<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/NCT03786237</url>
  </required_header>
  <id_info>
    <org_study_id>Rigosertib 4.0</org_study_id>
    <nct_id>NCT03786237</nct_id>
  </id_info>
  <brief_title>Rigosertib for RDEB-SCC</brief_title>
  <official_title>A Phase II, Open Study to Assess Efficacy and Safety of Rigosertib in Patients With Recessive Dystrophic Epidermolysis Bullosa Associated Locally Advanced/Metastatic Squamous Cell Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Prof. Johann Bauer</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Salzburger Landeskliniken</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>
      Epidermolysis bullosa (EB) is a heritable skin disease characterized by marked fragility of&#xD;
      epithelialized tissue with blistering in skin and mucous membranes following the slightest&#xD;
      mechanical trauma. Eighty percent of all patients suffering from recessive dystrophic EB&#xD;
      (RDEB), a subtype originating from mutations in the COL7A1 gene, develop squamous cell&#xD;
      carcinoma (SCC). In RDEB patients SCC presents early (most patients are in their 20s or 30s)&#xD;
      and shows a highly aggressive metastatic course which often leads to premature death at this&#xD;
      young age.&#xD;
&#xD;
      In light of scarce data on the efficacy and safety of systemic treatment regimens for&#xD;
      advanced SCC, the investigators propose to perform a small, &quot;first in EB &quot; trial of an&#xD;
      experimental drug called rigosertib for the treatment of EB cancer. The trial will be&#xD;
      conducted in two study centres, in London and Salzburg, and will last approximately 2.5 years&#xD;
      with each patient recruited being in the study for 1 year. The drug is a polo-like kinase&#xD;
      inhibitor interfering with different molecular pathways that are essential for cancer cell&#xD;
      growth. Rigosertib was developed by Onconova Therapeutics and is currently tested in several&#xD;
      clinical trials for a number of other cancers including myelodysplastic syndrome (a cancer of&#xD;
      the blood). The investigators have identified that rigosertib most selectively kills EB&#xD;
      cancer cells in vitro while leaving normal EB skin cells unaffected. This project will&#xD;
      evaluate whether rigosertib is capable of inducing an anti-cancer response in EB patients and&#xD;
      whether the drug is well-tolerated. Mechanisms of molecular targeting of squamous cancer&#xD;
      cells by rigosertib will further be investigated in EB patients, also aiming at the&#xD;
      identification of biomarkers that may allow the predictive identification of best responders.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 12, 2021</start_date>
  <completion_date type="Anticipated">June 2026</completion_date>
  <primary_completion_date type="Anticipated">December 2025</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>Efficacy: Objective Response Rate (ORR)</measure>
    <time_frame>1 year</time_frame>
    <description>The primary (efficacy) objective of this trial is to determine the Objective Response Rate (ORR) of therapy with Rigosertib in RDEB patients with locally advanced/metastatic squamous cell carcinoma of the skin using Response Criteria in Solid Tumors Version 1.1 (RECIST1.1) per site assessment up to 52 weeks by CT/MR Scan.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Treatment-related adverse events</measure>
    <time_frame>1 year</time_frame>
    <description>Safety will be evaluated for all treated patients, who receive at least one dose of Rigosertib, using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (http://ctep.cancer.gov). Safety assessments will be based on number of treatment related adverse events per grade.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of quality of life using the &quot;Quality of life in Epidermolysis bullosa questionnaire (QOLEB)&quot;</measure>
    <time_frame>1 year</time_frame>
    <description>Assess impact on quality of life using an Epidermolysis bullosa (EB) specific questionnaire developed and published by Murrell et al.2009. Total score is reported (range 0-75; 0 means EB has no affect on ones life, the higher the score the more affect and annoyance/handicap)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of presence or absence of cancer specific biomarkers</measure>
    <time_frame>1 year</time_frame>
    <description>Fixed tissue will be assessed using immuno-histochemistry with antibodies raised against phosphorylated AKT (p473 Akt), phosphorylated C-RAF (p-S338 RAF), phosphorylated ERK and cleaved caspase.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">12</enrollment>
  <condition>Epidermolysis Bullosa Dystrophica</condition>
  <condition>Squamous Cell Carcinoma</condition>
  <arm_group>
    <arm_group_label>Treatment Oral Capsules / Intravenous</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rigosertib Oral Capsules / Rigosertib Intravenous</intervention_name>
    <description>Patients will take Rigosertib either as oral capsules or will get intravenous infusions depending on the needs of the patients.&#xD;
Oral Capsules:&#xD;
Patients will take oral Rigosertib continuously for a total of three weeks, every four week cycle (three weeks on, one week off drug) for up to 13 cycles. Patients will take 560 mg of oral Rigosertib (ie, 2 capsules of 280 mg) in the morning and in the afternoon, total of 1120mg/day.&#xD;
Intravenous Infusions:&#xD;
For IV treatment Rigosertib 1800 mg/24 hr is diluted in 0.9% sodium chloride for injection just prior to dosing and is administered as a 72-hr CIV infusion on days 1, 2, and 3 of a 2-week cycle for the first eight 2-week cycles, then on days 1, 2, and 3 of a 4-week cycle thereafter.</description>
    <arm_group_label>Treatment Oral Capsules / Intravenous</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 18-79 years of age;&#xD;
&#xD;
          2. Diagnosis of unresectable, locally advanced or metastatic SCC confirmed prior to the&#xD;
             Screening Visit.&#xD;
&#xD;
          3. Failure to respond to RDEB SCC standard of care, such as surgical excision,&#xD;
             radiotherapy or conventional cytotoxic chemotherapy with e.g. platin derivates (i.e.&#xD;
&#xD;
             cisplatin or carboplatin), 5-fluorouracil, bleomycin, methotrexate, adriamycin,&#xD;
             taxanes, gemcitabine or ifosfamide alone or in combination or failure to respond to&#xD;
             previous alternative biologic treatments such as epidermal growth factor inhibitors&#xD;
             (like cetuximab and panitumumab) or immune checkpoint (programmed cell death&#xD;
&#xD;
             1) inhibitors (such as nivolumab, pembrolizumab, cemiplimab). For recent guidelines on&#xD;
             standard of care for RDEB SCC and non EB-SCC please see Mellerio et al., 2016;&#xD;
             Stratigos et al., 2015 and Kim et al., 2018.&#xD;
&#xD;
          4. Is not currently receiving any other cancer therapy.&#xD;
&#xD;
          5. Measurable disease based on Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1)&#xD;
&#xD;
          6. Patient (or patient's legally authorized representative) must have signed an informed&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Response to standard of care.&#xD;
&#xD;
          2. Uncontrolled intercurrent illness including, but not limited to, symptomatic&#xD;
             congestive heart failure or unstable angina pectoris.&#xD;
&#xD;
          3. Active systemic infection not adequately responding to appropriate therapy.&#xD;
&#xD;
          4. Total bilirubin ≥ 1.5 mg/dL (≥5.3 mg/dL in patients if related to hemolysis or&#xD;
             Gilbert's disease).&#xD;
&#xD;
          5. Alanine transaminase (ALT)/aspartate transaminase (AST) ≥ 2.5 x upper limit of normal&#xD;
             (ULN).&#xD;
&#xD;
          6. Serum creatinine ≥2 .0 mg/dL or eGFR (estimated Glomerular Filtration Rate) &lt;60mL/min.&#xD;
&#xD;
          7. White blood cell count ≤ 2000/μl, neutrophils ≤ 1500/μL, platelets ≤ 100 x103/μL,&#xD;
             hemoglobin ≤ 7.9 g/dL.&#xD;
&#xD;
          8. Known active HIV, hepatitis B or hepatitis C, where active is defined as follows: a.&#xD;
             HIV or Hepatitis C - presence of viral load; b. Hepatitis B - antigen positive&#xD;
&#xD;
          9. Uncorrected hyponatremia (defined as serum sodium value of &lt;125 mmol/L).&#xD;
&#xD;
         10. Male patients with partners of child-bearing potential who are unwilling to use male&#xD;
             contraception (condom) throughout the study, up to and including the 30-day&#xD;
             nontreatment follow-up period.&#xD;
&#xD;
         11. Female subjects: pregnant or lactating women and all women physiologically capable of&#xD;
             becoming pregnant (i.e. women of childbearing potential) UNLESS they are willing to&#xD;
             use one or more highly effective and reliable methods of contraception with a Pearl&#xD;
             index ≤1 including combined (estrogen and progestogen containing) hormonal&#xD;
             contraception associated with inhibition of ovulation (oral or intravaginal or&#xD;
             transdermal); progestogen-only hormonal contraception associated with inhibition of&#xD;
             ovulation (oral or injectable or implantable); an intrauterine device (IUD); an&#xD;
             intrauterine hormone-releasing system ( IUS); bilateral tubal occlusion; vasectomised&#xD;
             partner (provided that partner is the sole sexual partner of the WOCBP trial&#xD;
             participant and that the vasectomised partner has received medical assessment of the&#xD;
             surgical success) or sexual abstinence (The reliability of sexuality abstinence needs&#xD;
             to be evaluated in relation to the duration of the clinical trial and the preferred&#xD;
             and usual lifestyle of the subject). Reliable contraception should be maintained&#xD;
             throughout the study. A pregnancy test in serum will be performed at screening in all&#xD;
             women of childbearing potential, and in urine at all visits. Any postmenopausal women&#xD;
             (physiologic menopause defined as &quot;12 consecutive months of amenorrhea&quot;) or women&#xD;
             permanently sterilized (e.g. tubal occlusion, hysterectomy or bilateral salpingectomy)&#xD;
             will not be required to undergo pregnancy test.&#xD;
&#xD;
         12. Uncontrolled hypertension. (i.e.. systolic blood pressure greater than or equal to&#xD;
             140mmHg and diastolic blood pressure greater than or equal to 90mmHg despite intake of&#xD;
             ≥ 3 antihypertensive medications with complementary mechanisms of action (a diuretic&#xD;
             should be 1 component); (Whelton et al., 2018).&#xD;
&#xD;
         13. Patient is currently participating and receiving study therapy or systemic therapy or&#xD;
             has participated in a study of an investigational agent and received study therapy or&#xD;
             used an investigational device within 4 weeks of the first dose of treatment.&#xD;
&#xD;
         14. Psychiatric illness or social situation that would limit the patient's ability to&#xD;
             tolerate and/or comply with study requirements.&#xD;
&#xD;
         15. Patients (or parents in case of paediatric subject) unlikely to comply with the study&#xD;
             protocol or unable to understand the nature and scope of the study or the possible&#xD;
             benefits or unwanted effects of the study procedures and treatments.&#xD;
&#xD;
         16. History or current evidence of any condition, therapy, or laboratory abnormality that&#xD;
             might confound the results of the study, interfere with the patient's participation&#xD;
             for the full duration of the study, or is not in the best interest of the patient to&#xD;
             participate, in the opinion of the treating Investigator.&#xD;
&#xD;
         17. Known hypersensitivity reaction to any of the components of study treatment.&#xD;
&#xD;
         18. Presence of clinically significant ECG abnormalities based on the inverstigator´s&#xD;
             criteria.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>79 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Johann W Bauer, Prof., MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Dermatology, Paracelsus Medical University, Salzburger Landeskliniken</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Manager EB Study Center</last_name>
    <phone>+43 5 7255</phone>
    <phone_ext>82413</phone_ext>
    <email>Clinical-Trial-eb@salk.at</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Elisabeth Mayr, PhD</last_name>
    <phone>+43 5 7255</phone>
    <phone_ext>80087</phone_ext>
    <email>el.mayr@salk.at</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>EB House Austria/Dept. of Dermatology University Hospital</name>
      <address>
        <city>Salzburg</city>
        <zip>5020</zip>
        <country>Austria</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elisabeth Mayr, PhD</last_name>
      <phone>+4357255</phone>
      <phone_ext>82413</phone_ext>
      <email>el.mayr@salk.at</email>
    </contact>
    <contact_backup>
      <last_name>Sophie Kitzmüller, PhD</last_name>
      <phone>+4357255</phone>
      <phone_ext>52053</phone_ext>
      <email>s.kitzmueller@salk.at</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Austria</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>November 14, 2018</study_first_submitted>
  <study_first_submitted_qc>December 20, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 24, 2018</study_first_posted>
  <last_update_submitted>November 3, 2022</last_update_submitted>
  <last_update_submitted_qc>November 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Salzburger Landeskliniken</investigator_affiliation>
    <investigator_full_name>Prof. Johann Bauer</investigator_full_name>
    <investigator_title>Head of Department of Dermatology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Carcinoma, Squamous Cell</mesh_term>
    <mesh_term>Epidermolysis Bullosa</mesh_term>
    <mesh_term>Epidermolysis Bullosa Dystrophica</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>ON 01910</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03786237
org study id: Rigosertib 4.0
nct id: NCT03786237
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Epidermolysis bullosa (EB) is a heritable skin disease characterized by marked fragility of
      epithelialized tissue with blistering in skin and mucous membranes following the slightest
      mechanical trauma. Eighty percent of all patients suffering from recessive dystrophic EB
      (RDEB), a subtype originating from mutations in the COL7A1 gene, develop squamous cell
      carcinoma (SCC). In RDEB patients SCC presents early (most patients are in their 20s or 30s)
      and shows a highly aggressive metastatic course which often leads to premature death at this
      young age.

      In light of scarce data on the efficacy and safety of systemic treatment regimens for
      advanced SCC, the investigators propose to perform a small, "first in EB " trial of an
      experimental drug called rigosertib for the treatment of EB cancer. The trial will be
      conducted in two study centres, in London and Salzburg, and will last approximately 2.5 years
      with each patient recruited being in the study for 1 year. The drug is a polo-like kinase
      inhibitor interfering with different molecular pathways that are essential for cancer cell
      growth. Rigosertib was developed by Onconova Therapeutics and is currently tested in several
      clinical trials for a number of other cancers including myelodysplastic syndrome (a cancer of
      the blood). The investigators have identified that rigosertib most selectively kills EB
      cancer cells in vitro while leaving normal EB skin cells unaffected. This project will
      evaluate whether rigosertib is capable of inducing an anti-cancer response in EB patients and
      whether the drug is well-tolerated. Mechanisms of molecular targeting of squamous cancer
      cells by rigosertib will further be investigated in EB patients, also aiming at the
      identification of biomarkers that may allow the predictive identification of best responders.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Efficacy: Objective Response Rate (ORR)
time frame: 1 year
description: The primary (efficacy) objective of this trial is to determine the Objective Response Rate (ORR) of therapy with Rigosertib in RDEB patients with locally advanced/metastatic squamous cell carcinoma of the skin using Response Criteria in Solid Tumors Version 1.1 (RECIST1.1) per site assessment up to 52 weeks by CT/MR Scan.
measure: Number of Treatment-related adverse events
time frame: 1 year
description: Safety will be evaluated for all treated patients, who receive at least one dose of Rigosertib, using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (http://ctep.cancer.gov). Safety assessments will be based on number of treatment related adverse events per grade.
measure: Evaluation of quality of life using the "Quality of life in Epidermolysis bullosa questionnaire (QOLEB)"
time frame: 1 year
description: Assess impact on quality of life using an Epidermolysis bullosa (EB) specific questionnaire developed and published by Murrell et al.2009. Total score is reported (range 0-75; 0 means EB has no affect on ones life, the higher the score the more affect and annoyance/handicap)
measure: Rate of presence or absence of cancer specific biomarkers
time frame: 1 year
description: Fixed tissue will be assessed using immuno-histochemistry with antibodies raised against phosphorylated AKT (p473 Akt), phosphorylated C-RAF (p-S338 RAF), phosphorylated ERK and cleaved caspase.
arm group label: Treatment Oral Capsules / Intravenous
arm group type: Experimental
intervention type: Drug
intervention name: Rigosertib Oral Capsules / Rigosertib Intravenous
description: Patients will take Rigosertib either as oral capsules or will get intravenous infusions depending on the needs of the patients.
Oral Capsules:
Patients will take oral Rigosertib continuously for a total of three weeks, every four week cycle (three weeks on, one week off drug) for up to 13 cycles. Patients will take 560 mg of oral Rigosertib (ie, 2 capsules of 280 mg) in the morning and in the afternoon, total of 1120mg/day.
Intravenous Infusions:
For IV treatment Rigosertib 1800 mg/24 hr is diluted in 0.9% sodium chloride for injection just prior to dosing and is administered as a 72-hr CIV infusion on days 1, 2, and 3 of a 2-week cycle for the first eight 2-week cycles, then on days 1, 2, and 3 of a 4-week cycle thereafter.
arm group label: Treatment Oral Capsules / Intravenous
criteria: 
gender: All
minimum age: 18 Years
maximum age: 79 Years
healthy volunteers: No
last name: Johann W Bauer, Prof., MD
role: Principal Investigator
affiliation: Department of Dermatology, Paracelsus Medical University, Salzburger Landeskliniken
last name: Manager EB Study Center
phone: +43 5 7255
phone ext: 82413
email: Clinical-Trial-eb@salk.at
last name: Elisabeth Mayr, PhD
phone: +43 5 7255
phone ext: 80087
email: el.mayr@salk.at
facility: 
status: Recruiting
contact: 
contact backup: 
country: Austria
responsible party type: Sponsor-Investigator
investigator affiliation: Salzburger Landeskliniken
investigator full name: Prof. Johann Bauer
investigator title: Head of Department of Dermatology
mesh term: Carcinoma
mesh term: Carcinoma, Squamous Cell
mesh term: Epidermolysis Bullosa
mesh term: Epidermolysis Bullosa Dystrophica
mesh term: ON 01910
sharing ipd: Undecided