<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/NCT02220049</url>
  </required_header>
  <id_info>
    <org_study_id>2009-014354-15</org_study_id>
    <secondary_id>2009/1520</secondary_id>
    <nct_id>NCT02220049</nct_id>
  </id_info>
  <brief_title>Dose Escalation of Velcade Daily Dose in Patients With Solid Tumors</brief_title>
  <acronym>VELDAY</acronym>
  <official_title>Phase I Dose Escalation of Velcade (Bortezomib) Daily Dose in Patients With Advances or Metastatic Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Gustave Roussy, Cancer Campus, Grand Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Gustave Roussy, Cancer Campus, Grand Paris</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      VELCADE has demonstrated marked activity in haematological cancers leading to registration&#xD;
      (MM, MCL).&#xD;
&#xD;
      Currently only biweekly or weekly regimens have been explored. Key signalling pathways which&#xD;
      are aberrant in haematological cancers are also present in solid tumors.&#xD;
&#xD;
      VELCADE covers a broad spectrum of proteins, which are pivotal in carcinogenesis.VELCADE as a&#xD;
      single agent &amp; in combination with chemotherapy in solid cancers has shown modest and real&#xD;
      anti-tumor activity but insufficient for Phase III development.&#xD;
&#xD;
      VELCADE PK exposure may be inadequate in solid tumors compared to &quot;liquid cancers.&quot; VELCADE&#xD;
      daily low dose administration may allow a greater PK exposure to be achieved, which is&#xD;
      tolerated&#xD;
&#xD;
      Hypotheses:&#xD;
&#xD;
      VELCADE daily dosing (5-days on, 2-days off) is tolerable at biologically active doses&#xD;
      VELCADE daily dosing (5-days on, 2-days off) results in increased PK (AUC)/PD (20S proteasome&#xD;
      inhibition) VELCADE daily dosing (5-days on, 2-days off) with increased PK/PD results in&#xD;
      improved anti-tumor activity (Increased tolerable VELCADE AUC may potentially cross the&#xD;
      threshold required for clinically significant anti-tumor activity in solid cancers).&#xD;
&#xD;
      Some preclinical data suggest that: VELCADE daily dosing results in increased proteasome&#xD;
      inhibition in tumor tissues Combination of VELCADE + XRT/other daily dosing agent may have&#xD;
      increased anti-tumor activity compared to monotherapy alone.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>December 2010</start_date>
  <completion_date type="Actual">November 2013</completion_date>
  <primary_completion_date type="Actual">November 2013</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>Identify maximum tolerated dose</measure>
    <time_frame>Assessed every week from inclusion during the first 28 days and then every 28 days up to 19 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy</measure>
    <time_frame>Assessed within 7 days of every cycle (28 days) up to 19 months</time_frame>
    <description>According to the WHO criteria for tumor response</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">18</enrollment>
  <condition>Advanced or Metastatic Solid Tumors</condition>
  <arm_group>
    <arm_group_label>Velcade</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Dose level Dose(mg/m²) d1-5, d8-12, d15-19 Cohort -2 Velcade 0.3 mg/m² Cohort -1 Velcade 0.4 mg/m² Cohort 1 Velcade 0.5 mg/m² Cohort 2 Velcade 0.6 mg/m² Cohort 3 Velcade 0.7 mg/m² Cohort 4 Velcade 0.8 mg/m² Cohort 5 Velcade 0.9 mg/m² Cohort 6 Velcade 1.0 mg/m² Cohort 7 Velcade 1.1 mg/m²</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bortezomib</intervention_name>
    <arm_group_label>Velcade</arm_group_label>
    <other_name>VELCADE</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Signed written informed consent&#xD;
&#xD;
          2. Target population&#xD;
&#xD;
               -  Subjects with advanced or metastatic solid tumors for whom the standard of care&#xD;
                  is ineffective or inappropriate&#xD;
&#xD;
               -  Ability to comply with visits/procedures required by the protocol&#xD;
&#xD;
               -  Life expectancy of at least 3 months&#xD;
&#xD;
               -  ECOG performance status score 0-1&#xD;
&#xD;
               -  Subjects with Histologic or cytologic diagnosis of any solid tumor&#xD;
                  (nonhematologic malignancy).&#xD;
&#xD;
               -  A tumor paraffin tissue block or 20-30 unstained slides from the tumor tissue&#xD;
                  block or enough slides from an FNA to allow for biomarker and predictive marker&#xD;
                  analyses. (This biopsy need not be obtained fresh at the time of screening.&#xD;
                  Obtaining unstained slides from the original diagnostic biopsy will suffice to&#xD;
                  meet this requirement).&#xD;
&#xD;
               -  Measurable or evaluable disease&#xD;
&#xD;
               -  Prior anti-cancer treatments are permitted (i.e. chemotherapy, radiotherapy,&#xD;
                  hormonal, or immunotherapy) with the following exceptions:&#xD;
&#xD;
               -  Toxicity related to prior therapy must either have resolved, returned to baseline&#xD;
                  or been deemed irreversible but does not conflict with exclusion criteria.&#xD;
                  Peripheral pre-existent neuropathy of any grade related or not related to&#xD;
                  previous anticancer therapy is an exclusion criterion.&#xD;
&#xD;
               -  At least 3 weeks must have elapsed since the last chemo-therapy, immunotherapy or&#xD;
                  radiotherapy and the beginning of protocol therapy. At least 6 weeks for&#xD;
                  nitrosoureas, mitomycin C and liposomal doxorubicin.&#xD;
&#xD;
               -  At least 3 weeks must have elapsed since the last anti-cancer hormonal therapy or&#xD;
                  antibody targeted therapy (e.g. Bevacizumab, Cetuximab, Trastuzumab). Hormonal&#xD;
                  treatment by analog LHRH will be allowed for patients with prostate cancer For&#xD;
                  extended-release formulations, the washout period must extend 1 month beyond the&#xD;
                  duration of activity of the formulation (e.g., 3 months for the activity of a&#xD;
                  depot formulation + 1 month wash out).&#xD;
&#xD;
          3. Age and Sex&#xD;
&#xD;
               -  men and women 18 - 75&#xD;
&#xD;
               -  Male and female patients of childbearing potential must use effective&#xD;
                  contraceptive measures during the study an d for at least 3 months after the end&#xD;
                  of the study treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Sex and Reproductive Status&#xD;
&#xD;
               -  Male and female patients of childbearing potential who are unwilling or unable to&#xD;
                  use an acceptable method to avoid pregnancy for the entire study period and for&#xD;
                  up to three months after the study.&#xD;
&#xD;
               -  Male and female patients of childbearing potential using a prohibited&#xD;
                  contraceptive method.&#xD;
&#xD;
               -  Women who are pregnant or breastfeeding.&#xD;
&#xD;
               -  Women with a positive pregnancy test on enrollment or prior to study drug&#xD;
                  administration.&#xD;
&#xD;
          2. Target Disease Exclusions:&#xD;
&#xD;
             Subjects who have documented unstable or untreated brain metastasis for at least 4&#xD;
             weeks and who are still requiring steroids (Subjects with treated and stably&#xD;
             controlled CNS metastases for at least 4 weeks and are no longer on steroids are&#xD;
             eligible for this study).&#xD;
&#xD;
          3. Medical History and Concurrent Diseases&#xD;
&#xD;
               -  A serious uncontrolled medical disorder or active infection, which would impair&#xD;
                  the ability of the subject to receive protocol therapy&#xD;
&#xD;
               -  History of thromboembolic disease or bleeding diatheses within the last six (6)&#xD;
                  months. This includes those subjects with tumors that were known to have&#xD;
                  spontaneously bled in the past.&#xD;
&#xD;
               -  History or presence of the diffuse interstitial lung disease or pericardial&#xD;
                  disease&#xD;
&#xD;
               -  Previous history or current presence of neurological disorders, including&#xD;
                  epilepsy, Parkinson's disease, multiple sclerosis, stroke.&#xD;
&#xD;
               -  Pre-existent peripheral neuropathy of any grade, related or unrelated to previous&#xD;
                  anticancer therapy. However, asymptomatic infraclinical neuropathy with moderate&#xD;
                  measurable changes revealed by EMG will be allowed.&#xD;
&#xD;
               -  Uncontrolled or significant cardiovascular disease including&#xD;
&#xD;
               -  myocardial infarction within 12 months- uncontrolled angina within 6 months&#xD;
&#xD;
               -  congestive heart failure within 6 months&#xD;
&#xD;
               -  LVEF ≤ 45% at baseline, or &lt;55% if prior exposure to anthracyclines&#xD;
&#xD;
               -  diagnosed or suspected congenital long QT syndrome.&#xD;
&#xD;
               -  any history of clinically significant ventricular arrhythmias (such as&#xD;
                  ventricular tachycardia, ventricular fibrillation, or &quot;Torsade de Pointes&quot;).&#xD;
                  Controlled atrial fibrillation is not an exclusion criterion.&#xD;
&#xD;
               -  pericardial effusion&#xD;
&#xD;
               -  Subjects with concomitant other malignancies (except non-melanomatous skin&#xD;
                  cancers, early stage prostate or cervical cancers) are excluded unless a complete&#xD;
                  remission was achieved at least 5 years prior to study entry and no additional&#xD;
                  therapy is required or anticipated to be required during the study period&#xD;
&#xD;
               -  Subjects receiving any drugs or agents that inhibit (e.g., cimetidine,&#xD;
                  erythromycin, fluoxetine, ketoconazole, paroxetine) or induce (e.g.,&#xD;
                  carbamazepine, glucocorticoids, phenobarbital, rifampin) CYP2C19 or CYP3A4 within&#xD;
                  14 days before the first dose of VELCADE&#xD;
&#xD;
               -  Need for therapy with concomitant CYP 3A4 inhibitors (e.g.,&#xD;
                  itraconazole,fluconazole,clarithromycin,erythromycin, norfloxacin, fluvoxamine,&#xD;
                  cimetidine, indinavir, ritonavir) or inducers (e.g., efavirenz, barbiturates,&#xD;
                  phenytoin, rifampin, glitazones)&#xD;
&#xD;
               -  Green tea consummation&#xD;
&#xD;
          4. Physical and Laboratory Test Findings (as confirmed by repeat test/results)&#xD;
&#xD;
               -  Inadequate bone marrow function defined as:&#xD;
&#xD;
               -  absolute neutrophil count &lt; 1,500 cells/mm3.&#xD;
&#xD;
               -  platelet count &lt; 100,000 cells/mm3.&#xD;
&#xD;
               -  hemoglobin &lt; 9.0 g/dl&#xD;
&#xD;
               -  Inadequate hepatic function defined as:&#xD;
&#xD;
               -  total bilirubin &gt; 1.5 times the institutional upper limit of normal (IULN) unless&#xD;
                  identified as a result of a confirmed genetic disorder of bilirubin metabolism&#xD;
                  (e.g., Gilbert's syndrome or familial benign unconjugated hyperbilirubinaemia).&#xD;
&#xD;
               -  alanine transaminase (ALT) and aspartate transaminase (AST) &gt; 2.5 times the IULN&#xD;
&#xD;
               -  Inadequate renal function defined as serum creatinine &gt;1.5 times the IULN&#xD;
&#xD;
               -  PT- INR/PTT &gt;1.5 times the IULN is an exclusion criteria&#xD;
&#xD;
               -  If proteinuria ≥ 1+ then quantify by urinary protein in random urine sample;&#xD;
                  eligible if &lt;1 g/l .&#xD;
&#xD;
          5. Allergies and Adverse Drug Reactions history of allergy to Velcade or chemically&#xD;
             related compounds&#xD;
&#xD;
          6. Other Exclusion Criteria:&#xD;
&#xD;
        prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for&#xD;
        treatment of either a psychiatric or physical (e.g., infectious disease) illness must not&#xD;
        be enrolled into this study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Rastislav BAHLEDA, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Gustave Roussy, Cancer Campus, Grand Paris</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <state>Val de Marne</state>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>March 2016</verification_date>
  <study_first_submitted>August 18, 2014</study_first_submitted>
  <study_first_submitted_qc>August 18, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 19, 2014</study_first_posted>
  <last_update_submitted>March 24, 2016</last_update_submitted>
  <last_update_submitted_qc>March 24, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">March 25, 2016</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>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bortezomib</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/NCT02220049
org study id: 2009-014354-15
secondary id: 2009/1520
nct id: NCT02220049
lead sponsor: 
has dmc: No
VELCADE has demonstrated marked activity in haematological cancers leading to registration
      (MM, MCL).

      Currently only biweekly or weekly regimens have been explored. Key signalling pathways which
      are aberrant in haematological cancers are also present in solid tumors.

      VELCADE covers a broad spectrum of proteins, which are pivotal in carcinogenesis.VELCADE as a
      single agent & in combination with chemotherapy in solid cancers has shown modest and real
      anti-tumor activity but insufficient for Phase III development.

      VELCADE PK exposure may be inadequate in solid tumors compared to "liquid cancers." VELCADE
      daily low dose administration may allow a greater PK exposure to be achieved, which is
      tolerated

      Hypotheses:

      VELCADE daily dosing (5-days on, 2-days off) is tolerable at biologically active doses
      VELCADE daily dosing (5-days on, 2-days off) results in increased PK (AUC)/PD (20S proteasome
      inhibition) VELCADE daily dosing (5-days on, 2-days off) with increased PK/PD results in
      improved anti-tumor activity (Increased tolerable VELCADE AUC may potentially cross the
      threshold required for clinically significant anti-tumor activity in solid cancers).

      Some preclinical data suggest that: VELCADE daily dosing results in increased proteasome
      inhibition in tumor tissues Combination of VELCADE + XRT/other daily dosing agent may have
      increased anti-tumor activity compared to monotherapy alone.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Identify maximum tolerated dose
time frame: Assessed every week from inclusion during the first 28 days and then every 28 days up to 19 months
measure: Efficacy
time frame: Assessed within 7 days of every cycle (28 days) up to 19 months
description: According to the WHO criteria for tumor response
arm group label: Velcade
arm group type: Experimental
description: Dose level Dose(mg/m²) d1-5, d8-12, d15-19 Cohort -2 Velcade 0.3 mg/m² Cohort -1 Velcade 0.4 mg/m² Cohort 1 Velcade 0.5 mg/m² Cohort 2 Velcade 0.6 mg/m² Cohort 3 Velcade 0.7 mg/m² Cohort 4 Velcade 0.8 mg/m² Cohort 5 Velcade 0.9 mg/m² Cohort 6 Velcade 1.0 mg/m² Cohort 7 Velcade 1.1 mg/m²
intervention type: Drug
intervention name: Bortezomib
arm group label: Velcade
other name: VELCADE
criteria: 
gender: All
minimum age: 18 Years
maximum age: 75 Years
healthy volunteers: No
last name: Rastislav BAHLEDA, MD
role: Principal Investigator
affiliation: Gustave Roussy, Cancer Campus, Grand Paris
facility: 
country: France
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Bortezomib