<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/NCT02999893</url>
  </required_header>
  <id_info>
    <org_study_id>16/012</org_study_id>
    <nct_id>NCT02999893</nct_id>
  </id_info>
  <brief_title>A Study of APR-246 in Oesophageal Cancer</brief_title>
  <acronym>APROC</acronym>
  <official_title>A phase1b/2 Study Evaluating the Efficacy of APR-246, a First-in-class Agent Targeting Mutant p53 in the Treatment of Platinum Resistant Advanced and Metastatic Oesophageal or Gastro-oesophageal Junction Cancers</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Peter MacCallum Cancer Centre, Australia</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Peter MacCallum Cancer Centre, Australia</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether APR-246, 5-FU and cisplatin are safe and&#xD;
      effective in the treatment of platinum resistant oesophageal cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cancer of the oesophagus (OC) is distinguished by having a poor outcome for most patients and&#xD;
      an incidence that is rising faster than any other solid cancer. It is already the eighth most&#xD;
      common cancer, and the sixth most common cause of death from cancer, worldwide. The majority&#xD;
      of patients are diagnosed with late stage disease, which is incurable with the current&#xD;
      standard multimodality therapy. Thus, there is a critical need to develop new treatments for&#xD;
      this disease.&#xD;
&#xD;
      Surprisingly, despite its high prevalence in developing countries, and its increasing&#xD;
      incidence in Western populations, metastatic OC remains an 'orphan disease' with very few&#xD;
      good quality or randomised trials available to guide practice. As a result, treatment for OC&#xD;
      has changed little over the past few decades, and as a consequence there has been only modest&#xD;
      improvement in overall survival for patients with this disease.&#xD;
&#xD;
      TP53, a key tumour suppressor gene, is mutated in 70-80% of OC (both adenocarcinoma and&#xD;
      squamous cell carcinoma) providing an attractive potential target for an OC therapy.&#xD;
&#xD;
      Although paired tissue studies in primary and metastatic OC are lacking, p53 mutations occur&#xD;
      very early in oesophageal carcinogenesis and are unlikely to be lost in advanced disease. OC&#xD;
      with mutant (mut)-p53 are more resistant to conventional chemotherapy and mut-p53 is&#xD;
      associated with poor patient prognosis. Over the last decade, several novel drugs have been&#xD;
      developed that target mut-p53 and restore wild-type (wt)-p53 function in cancer cells. Of&#xD;
      these, APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53&#xD;
      resulting in re-expression of wild-type p53 activity, has proven to be the most effective&#xD;
      against a wide range of mutants. APR-246 is a pro-drug that gives rise to the active compound&#xD;
      methylene quinuclidinone (MQ), which covalently binds to thiol groups on cysteine residues in&#xD;
      the p53 core domain resulting in refolding of mut-p53 protein and restoration of its tumour&#xD;
      suppressor activity.&#xD;
&#xD;
      While the reactivation of mut-p53 is thought to be the primary mode of action of APR-246,&#xD;
      preclinical studies have suggested potential alternative mechanisms (e.g. through the&#xD;
      depletion of cellular glutathione levels) may also be contributing to the efficacy of&#xD;
      APR-246, especially when used in combination with cisplatin/5-FU chemotherapy. Thus, the&#xD;
      anti-tumour activity of APR-246 may not be limited to mut-p53 bearing tumours.&#xD;
&#xD;
      Mutation of p53 is the most common genetic aberration in oesophageal cancer being detected in&#xD;
      up to 80% of both oesophageal squamous cell cancers and adenocarcinomas.&#xD;
&#xD;
      APR-246 is a first-in-class agent targeting mutant p53. In vitro and in vivo preclinical&#xD;
      models have demonstrated that APR-246 has excellent efficacy in OC (both adenocarcinoma and&#xD;
      squamous cell carcinoma) and potently synergises with chemotherapies used in the treatment of&#xD;
      OC, restoring sensitivity to chemotherapy-resistant tumours. An initial phase I clinical&#xD;
      trial has shown APR-246 to be safe in humans and early results from a currently running phase&#xD;
      Ib/II trial of APR-246 with carboplatin and liposomal doxorubicin in ovarian cancer have been&#xD;
      promising. Together, these data provide a strong rationale for investigating the efficacy of&#xD;
      APR-246 in OC.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Funding ceased&#xD;
  </why_stopped>
  <start_date type="Actual">April 11, 2017</start_date>
  <completion_date type="Actual">February 7, 2021</completion_date>
  <primary_completion_date type="Actual">October 16, 2020</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>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>Establish the safety profile of combined APR-246 plus cisplatin and 5FU as measured by the satisfactorily low rate of adverse events described according to NCI CTCAE v 4.03.</measure>
    <time_frame>3 weeks post commencement of treatment.</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evidence of clinical efficacy of a combined APR-246 and cisplatin/5FU chemotherapy regimen as confirmed by CT/PET/MRI scan.</measure>
    <time_frame>6 and 12 weeks post commencement of treatment.</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of patients who will benefit from APR-246 therapy as assessed by quantitation of ctDNA levels in patient serum and plasma samples.</measure>
    <time_frame>Through study completion, an average of 7 years.</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Oesophageal Carcinoma</condition>
  <arm_group>
    <arm_group_label>APR-246</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The trial regimen consists of the investigational agent APR-246, along with standard chemotherapy, Cisplatin and 5-FU. A maximum of 8 cycles of treatment will be given.&#xD;
APR-246 and 5-FU must both commence on Day 1 and given on days 1 to 4 via intravenous infusion over 6 hours, whilst 5-FU must be given as a continuous infusion over 96 hours.&#xD;
On Days 2-4, APR-246 must be given first via intravenous infusion over 6 hours, then commence cisplatin via intravenous infusion over one hour.&#xD;
This is a dose-escalation study to determine the maximum tolerated dose (MTD) of the combination therapy. The 3 dose levels are described as follows:&#xD;
Dose Level 1:&#xD;
APR-246 Dose: 75mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI&#xD;
Dose Level 2:&#xD;
APR-246 Dose: 100mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI&#xD;
Dose Level -1:&#xD;
APR-246 Dose: 50mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APR-246</intervention_name>
    <description>APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53 resulting in re-expression of wild-type p53 activity.</description>
    <arm_group_label>APR-246</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Male or female aged 18 years or older at screening&#xD;
&#xD;
          2. Histologically-confirmed metastatic or advanced oesophageal or oesophago-gastric&#xD;
             junction adenocarcinoma or squamous cell carcinoma&#xD;
&#xD;
          3. Radiologic disease progression at or within 6 months of platinum containing&#xD;
             chemotherapy in the advanced/metastatic or adjuvant setting&#xD;
&#xD;
          4. Measurable disease as per RECIST1.1 criteria&#xD;
&#xD;
          5. Measurable lesions must not have previously had radiotherapy or must have progressed&#xD;
             following radiotherapy&#xD;
&#xD;
          6. Patients may have had up to 2 lines of previous chemotherapy in the&#xD;
             metastatic/advanced setting or 3 lines including adjuvant therapy. If patients have a&#xD;
             maintenance strategy following platinum containing chemotherapy (e.g. fluoropyrimidine&#xD;
             alone) this will not be considered a separate line of treatment.&#xD;
&#xD;
          7. Patient has provided written informed consent for the trial&#xD;
&#xD;
          8. Tumour tissue available from the initial surgical resection or any previous biopsies&#xD;
             taken at any time before screening. Either a FFPE block or 15 unstained sections from&#xD;
             the tumour tissue block must be available for the purpose of translation research&#xD;
             studies. Obtaining archived tumour material or unstained sections from an archived&#xD;
             tumour block will suffice to meet this requirement. The availability of the tumour&#xD;
             material must be confirmed at Screening for a patient to be eligible. If no archival&#xD;
             tissue block is available and/or fewer than 15 unstained sections are available,&#xD;
             eligibility must be confirmed with the Coordinating Principal Investigator or&#xD;
             delegate.&#xD;
&#xD;
          9. Patients must have adequate haematological, renal, hepatic and pulmonary functions as&#xD;
             defined by:&#xD;
&#xD;
               -  Absolute neutrophil count ≥1.5 x 109/L&#xD;
&#xD;
               -  Haemoglobin ≥ 10 g/L&#xD;
&#xD;
               -  Platelet count ≥100 x 109/L&#xD;
&#xD;
               -  Total serum bilirubin ≤ 1.5 x upper normal limit&#xD;
&#xD;
               -  Alanine aminotransferase (ALT) ≤ 2.5 x upper normal limit or ≤ 5 x upper limit of&#xD;
                  normal if liver metastases are present&#xD;
&#xD;
               -  Renal: A creatinine clearance rate of greater than 60 mL/minute&#xD;
&#xD;
         10. Have a performance status of 0 or 1 on the ECOG Performance Scale&#xD;
&#xD;
         11. Life expectancy greater than 3 months&#xD;
&#xD;
         12. Female patients of childbearing potential must be willing to use two methods of birth&#xD;
             control or be surgically sterile, or abstain from heterosexual activity for the course&#xD;
             of the study through 60 days after the last dose of study medication. Patients of&#xD;
             childbearing potential are those who have not been surgically sterilized or have not&#xD;
             been free from menses for &gt; 1 year.&#xD;
&#xD;
         13. Male patients should agree to use an adequate method of contraception starting with&#xD;
             the first dose of study therapy through 60 days after the last dose of study therapy.&#xD;
&#xD;
         14. Willing to comply with trial therapy and trial-related investigations and evaluations&#xD;
&#xD;
         15. Willing to consent to the use of their collected tumour specimen and blood samples as&#xD;
             detailed in the protocol for future scientific research including but not limited to&#xD;
             DNA, RNA and protein based biomarker detection&#xD;
&#xD;
         16. Patient is available for follow up throughout time on trial&#xD;
&#xD;
         17. Recovered from previous toxicities (except alopecia)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women who are pregnant or lactating&#xD;
&#xD;
          2. More than 2 lines of previous chemotherapy in the advanced or metastatic setting&#xD;
&#xD;
          3. Previous radiotherapy to all sites of measurable disease without post-radiotherapy&#xD;
             progression&#xD;
&#xD;
          4. Is currently participating and receiving study therapy or has participated in a study&#xD;
             of an investigational agent and received study therapy or used an investigational&#xD;
             device within 4 weeks of the date of registration&#xD;
&#xD;
          5. Has a history or current evidence of any condition, therapy, or laboratory abnormality&#xD;
             that might confound the results of the trial, interfere with the patient's&#xD;
             participation for the full duration of the trial, or is not in the best interest of&#xD;
             the patient to participate, in the opinion of the treating investigator&#xD;
&#xD;
          6. Has known psychiatric or substance abuse disorders that would interfere with&#xD;
             cooperation with the requirements of the trial&#xD;
&#xD;
          7. Patients with a history of non-compliance to medical regimens or who are considered&#xD;
             potentially unreliable or will be unable to complete the entire study&#xD;
&#xD;
          8. Surgery or over 40Gy radiation to the primary tumour within 6 weeks of date of&#xD;
             registration&#xD;
&#xD;
          9. Presence of symptomatic or uncontrolled brain or central nervous system metastases&#xD;
             which require radiotherapy, surgery or ongoing use of corticosteroids&#xD;
&#xD;
         10. Known HIV positive status, active hepatitis B or C&#xD;
&#xD;
         11. Patients requiring or undergoing concurrent treatment with live vaccines&#xD;
&#xD;
         12. Patients requiring or undergoing concurrent treatment with phenytoin&#xD;
&#xD;
         13. Concurrent malignancy requiring therapy (excluding non-invasive carcinoma or carcinoma&#xD;
             in-situ)&#xD;
&#xD;
         14. Common Terminology Criteria for Adverse Events of at least grade 2 neuropathy&#xD;
&#xD;
         15. Patient has hearing loss requiring a hearing aid or intervention indicated.&#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>Lara Lipton, MB.BS FRACP</last_name>
    <role>Study Chair</role>
    <affiliation>Peter MacCallum Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Monash Medical Centre</name>
      <address>
        <city>Clayton</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Austin Health</name>
      <address>
        <city>Heidelberg</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peter MacCallum Cancer Centre</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3002</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Alfred Hospital</name>
      <address>
        <city>Prahran</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sunshine Hospital Western Health</name>
      <address>
        <city>Sunshine</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
  </location_countries>
  <verification_date>December 2021</verification_date>
  <study_first_submitted>December 5, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 21, 2016</study_first_posted>
  <last_update_submitted>December 10, 2021</last_update_submitted>
  <last_update_submitted_qc>December 10, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Esophageal Neoplasms</mesh_term>
  </condition_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/NCT02999893
org study id: 16/012
nct id: NCT02999893
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to determine whether APR-246, 5-FU and cisplatin are safe and
      effective in the treatment of platinum resistant oesophageal cancer.
Cancer of the oesophagus (OC) is distinguished by having a poor outcome for most patients and
      an incidence that is rising faster than any other solid cancer. It is already the eighth most
      common cancer, and the sixth most common cause of death from cancer, worldwide. The majority
      of patients are diagnosed with late stage disease, which is incurable with the current
      standard multimodality therapy. Thus, there is a critical need to develop new treatments for
      this disease.

      Surprisingly, despite its high prevalence in developing countries, and its increasing
      incidence in Western populations, metastatic OC remains an 'orphan disease' with very few
      good quality or randomised trials available to guide practice. As a result, treatment for OC
      has changed little over the past few decades, and as a consequence there has been only modest
      improvement in overall survival for patients with this disease.

      TP53, a key tumour suppressor gene, is mutated in 70-80% of OC (both adenocarcinoma and
      squamous cell carcinoma) providing an attractive potential target for an OC therapy.

      Although paired tissue studies in primary and metastatic OC are lacking, p53 mutations occur
      very early in oesophageal carcinogenesis and are unlikely to be lost in advanced disease. OC
      with mutant (mut)-p53 are more resistant to conventional chemotherapy and mut-p53 is
      associated with poor patient prognosis. Over the last decade, several novel drugs have been
      developed that target mut-p53 and restore wild-type (wt)-p53 function in cancer cells. Of
      these, APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53
      resulting in re-expression of wild-type p53 activity, has proven to be the most effective
      against a wide range of mutants. APR-246 is a pro-drug that gives rise to the active compound
      methylene quinuclidinone (MQ), which covalently binds to thiol groups on cysteine residues in
      the p53 core domain resulting in refolding of mut-p53 protein and restoration of its tumour
      suppressor activity.

      While the reactivation of mut-p53 is thought to be the primary mode of action of APR-246,
      preclinical studies have suggested potential alternative mechanisms (e.g. through the
      depletion of cellular glutathione levels) may also be contributing to the efficacy of
      APR-246, especially when used in combination with cisplatin/5-FU chemotherapy. Thus, the
      anti-tumour activity of APR-246 may not be limited to mut-p53 bearing tumours.

      Mutation of p53 is the most common genetic aberration in oesophageal cancer being detected in
      up to 80% of both oesophageal squamous cell cancers and adenocarcinomas.

      APR-246 is a first-in-class agent targeting mutant p53. In vitro and in vivo preclinical
      models have demonstrated that APR-246 has excellent efficacy in OC (both adenocarcinoma and
      squamous cell carcinoma) and potently synergises with chemotherapies used in the treatment of
      OC, restoring sensitivity to chemotherapy-resistant tumours. An initial phase I clinical
      trial has shown APR-246 to be safe in humans and early results from a currently running phase
      Ib/II trial of APR-246 with carboplatin and liposomal doxorubicin in ovarian cancer have been
      promising. Together, these data provide a strong rationale for investigating the efficacy of
      APR-246 in OC.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Establish the safety profile of combined APR-246 plus cisplatin and 5FU as measured by the satisfactorily low rate of adverse events described according to NCI CTCAE v 4.03.
time frame: 3 weeks post commencement of treatment.
measure: Evidence of clinical efficacy of a combined APR-246 and cisplatin/5FU chemotherapy regimen as confirmed by CT/PET/MRI scan.
time frame: 6 and 12 weeks post commencement of treatment.
measure: Number of patients who will benefit from APR-246 therapy as assessed by quantitation of ctDNA levels in patient serum and plasma samples.
time frame: Through study completion, an average of 7 years.
arm group label: APR-246
arm group type: Experimental
description: The trial regimen consists of the investigational agent APR-246, along with standard chemotherapy, Cisplatin and 5-FU. A maximum of 8 cycles of treatment will be given.
APR-246 and 5-FU must both commence on Day 1 and given on days 1 to 4 via intravenous infusion over 6 hours, whilst 5-FU must be given as a continuous infusion over 96 hours.
On Days 2-4, APR-246 must be given first via intravenous infusion over 6 hours, then commence cisplatin via intravenous infusion over one hour.
This is a dose-escalation study to determine the maximum tolerated dose (MTD) of the combination therapy. The 3 dose levels are described as follows:
Dose Level 1:
APR-246 Dose: 75mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI
Dose Level 2:
APR-246 Dose: 100mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI
Dose Level -1:
APR-246 Dose: 50mg/kg LBM Cisplatin Dose: 25mg/m2 5-FU Dose: 750mg/m2/ day CI
intervention type: Drug
intervention name: APR-246
description: APR-246 (also known as PRIMA-1MET), a first-in-class agent targeting mutant p53 resulting in re-expression of wild-type p53 activity.
arm group label: APR-246
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Lara Lipton, MB.BS FRACP
role: Study Chair
affiliation: Peter MacCallum Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
responsible party type: Sponsor
mesh term: Esophageal Neoplasms