<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/NCT01668550</url>
  </required_header>
  <id_info>
    <org_study_id>CRUKD/07/061</org_study_id>
    <nct_id>NCT01668550</nct_id>
  </id_info>
  <brief_title>A Phase I Study of AZD0424 Alone and in Combination in Advanced Solid Tumours</brief_title>
  <acronym>AZD0424</acronym>
  <official_title>A Cancer Research UK Phase I Study to Determine the Maximum Tolerated Dose of the Oral Src/Abl Inhibitor AZD0424, and to Identify Tolerable and Effective AZD0424 Combination Regimens for the Treatment of Advanced Solid Tumours</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cancer Research UK</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cancer Research UK</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the maximum tolerated dose of the oral Src/Abl&#xD;
      inhibitor AZD0424, and to find tolerable and effective AZD0424 combination regimens for the&#xD;
      treatment of advanced solid tumours&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      AZD0424 is a potent orally available, potent (IC50 approximately 4 nM) inhibitor of Src and&#xD;
      ABL1 kinases with additional activity against Src family kinase (SFK) members including Yes&#xD;
      and Lck. AZD0424 was selective for SFKs and ABL1 kinase over C-terminal Src kinase (a&#xD;
      negative regulator of Src) and a range of other kinase targets. The anti-cancer activity of&#xD;
      AZD0424 is thought to be mediated primarily by anti-migratory and anti-invasive signalling&#xD;
      and, as such, it is expected that in the late stage cancer setting strong signals of efficacy&#xD;
      with this compound used as a single agent are unlikely, requiring it to be administered in&#xD;
      combination with other anti-cancer agents.&#xD;
&#xD;
      In summary the study will be performed in four main stages:&#xD;
&#xD;
        -  AZD0424 monotherapy, dose escalation: Phase Ia single agent (AZD0424) dose escalation&#xD;
           study to determine the MTD.&#xD;
&#xD;
        -  AZD0424 monotherapy, dose expansion: Phase Ib single agent dose expansion at MTD (up to&#xD;
           six additional patients may be recruited in order to provide paired tumour biopsies for&#xD;
           PD analysis).&#xD;
&#xD;
        -  Combination arm dose escalation: Provided that it is deemed appropriate (after review of&#xD;
           available clinical data from the monotherapy part of the trial, and available&#xD;
           preclinical and published data on the combination), a Phase Ia dose escalation arm of&#xD;
           AZD0424 in combination with the selected agent will proceed to determine the MTD for the&#xD;
           combination and a recommended Phase II dose.&#xD;
&#xD;
        -  Combination arm dose expansion: Phase Ib combination arm using the recommended Phase II&#xD;
           dose for both AZD0424 and the combination agent.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Single agent phase completed, insufficient supportive preclinical data to proceed with&#xD;
    combination phase&#xD;
  </why_stopped>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">May 2016</completion_date>
  <primary_completion_date type="Actual">May 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination</measure>
  </primary_outcome>
  <primary_outcome>
    <measure>Determining the causality and duration of adverse events observed during the study according to NCI CTCAE Version 4.02</measure>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determining the correlation between PK studies and toxicity and/or efficacy.</measure>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of urinary and serum N terminal Telopeptide (NTx) and serum C-terminal peptide (CTx) levels before the first AZD0424 administration and then following first AZD0424 administration, to evaluate bone turnover</measure>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of the following biomarkers in tumour tissue before and after the first AZD0424 administration: p-Src, MKI67 (Ki-67), p-PAX, p-CRKL, p-FAK.</measure>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Evaluate responses (stable disease (SD), partial response (PR) or complete response (CR)) in any of the patients as determined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.</measure>
  </secondary_outcome>
  <enrollment type="Actual">43</enrollment>
  <condition>Advanced Solid Tumours</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD0424</intervention_name>
    <description>AZD0424 will be administered as a flat dose orally once a day. One treatment cycle consists of 28 days of continuous drug administration with AZD0424, with the flexibility to introduce treatment breaks if required due to cumulative toxicity.&#xD;
Combination agents and treatment regimen with AZD0424 will be confirmed and approved at a later date.</description>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically proven solid tumour, refractory to conventional&#xD;
             treatment, or for which no conventional therapy exists or is declined by the patient&#xD;
             or for whom there is the prospect of clinical benefit&#xD;
&#xD;
          -  Life expectancy of at least 12 weeks&#xD;
&#xD;
          -  World Health Organisation (WHO) performance status of 0-2&#xD;
&#xD;
          -  Haematological and biochemical indices within the ranges shown below. These&#xD;
             measurements must be performed within one week (Day -7 to Day 1) before the patient&#xD;
             receives AZD0424&#xD;
&#xD;
               -  Haemoglobin (Hb) ≥ 9.0 g/dL&#xD;
&#xD;
               -  Absolute neutrophil count (ANC) ≥ 1.5 x 109/L&#xD;
&#xD;
               -  Platelet count ≥ 100 x 109/L&#xD;
&#xD;
               -  Serum bilirubin ≤ 1.5 x upper limit of normal (ULN)&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x (ULN)&#xD;
                  Either: Calculated creatinine clearance ≥ 50 mL/min Or Or Isotope Clearance&#xD;
                  measurement ≥ 50 mL/min (uncorrected)&#xD;
&#xD;
          -  18 years or over&#xD;
&#xD;
          -  Written (signed and dated) informed consent and be capable of co-operating with&#xD;
             treatment and follow-up&#xD;
&#xD;
          -  MTD Expansion cohorts only: A tumour which is safely accessible for biopsy (single and&#xD;
             combination)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or&#xD;
             chemotherapy during the previous four weeks (six weeks for nitrosoureas, Mitomycin-C&#xD;
             and four weeks for investigational medicinal products) before treatment.&#xD;
&#xD;
          -  Ongoing toxic manifestations of previous treatments. Exceptions to this are alopecia&#xD;
             or certain Grade 1 toxicities, which in the opinion of the Investigator and the DDO&#xD;
             should not exclude the patient.&#xD;
&#xD;
          -  Symptomatic brain metastases (if brain metastases are present they must have been&#xD;
             stable for &gt; 3 months).&#xD;
&#xD;
          -  Patients with evidence of interstitial lung disease (bilateral, diffuse, parenchymal&#xD;
             lung disease).&#xD;
&#xD;
          -  Patients with a peanut allergy will be excluded.&#xD;
&#xD;
          -  Ability to become pregnant (or already pregnant or lactating). However, those female&#xD;
             patients who have a negative serum or urine pregnancy test before enrollment and agree&#xD;
             to use two highly effective forms of contraception as detailed in the protocol are&#xD;
             considered eligible.&#xD;
&#xD;
          -  Male patients with partners of child-bearing potential (unless they agree to take&#xD;
             measures not to father children by using one form of highly effective contraception as&#xD;
             detailed in the protocol). Men with pregnant or lactating partners should be advised&#xD;
             to use barrier method contraception (for example, condom plus spermicidal gel) to&#xD;
             prevent exposure to the foetus or neonate.&#xD;
&#xD;
          -  Major thoracic or abdominal surgery from which the patient has not yet recovered.&#xD;
&#xD;
          -  At high medical risk because of non-malignant systemic disease including active&#xD;
             uncontrolled infection.&#xD;
&#xD;
          -  Known to be serologically positive for hepatitis B, hepatitis C or human&#xD;
             immunodeficiency virus (HIV).&#xD;
&#xD;
          -  Resting ECG with measurable QTc interval of &gt;480 msec (mean value and manually&#xD;
             verified) of at least 3 time points within a 24 hour period.&#xD;
&#xD;
          -  Concurrent hypotension defined as a baseline supine blood pressure (BP) systolic &lt; 90&#xD;
             mmHg.&#xD;
&#xD;
          -  Concurrent congestive heart failure, prior history of class III/ IV cardiac disease&#xD;
             (New York Heart Association [NYHA]), prior history of cardiac ischaemia or prior&#xD;
             history of cardiac arrhythmia within 6 months. Coronary angioplasty or stenting in the&#xD;
             previous 12 months.&#xD;
&#xD;
          -  Is a participant or plans to participate in another interventional clinical trial,&#xD;
             whilst taking part in this Phase Ia/Ib study of AZD0424 single agent and in&#xD;
             combination. Participation in an observational, counseling or psychological trial&#xD;
             would be acceptable.&#xD;
&#xD;
          -  Any other condition which in the Investigator's opinion would not make the patient a&#xD;
             good candidate for the clinical trial.&#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>Professor Adrian Harris</last_name>
    <role>Study Chair</role>
    <affiliation>Oxford University Hospitals NHS Trust</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Belfast City Hospital</name>
      <address>
        <city>Belfast</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Edinburgh Cancer Centre - Western General Hospital</name>
      <address>
        <city>Edinburgh</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Oxford University Hospitals NHS Trust</name>
      <address>
        <city>Oxford</city>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>July 2016</verification_date>
  <study_first_submitted>May 31, 2012</study_first_submitted>
  <study_first_submitted_qc>August 16, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 20, 2012</study_first_posted>
  <last_update_submitted>February 1, 2018</last_update_submitted>
  <last_update_submitted_qc>February 1, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">February 5, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Phase I</keyword>
  <keyword>Src/Abl inhibitor</keyword>
  <keyword>Solid Tumours</keyword>
  <keyword>Cancer</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>AZD-0424</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/NCT01668550
org study id: CRUKD/07/061
nct id: NCT01668550
lead sponsor: 
has dmc: No
The purpose of this study is to determine the maximum tolerated dose of the oral Src/Abl
      inhibitor AZD0424, and to find tolerable and effective AZD0424 combination regimens for the
      treatment of advanced solid tumours
AZD0424 is a potent orally available, potent (IC50 approximately 4 nM) inhibitor of Src and
      ABL1 kinases with additional activity against Src family kinase (SFK) members including Yes
      and Lck. AZD0424 was selective for SFKs and ABL1 kinase over C-terminal Src kinase (a
      negative regulator of Src) and a range of other kinase targets. The anti-cancer activity of
      AZD0424 is thought to be mediated primarily by anti-migratory and anti-invasive signalling
      and, as such, it is expected that in the late stage cancer setting strong signals of efficacy
      with this compound used as a single agent are unlikely, requiring it to be administered in
      combination with other anti-cancer agents.

      In summary the study will be performed in four main stages:

        -  AZD0424 monotherapy, dose escalation: Phase Ia single agent (AZD0424) dose escalation
           study to determine the MTD.

        -  AZD0424 monotherapy, dose expansion: Phase Ib single agent dose expansion at MTD (up to
           six additional patients may be recruited in order to provide paired tumour biopsies for
           PD analysis).

        -  Combination arm dose escalation: Provided that it is deemed appropriate (after review of
           available clinical data from the monotherapy part of the trial, and available
           preclinical and published data on the combination), a Phase Ia dose escalation arm of
           AZD0424 in combination with the selected agent will proceed to determine the MTD for the
           combination and a recommended Phase II dose.

        -  Combination arm dose expansion: Phase Ib combination arm using the recommended Phase II
           dose for both AZD0424 and the combination agent.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Establishing the Maximum Tolerated Dose (MTD) of AZD0424 alone and in combination
measure: Determining the causality and duration of adverse events observed during the study according to NCI CTCAE Version 4.02
measure: Determining the correlation between PK studies and toxicity and/or efficacy.
measure: Measurement of urinary and serum N terminal Telopeptide (NTx) and serum C-terminal peptide (CTx) levels before the first AZD0424 administration and then following first AZD0424 administration, to evaluate bone turnover
measure: Measurement of the following biomarkers in tumour tissue before and after the first AZD0424 administration: p-Src, MKI67 (Ki-67), p-PAX, p-CRKL, p-FAK.
measure: Evaluate responses (stable disease (SD), partial response (PR) or complete response (CR)) in any of the patients as determined by Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1.
intervention type: Drug
intervention name: AZD0424
description: AZD0424 will be administered as a flat dose orally once a day. One treatment cycle consists of 28 days of continuous drug administration with AZD0424, with the flexibility to introduce treatment breaks if required due to cumulative toxicity.
Combination agents and treatment regimen with AZD0424 will be confirmed and approved at a later date.
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Professor Adrian Harris
role: Study Chair
affiliation: Oxford University Hospitals NHS Trust
facility: 
facility: 
facility: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: AZD-0424