca</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      First time in patients study of AZD8835. The study has four parts. Part A AZD8835 is&#xD;
      administered as a single agent in a multiple ascending dose escalation phase to investigate&#xD;
      dose level for monotherapy. Part B follows the multiple ascending dose phase, additional&#xD;
      patients with tumors with documented PIK3CA gene mutation will be enrolled to a single dose&#xD;
      expansion phase. Part C is a second dose escalation phase in which post-menopausal patients&#xD;
      with estrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in&#xD;
      combination with fulvestrant. Part D follows the combination dose escalation phase of the&#xD;
      study, additional postmenopausal patients with ER+/HER2 negative breast cancer with&#xD;
      documented PIK3CA gene mutation will be enrolled to a AZD8835 and fulvestrant combination&#xD;
      dose-expansion phase at maximum tolerated dose or recommended phase II dose.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      AZD8835 is a novel small molecule that inhibits cancer progression by blocking PI3 kinase&#xD;
      pathway components p110α and p110δ.&#xD;
&#xD;
      In this first-time-in-patient study, AZD8835 will initially be administered as a single agent&#xD;
      to patients with advanced solid malignancies. Patients will be treated at a starting dose of&#xD;
      20 mg twice daily (BID), administered weekly on Days 1 and 4 and will be escalated to reach a&#xD;
      maximum-tolerated dose (MTD) in patients as defined by dose-limiting toxicities (DLTs). A BID&#xD;
      intermittent dosing schedule administered weekly on Days 1 and 4 of an oral formulation of&#xD;
      AZD8835 will be used, as deemed optimal and effective in non-clinical studies, primarily to&#xD;
      determine the safety and tolerability of AZD8835. The pharmacokinetics (PK) of AZD8835 and&#xD;
      potential biological activity will also be investigated. In Part A of this study, AZD8835&#xD;
      will be administered as a single agent in a multiple ascending dose escalation phase to&#xD;
      investigate the appropriate monotherapy dose level for clinical use. Additional dosing&#xD;
      schedules may be studies, including dosing on Days 1 and 2 of each week, rather than Days 1&#xD;
      and 4.&#xD;
&#xD;
      Backfilled pharmacodynamic (PDc) cohorts in selected patients with tumours that have&#xD;
      documented mutations in the phosphatidylinositol-4,5- bisphosphate 3-kinase, catalytic&#xD;
      subunit alpha (PIK3CA) gene will allow further preliminary assessment of the biological&#xD;
      effect of AZD8835 in these patients.&#xD;
&#xD;
      Following the single-agent dose-escalation phase of the study, additional patients with&#xD;
      tumours that have documented mutations in the PIK3CA gene will be enrolled to a single-agent&#xD;
      dose-expansion phase at the MTD or recommended Phase II dose (RP2D) at the selected dose&#xD;
      schedule (as appropriate) to explore further the safety, tolerability, PK, and biological&#xD;
      activity at the selected dose (Part B).&#xD;
&#xD;
      In addition, a further dose-escalation phase will be initiated following the observation of&#xD;
      specific pre-determined criteria in the single-agent dose escalation, in which postmenopausal&#xD;
      patients with oestrogen receptor positive (ER+), HER2 negative breast cancer will receive&#xD;
      AZD8835 in combination with fulvestrant (Part C). The combination dose-escalation phase will&#xD;
      investigate the appropriate combination dose level for clinical use.&#xD;
&#xD;
      Following the combination dose-escalation phase of the study, additional postmenopausal&#xD;
      patients with ER+ breast cancer and tumours with documented mutations of the PIK3CA gene will&#xD;
      be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at the MTD or RP2D&#xD;
      (as appropriate) to explore further the safety, tolerability, PK, and biological activity at&#xD;
      the selected dose (Part D).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>November 2014</start_date>
  <completion_date type="Actual">July 2016</completion_date>
  <primary_completion_date type="Actual">July 2016</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>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Determine the maximum tolerated dose (MTD) or recommended Phase II dose of oral AZD8835 as a single agent and in combination with fulvestrant</measure>
    <time_frame>At the end of one cycle of treatment</time_frame>
    <description>MTD - A dose will be considered non-tolerated and dose escalation will stop if 2 or more of up to 6 evaluable patients experience a dose limiting toxicity at a dose level. Once the non-tolerated dose is defined, the MTD will be confirmed at the previous dose level below the non-tolerated dose or a dose between the non-tolerated dose and the last tolerated dose my be investigated. A minimum of 6 evaluable patients are required to determine the MTD. Recommended Phase II dose - A minimum of 6 evaluable patients is necessary to determine the recommended dose. A dose will be considered non-tolerated and dose escalation will stop if 2 or more patients experience a dose dose limiting toxicity at a dose level.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Establish the preliminary safety and tolerability profile of oral AZD8835 as a single agent and in combination with fulvestrant</measure>
    <time_frame>Up to a projected 36 months</time_frame>
    <description>Assessed in terms of adverse events and laboratory data that is collected on all patients</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To establish the pharmacokinetic profile of oral AZD8835 as a single agent and in combination with fulvestrant</measure>
    <time_frame>Venous blood samples will be collected pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 96 hours post dose - exact schedule varies according to Part A, B, C, or D</time_frame>
    <description>Venous blood samples (2 mL) for determination of concentrations of AZD8835 and the investigation of AZ8835 metabolites in plasma will be taken during Parts A, B, C, D</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the preliminary efficacy and anti-tumor activity of oral AZD8835 as a single agent or in combination with fulvestrant</measure>
    <time_frame>Tumour response will be assessed at the completion of Cycle 2 (Week 8) and patients will be restaged after every 8 weeks for up to 1 year and every 12 weeks thereafter; assessments should be performed until disease progression.</time_frame>
    <description>Categorization of objective tumor response will be based on RECIST v1.1 guidelines for complete response, partial response, stable disease, or progression of disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>To evaluate the pharmacodynamic (PDc) effect of oral AZD8835 as a single agent and in combination with fulvestrant</measure>
    <time_frame>Tumour biopsies will be collected: (1) at pretreatment, (2) at one on-treatment time point (preferably Cycle 2 Day 1), and (3) at end of study treatment (preferably at disease progression)</time_frame>
    <description>Tumor samples will be analyzed to assess PRAS40 phosphorylation, AKT phosphorylation, S6 phosphorylation, FOXO3a localisation</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Advanced Solid Malignancies</condition>
  <condition>Breast Cancer - ER+, HER2 -</condition>
  <condition>Breast Cancer - ER+, HER2-, PIK3CA Gene Mutation</condition>
  <arm_group>
    <arm_group_label>Part A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AZD8835 single agent dose escalation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Following the single agent dose escalation (Part A), additional patients with mutations in the PIK3CA gene will be enrolled to a single agent dose expansion phase at the MTD or recommended phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part B). Part B will include patients with ER+/HER2 negative breast cancer whose tumours have a mutation of the PIK3CA gene and patients with any solid tumours which have a mutation of the PIK3CA gene.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part C</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>AZD8835 in combination with fulvestrant dose escalation</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Part D</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Following the combination dose escalation segment of the study (Part C), additional postmenopausal patients with ER+/HER negative breast cancer and mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose expansion phase at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part D).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD8835</intervention_name>
    <description>AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components</description>
    <arm_group_label>Part A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD8835</intervention_name>
    <description>AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components</description>
    <arm_group_label>Part B</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD8835 in combination with fulvestrant</intervention_name>
    <description>AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy.</description>
    <arm_group_label>Part C</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD8835 in combination with fulvestrant</intervention_name>
    <description>AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy</description>
    <arm_group_label>Part D</arm_group_label>
    <other_name>Faslodex</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Part A: Histological or cytological confirmation of a solid tumor and disease&#xD;
             progression. Part B: Histological or cytological confirmation of ER positive, HER2&#xD;
             negative breast cancer and disease progression or any other solid tumor with a PIK3CA&#xD;
             gene mutation. Part C: Histological or cytological confirmation of ER positive, HER2&#xD;
             negative postmenopausal breast cancer with locally advanced or metastatic disease that&#xD;
             is eligible for fulvestrant treatment. Part D: Histological or cytological&#xD;
             confirmation of ER positive, HER2 negative postmenopausal breast cancer with locally&#xD;
             advanced or metastatic disease that is eligible for fulvestrant treatment. Patients&#xD;
             must also present with a tumor related mutation of the PIK3CA gene.&#xD;
&#xD;
          2. Availability of archival tumour tissue sample. If archival sample is not available, a&#xD;
             fresh tumour biopsy must be provided.&#xD;
&#xD;
          3. At least one measurable lesion per RECIST v1.1. However, breast cancer patients with&#xD;
             only bone disease are also eligible.&#xD;
&#xD;
          4. ECOG Performance Status 0-1.&#xD;
&#xD;
          5. Adequate organ function at baseline:&#xD;
&#xD;
               1. Serum total bilirubin ≤ 1.5 x ULN and AST/SGOT and ALT/SGPT ≤ 2.5 x ULN or ≤ 5 x&#xD;
                  ULN if liver metastases are present.&#xD;
&#xD;
               2. Creatinine ≤ 1.5 x ULN, or calculated or measured creatinine clearance ≥ 50&#xD;
                  mL/min, or 24-hour measured urine creatinine clearance ≥ 50 mL/min.&#xD;
&#xD;
               3. Platelets ≥ 100 x 10^9, Hb ≥ 90 g/L, ANC ≥ 1.5 x 10^9/L.&#xD;
&#xD;
               4. aPTT ≤ 1.5 x ULN&#xD;
&#xD;
               5. Fasting glucose &lt; 140 mg/dL (7.8 mmol/L).&#xD;
&#xD;
               6. Glycated haemoglobin (HbA1c) &lt; 8%&#xD;
&#xD;
          6. Female patients and male patients with female partners of child bearing potential must&#xD;
             be using adequate contraception.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Recent chemotherapy, radiotherapy, hormonal therapy, immunotherapy or investigational&#xD;
             drugs within 21 days or 5 half-days from enrolment.&#xD;
&#xD;
          2. Received palliative/focal radiotherapy within 2 weeks of first dose of study&#xD;
             treatment.&#xD;
&#xD;
          3. Major surgery ≤ 21 days from beginning of study drug&#xD;
&#xD;
          4. Any of the following cardiac criteria: CHF &gt; Class II, cardiac ventricular arrhythmia&#xD;
             requiring therapy, unstable angina or new-onset angina, QTcF interval &gt;470ms, abnormal&#xD;
             ECHO or MUGA at baseline (LVEF &lt;50%).&#xD;
&#xD;
          5. Leptomeningeal disease&#xD;
&#xD;
          6. Part A: Intolerable AEs due to other PI3K inhibitors, dual PI3K and mTOR inhibitors or&#xD;
             AKT inhibitors. Parts B, C, and D: Prior exposure to any of the following:&#xD;
             pharmacological inhibitors of AKT, PI3K, or dual PI3K and mTOR kinase activity&#xD;
&#xD;
          7. Strong inhibitors and potent inducers of CYP3A4&#xD;
&#xD;
          8. Peripheral neuropathy CTCAE v4.03 Grade ≥ 3&#xD;
&#xD;
          9. Diarrhoea CTCAE v4.03 Grade ≥ 2&#xD;
&#xD;
         10. Acute or chronic pancreatitis&#xD;
&#xD;
         11. Clinically manifest diabetes mellitus, history of gestational diabetes mellitus and/or&#xD;
             known glucose intolerance.&#xD;
&#xD;
         12. Patients currently receiving any medication that has the potential to prolong the QT&#xD;
             interval or induce Torsades de Pointes&#xD;
&#xD;
         13. Spinal cord compression or brain metastases unless asymptomatic and not requiring&#xD;
             steroids for at least 4 weeks&#xD;
&#xD;
         14. Patients in the combination arms - known hypersensitivity to fulvestrant&#xD;
&#xD;
         15. Therapeutic treatment with Coumadin or any other coumarin-derivative anticoagulant&#xD;
&#xD;
         16. Impaired GI function or GI disease that may interfere with absorption of AZD8835 or&#xD;
             patients unable to take oral medication&#xD;
&#xD;
         17. As judged by the investigator any evidence of severe or uncontrolled systemic disease&#xD;
&#xD;
         18. Patients treated with hematopoietic colony-stimulating growth factors e.g., G-CSF,&#xD;
             GM-CSF, M-CSF) ≤ 2 weeks prior to start. Erythropoietin or darbepoetin is allowed if&#xD;
             it was initiated at least 2 weeks prior to entry&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>130 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hendrik-Tobias Arkenau, FRCP, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sarah Cannon Research Institute, United Kingdom</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Denver</city>
        <state>Colorado</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Greenville</city>
        <state>South Carolina</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Milwaukee</city>
        <state>Wisconsin</state>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Cambridge</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarah Cannon Research Institute, United Kingdom</name>
      <address>
        <city>London</city>
        <zip>W1G 6AD</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Research Site</name>
      <address>
        <city>Manchester</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2016</verification_date>
  <study_first_submitted>October 6, 2014</study_first_submitted>
  <study_first_submitted_qc>October 6, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 9, 2014</study_first_posted>
  <last_update_submitted>October 7, 2016</last_update_submitted>
  <last_update_submitted_qc>October 7, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">October 10, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>AZD8835</keyword>
  <keyword>Fulvestrant</keyword>
  <keyword>Breast Cancer</keyword>
  <keyword>PIK3CA Gene Mutation</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>Fulvestrant</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/NCT02260661
org study id: D6140C00001
nct id: NCT02260661
lead sponsor: 
has dmc: No
First time in patients study of AZD8835. The study has four parts. Part A AZD8835 is
      administered as a single agent in a multiple ascending dose escalation phase to investigate
      dose level for monotherapy. Part B follows the multiple ascending dose phase, additional
      patients with tumors with documented PIK3CA gene mutation will be enrolled to a single dose
      expansion phase. Part C is a second dose escalation phase in which post-menopausal patients
      with estrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in
      combination with fulvestrant. Part D follows the combination dose escalation phase of the
      study, additional postmenopausal patients with ER+/HER2 negative breast cancer with
      documented PIK3CA gene mutation will be enrolled to a AZD8835 and fulvestrant combination
      dose-expansion phase at maximum tolerated dose or recommended phase II dose.
AZD8835 is a novel small molecule that inhibits cancer progression by blocking PI3 kinase
      pathway components p110α and p110δ.

      In this first-time-in-patient study, AZD8835 will initially be administered as a single agent
      to patients with advanced solid malignancies. Patients will be treated at a starting dose of
      20 mg twice daily (BID), administered weekly on Days 1 and 4 and will be escalated to reach a
      maximum-tolerated dose (MTD) in patients as defined by dose-limiting toxicities (DLTs). A BID
      intermittent dosing schedule administered weekly on Days 1 and 4 of an oral formulation of
      AZD8835 will be used, as deemed optimal and effective in non-clinical studies, primarily to
      determine the safety and tolerability of AZD8835. The pharmacokinetics (PK) of AZD8835 and
      potential biological activity will also be investigated. In Part A of this study, AZD8835
      will be administered as a single agent in a multiple ascending dose escalation phase to
      investigate the appropriate monotherapy dose level for clinical use. Additional dosing
      schedules may be studies, including dosing on Days 1 and 2 of each week, rather than Days 1
      and 4.

      Backfilled pharmacodynamic (PDc) cohorts in selected patients with tumours that have
      documented mutations in the phosphatidylinositol-4,5- bisphosphate 3-kinase, catalytic
      subunit alpha (PIK3CA) gene will allow further preliminary assessment of the biological
      effect of AZD8835 in these patients.

      Following the single-agent dose-escalation phase of the study, additional patients with
      tumours that have documented mutations in the PIK3CA gene will be enrolled to a single-agent
      dose-expansion phase at the MTD or recommended Phase II dose (RP2D) at the selected dose
      schedule (as appropriate) to explore further the safety, tolerability, PK, and biological
      activity at the selected dose (Part B).

      In addition, a further dose-escalation phase will be initiated following the observation of
      specific pre-determined criteria in the single-agent dose escalation, in which postmenopausal
      patients with oestrogen receptor positive (ER+), HER2 negative breast cancer will receive
      AZD8835 in combination with fulvestrant (Part C). The combination dose-escalation phase will
      investigate the appropriate combination dose level for clinical use.

      Following the combination dose-escalation phase of the study, additional postmenopausal
      patients with ER+ breast cancer and tumours with documented mutations of the PIK3CA gene will
      be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at the MTD or RP2D
      (as appropriate) to explore further the safety, tolerability, PK, and biological activity at
      the selected dose (Part D).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Determine the maximum tolerated dose (MTD) or recommended Phase II dose of oral AZD8835 as a single agent and in combination with fulvestrant
time frame: At the end of one cycle of treatment
description: MTD - A dose will be considered non-tolerated and dose escalation will stop if 2 or more of up to 6 evaluable patients experience a dose limiting toxicity at a dose level. Once the non-tolerated dose is defined, the MTD will be confirmed at the previous dose level below the non-tolerated dose or a dose between the non-tolerated dose and the last tolerated dose my be investigated. A minimum of 6 evaluable patients are required to determine the MTD. Recommended Phase II dose - A minimum of 6 evaluable patients is necessary to determine the recommended dose. A dose will be considered non-tolerated and dose escalation will stop if 2 or more patients experience a dose dose limiting toxicity at a dose level.
measure: Establish the preliminary safety and tolerability profile of oral AZD8835 as a single agent and in combination with fulvestrant
time frame: Up to a projected 36 months
description: Assessed in terms of adverse events and laboratory data that is collected on all patients
measure: To establish the pharmacokinetic profile of oral AZD8835 as a single agent and in combination with fulvestrant
time frame: Venous blood samples will be collected pre-dose and at 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, and 96 hours post dose - exact schedule varies according to Part A, B, C, or D
description: Venous blood samples (2 mL) for determination of concentrations of AZD8835 and the investigation of AZ8835 metabolites in plasma will be taken during Parts A, B, C, D
measure: To evaluate the preliminary efficacy and anti-tumor activity of oral AZD8835 as a single agent or in combination with fulvestrant
time frame: Tumour response will be assessed at the completion of Cycle 2 (Week 8) and patients will be restaged after every 8 weeks for up to 1 year and every 12 weeks thereafter; assessments should be performed until disease progression.
description: Categorization of objective tumor response will be based on RECIST v1.1 guidelines for complete response, partial response, stable disease, or progression of disease
measure: To evaluate the pharmacodynamic (PDc) effect of oral AZD8835 as a single agent and in combination with fulvestrant
time frame: Tumour biopsies will be collected: (1) at pretreatment, (2) at one on-treatment time point (preferably Cycle 2 Day 1), and (3) at end of study treatment (preferably at disease progression)
description: Tumor samples will be analyzed to assess PRAS40 phosphorylation, AKT phosphorylation, S6 phosphorylation, FOXO3a localisation
arm group label: Part A
arm group type: Experimental
description: AZD8835 single agent dose escalation
arm group label: Part B
arm group type: Experimental
description: Following the single agent dose escalation (Part A), additional patients with mutations in the PIK3CA gene will be enrolled to a single agent dose expansion phase at the MTD or recommended phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part B). Part B will include patients with ER+/HER2 negative breast cancer whose tumours have a mutation of the PIK3CA gene and patients with any solid tumours which have a mutation of the PIK3CA gene.
arm group label: Part C
arm group type: Experimental
description: AZD8835 in combination with fulvestrant dose escalation
arm group label: Part D
arm group type: Experimental
description: Following the combination dose escalation segment of the study (Part C), additional postmenopausal patients with ER+/HER negative breast cancer and mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose expansion phase at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part D).
intervention type: Drug
intervention name: AZD8835
description: AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components
arm group label: Part A
intervention type: Drug
intervention name: AZD8835
description: AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components
arm group label: Part B
intervention type: Drug
intervention name: AZD8835 in combination with fulvestrant
description: AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy.
arm group label: Part C
other name: Faslodex
intervention type: Drug
intervention name: AZD8835 in combination with fulvestrant
description: AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy
arm group label: Part D
other name: Faslodex
criteria: 
gender: All
minimum age: 18 Years
maximum age: 130 Years
healthy volunteers: No
last name: Hendrik-Tobias Arkenau, FRCP, PhD
role: Principal Investigator
affiliation: Sarah Cannon Research Institute, United Kingdom
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country: United Kingdom
country: United States
responsible party type: Sponsor
mesh term: Breast Neoplasms
mesh term: Fulvestrant