<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/NCT01664000</url>
  </required_header>
  <id_info>
    <org_study_id>CTIX 12-101</org_study_id>
    <secondary_id>12-151</secondary_id>
    <nct_id>NCT01664000</nct_id>
  </id_info>
  <brief_title>A Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin in Patients With Advanced Solid Tumors</brief_title>
  <official_title>A Phase 1, Open-Label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin (Thioureidobutyronitrile) Administered Intravenously, in Patients With Advanced Solid Tumors</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cellceutix Corporation</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Beth Israel Deaconess Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Cellceutix Corporation</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      In the laboratory, Kevetrin activates p53, a tumor suppressor protein that has an important&#xD;
      role in protecting the body. p53 functions by activating proteins that repair DNA and kill&#xD;
      cells that have genetic mutations such as in cancers. Research experiments showed that when&#xD;
      cancer cells were treated with Kevetrin, it activated p53 which induced p21, a protein that&#xD;
      inhibits cancer cell growth. p53 also induced PUMA (p53 up-regulated modulator of apoptosis),&#xD;
      a protein that causes tumor cell death. Because of these activities, slowing cancer cell&#xD;
      growth and causing cancer cell death, Kevetrin may help to treat tumors.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Kevetrin was found to be effective in pre-clinical studies of human xenograft tumor models&#xD;
      and was reasonably well-tolerated at therapeutic doses in the non-clinical animal studies.&#xD;
      Kevetrin was also effective in multi-drug resistant tumor models; therefore, Kevetrin has the&#xD;
      potential to treat tumors that have become resistant to standard chemotherapy. This trial&#xD;
      will determine tolerance in humans and, possibly, efficacy with a Phase I, open-label,&#xD;
      dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Kevetrin, in adult&#xD;
      patients with solid tumors.&#xD;
&#xD;
      The primary objectives are the following:&#xD;
&#xD;
        -  To determine the maximum tolerated dose (MTD) of Kevetrin.&#xD;
&#xD;
        -  To determine the dose limiting toxicities (DLT) of Kevetrin.&#xD;
&#xD;
        -  To establish a safe dose level of Kevetrin that can be used for future studies.&#xD;
&#xD;
      The secondary objectives are to determine the following:&#xD;
&#xD;
        -  The pharmacokinetics of Kevetrin in humans.&#xD;
&#xD;
        -  Observe for evidence of antitumor activity following administration of Kevetrin.&#xD;
&#xD;
        -  If Kevetrin induces changes in the biomarker p21 in peripheral blood lymphocytes.&#xD;
&#xD;
        -  If there is a pharmacodynamic relationship between the plasma concentrations of Kevetrin&#xD;
           and a clinical or cellular effect.&#xD;
&#xD;
      During each 4 week cycle, each patient will receive three weekly doses of Kevetrin given as a&#xD;
      1 hour intravenous infusion followed by a 1 week off-treatment period. Following each dose,&#xD;
      each patient will be monitored. If the patients have acceptable safety and tolerance,&#xD;
      Kevetrin will be given once weekly for a total of 3 weeks. During each cycle patients will be&#xD;
      evaluated for safety, tolerance, and Dose-Limiting Toxicity (DLT) that occur during a cycle.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">February 2016</completion_date>
  <primary_completion_date type="Actual">January 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>Maximum Tolerated Dose (MTD) of Kevetrin</measure>
    <time_frame>up to 6 months</time_frame>
    <description>A dose will be declared the MTD if at least 1 patient out of 6 patients experience a dose limiting toxicity (DLT) at the highest dose level below the maximally administered dose. Once an MTD has been established, up to 12 additional patients may be enrolled at the MTD dose level for confirmation of safety.&#xD;
The maximally administered dose is if 1 or more of 6 patients experience a DLT.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Dose Limiting Toxicities (DLT) of Kevetrin.</measure>
    <time_frame>up to 4 weeks</time_frame>
    <description>The definition of dose limiting toxicity (DLT) is in accord with the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Dose limiting toxicity will be defined as:&#xD;
Grade 3 or 4 neutropenia complicated by fever, or greater than 38.5°C documented infection, or Grade 4 neutropenia of greater than 7 days duration&#xD;
Grade 4 thrombocytopenia or grade 3 thrombocytopenia complicated by hemorrhage&#xD;
Any grade greater than 3 non-hematologic toxicity unless there is clear alternative evidence that the adverse event (AE) was not caused by Kevetrin&#xD;
Grade 3 diarrhea, nausea, or vomiting may be excluded from dose-limiting toxicities provided that the maximum time limit for supportive measures is 48 hours.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Profile of Kevetrin</measure>
    <time_frame>Day 1 Pre-dose, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion</time_frame>
    <description>The pharmacokinetics (PK) of Kevetrin will be determined for all patients enrolled in the study on Day 1 of Cycle 1 and Day 15 of Cycle 2. Blood samples will be obtained before dosing, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion.&#xD;
The pharmacokinetic profile will be analyzed by standard noncompartmental methods to provide estimated values of the pharmacokinetic parameters and associated variables, such as area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of Kevetrin. Associations between pharmacokinetic variables and drug-related toxicities will be evaluated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic Profile of Kevetrin</measure>
    <time_frame>Day 15 Pre-dose, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion</time_frame>
    <description>The pharmacokinetics (PK) of Kevetrin will be determined for all patients enrolled in the study on Day 1 of Cycle 1 and Day 15 of Cycle 2. Blood samples will be obtained before dosing, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion.&#xD;
The pharmacokinetic profile will be analyzed by standard noncompartmental methods to provide estimated values of the pharmacokinetic parameters and associated variables, including area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of Kevetrin. Associations between pharmacokinetic variables and drug-related toxicities will be evaluated.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in tumor size</measure>
    <time_frame>baseline and 2 months</time_frame>
    <description>Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in tumor size</measure>
    <time_frame>baseline and 4 months</time_frame>
    <description>Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in tumor size</measure>
    <time_frame>baseline and 6 months</time_frame>
    <description>Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease in serum tumor marker</measure>
    <time_frame>baseline and 1 month</time_frame>
    <description>A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease in serum tumor marker</measure>
    <time_frame>baseline and 2 months</time_frame>
    <description>A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease in serum tumor marker</measure>
    <time_frame>baseline and 3 months</time_frame>
    <description>A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease in serum tumor marker</measure>
    <time_frame>baseline and 4 months</time_frame>
    <description>A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease in serum tumor marker</measure>
    <time_frame>baseline and 5 months</time_frame>
    <description>A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Decrease in serum tumor marker</measure>
    <time_frame>baseline and 6 months</time_frame>
    <description>A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the biomarker p21 in peripheral blood lymphocytes</measure>
    <time_frame>baseline and 7 hours</time_frame>
    <description>For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the biomarker p21 in peripheral blood lymphocytes</measure>
    <time_frame>baseline and 24 hours</time_frame>
    <description>For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">48</enrollment>
  <condition>Solid Tumors</condition>
  <arm_group>
    <arm_group_label>Kevetrin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>thioureidobutyronitrile intravenous once/week for 3 weeks/ cycle</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>thioureidobutyronitrile</intervention_name>
    <description>Kevetrin (thioureidobutyronitrile)</description>
    <arm_group_label>Kevetrin</arm_group_label>
    <other_name>Kevetrin</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males / females, ≥ 18 years old, any race / ethnicity, who can provide written&#xD;
             Informed Consent&#xD;
&#xD;
          -  Life expectancy ≥ 3 months&#xD;
&#xD;
          -  Pathologically confirmed solid tumor, locally advanced / metastatic, refractory after&#xD;
             standard therapy, or for which no effective curative or surgical treatment options are&#xD;
             available&#xD;
&#xD;
          -  Measurable disease on baseline imaging per RECIST 1.1 criteria&#xD;
&#xD;
          -  ECOG performance status ≤ 1&#xD;
&#xD;
          -  Liver function:&#xD;
&#xD;
          -  Bilirubin ≤ 1.5 X upper limit of normal&#xD;
&#xD;
          -  AST, SGOT, ALT, SGPT ≤ 2.5 X upper limit of normal, &lt; 5 upper limit if there are liver&#xD;
             metastases&#xD;
&#xD;
          -  Renal function:&#xD;
&#xD;
          -  Serum creatinine within normal limits&#xD;
&#xD;
          -  Hematologic status:&#xD;
&#xD;
          -  Absolute neutrophil count ≥ 1500 cells/mm3.&#xD;
&#xD;
          -  Platelet count ≥ 100,000/mm3.&#xD;
&#xD;
          -  Hemoglobin ≥ 9 g/dL&#xD;
&#xD;
          -  Coagulation status:&#xD;
&#xD;
          -  Coagulation Prothrombin time ≤ 1.5 X upper limit&#xD;
&#xD;
          -  Partial thromboplastin time ≤ 1.5 X upper limit&#xD;
&#xD;
          -  Males must agree to use condoms during sex to prevent spillage of semen for the&#xD;
             duration of the study and for 3 months after the patient leaves the study&#xD;
&#xD;
          -  Females in the study must not be pregnant or breast feeding and not planning to become&#xD;
             pregnant or breast feed for the duration of the study, and for at least three months&#xD;
             after study completion&#xD;
&#xD;
          -  Women of childbearing potential must commit to using a double barrier method of&#xD;
             contraception, an intrauterine device, or sexual abstinence for the duration of the&#xD;
             study and for at least three months after study completion&#xD;
&#xD;
          -  Serum pregnancy test for women of child bearing potential must be negative at entry&#xD;
             into study&#xD;
&#xD;
          -  Written voluntary informed consent: the patient is capable of complying with the&#xD;
             requirements of the written Informed Consent Form and complying with protocol&#xD;
             requirements&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History of significant disease that in the Investigator's opinion would put the&#xD;
             patient at high risk on the trial&#xD;
&#xD;
          -  Cognitive impairment sufficient to render the patient incapable of giving informed&#xD;
             consent&#xD;
&#xD;
          -  History of clinically significant psychiatric illness that would prevent the patient&#xD;
             from providing a valid ICF and complying with protocol requirements&#xD;
&#xD;
          -  Unwillingness or inability to comply with procedures required in this protocol&#xD;
&#xD;
          -  History or presence of alcoholism or drug abuse within the past 2 years&#xD;
&#xD;
          -  Patients who have had a major surgical procedure within the past 6 weeks&#xD;
&#xD;
          -  History of HIV, hepatitis B, or hepatitis C&#xD;
&#xD;
          -  Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy&#xD;
&#xD;
          -  Women of childbearing potential who are lactating, pregnant or there is the likelihood&#xD;
             of becoming pregnant within the coming 12 months; a positive serum beta-human&#xD;
             chorionic gonadotropin test at time of screening for entry into study&#xD;
&#xD;
          -  New York Heart Association Class III or IV, cardiac disease, myocardial infarction&#xD;
             within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG&#xD;
&#xD;
          -  Patients with a mean QTc interval greater than 480ms are excluded. Avoid concomitant&#xD;
             administration of agents that prolong the QT interval, except at the discretion of the&#xD;
             investigator. If advised, patients should discontinue the use of these agents at least&#xD;
             2 weeks before the study begins. No uncontrolled arrhythmias.&#xD;
&#xD;
          -  Patients currently receiving other investigational agents&#xD;
&#xD;
          -  Participation in a study of an investigational drug within 4 weeks prior to the&#xD;
             planned first day of study drug administration&#xD;
&#xD;
          -  Patients who have undergone radiation within the past 4 weeks&#xD;
&#xD;
          -  Treatment with molecularly targeted agents within the past 3 weeks prior to planned&#xD;
             first study drug administration. Patients who were receiving standard chemotherapy or&#xD;
             experimental therapies must wait 4 weeks from their last dose prior to the planned&#xD;
             first study drug administration. Patients treated with nitrosoureas or mitomycin C&#xD;
             must wait 6 weeks from their last dose prior to the planned first study drug&#xD;
             administration.&#xD;
&#xD;
          -  Patients with known brain metastases may be excluded from this study. However,&#xD;
             patients may be eligible if scans show limited disease or repeat scans show stable&#xD;
             disease in the opinion of the investigator and patients have no ill effect from the&#xD;
             metastases.&#xD;
&#xD;
          -  Herbal supplements are prohibited 1 week prior to the planned first study drug&#xD;
             administration, during the clinical study, and up to the time that the patient is&#xD;
             discharged from the study&#xD;
&#xD;
          -  Patients who have been exposed to medications, herbal preparations, or foods known to&#xD;
             be predominant Cytochrome P450 2C9, 2C19, 2D6, 3A4/5 substrates, strong inhibitors or&#xD;
             inducers within 7 days of planned first study treatment day&#xD;
&#xD;
          -  Patients who in the opinion of the Investigator would not be able to provide reliable&#xD;
             study data or be available for study follow-up&#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>Geoffrey Shapiro, MD PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Dana-Farber / Beth Israel Deaconess Medical Center / Harvard Cancer Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>August 2, 2012</study_first_submitted>
  <study_first_submitted_qc>August 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 14, 2012</study_first_posted>
  <last_update_submitted>February 23, 2016</last_update_submitted>
  <last_update_submitted_qc>February 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 24, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tumors</keyword>
  <keyword>carcinoma</keyword>
  <keyword>apoptosis</keyword>
  <keyword>p53</keyword>
  <keyword>p21</keyword>
  <keyword>Caspase3</keyword>
  <keyword>PARP</keyword>
  <keyword>MDM2</keyword>
  <keyword>PUMA</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</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/NCT01664000
org study id: CTIX 12-101
secondary id: 12-151
nct id: NCT01664000
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
In the laboratory, Kevetrin activates p53, a tumor suppressor protein that has an important
      role in protecting the body. p53 functions by activating proteins that repair DNA and kill
      cells that have genetic mutations such as in cancers. Research experiments showed that when
      cancer cells were treated with Kevetrin, it activated p53 which induced p21, a protein that
      inhibits cancer cell growth. p53 also induced PUMA (p53 up-regulated modulator of apoptosis),
      a protein that causes tumor cell death. Because of these activities, slowing cancer cell
      growth and causing cancer cell death, Kevetrin may help to treat tumors.
Kevetrin was found to be effective in pre-clinical studies of human xenograft tumor models
      and was reasonably well-tolerated at therapeutic doses in the non-clinical animal studies.
      Kevetrin was also effective in multi-drug resistant tumor models; therefore, Kevetrin has the
      potential to treat tumors that have become resistant to standard chemotherapy. This trial
      will determine tolerance in humans and, possibly, efficacy with a Phase I, open-label,
      dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of Kevetrin, in adult
      patients with solid tumors.

      The primary objectives are the following:

        -  To determine the maximum tolerated dose (MTD) of Kevetrin.

        -  To determine the dose limiting toxicities (DLT) of Kevetrin.

        -  To establish a safe dose level of Kevetrin that can be used for future studies.

      The secondary objectives are to determine the following:

        -  The pharmacokinetics of Kevetrin in humans.

        -  Observe for evidence of antitumor activity following administration of Kevetrin.

        -  If Kevetrin induces changes in the biomarker p21 in peripheral blood lymphocytes.

        -  If there is a pharmacodynamic relationship between the plasma concentrations of Kevetrin
           and a clinical or cellular effect.

      During each 4 week cycle, each patient will receive three weekly doses of Kevetrin given as a
      1 hour intravenous infusion followed by a 1 week off-treatment period. Following each dose,
      each patient will be monitored. If the patients have acceptable safety and tolerance,
      Kevetrin will be given once weekly for a total of 3 weeks. During each cycle patients will be
      evaluated for safety, tolerance, and Dose-Limiting Toxicity (DLT) that occur during a cycle.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of Kevetrin
time frame: up to 6 months
description: A dose will be declared the MTD if at least 1 patient out of 6 patients experience a dose limiting toxicity (DLT) at the highest dose level below the maximally administered dose. Once an MTD has been established, up to 12 additional patients may be enrolled at the MTD dose level for confirmation of safety.
The maximally administered dose is if 1 or more of 6 patients experience a DLT.
measure: Dose Limiting Toxicities (DLT) of Kevetrin.
time frame: up to 4 weeks
description: The definition of dose limiting toxicity (DLT) is in accord with the NCI Common Terminology Criteria for Adverse Events v4.0 (CTCAE). Dose limiting toxicity will be defined as:
Grade 3 or 4 neutropenia complicated by fever, or greater than 38.5°C documented infection, or Grade 4 neutropenia of greater than 7 days duration
Grade 4 thrombocytopenia or grade 3 thrombocytopenia complicated by hemorrhage
Any grade greater than 3 non-hematologic toxicity unless there is clear alternative evidence that the adverse event (AE) was not caused by Kevetrin
Grade 3 diarrhea, nausea, or vomiting may be excluded from dose-limiting toxicities provided that the maximum time limit for supportive measures is 48 hours.
measure: Pharmacokinetic Profile of Kevetrin
time frame: Day 1 Pre-dose, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion
description: The pharmacokinetics (PK) of Kevetrin will be determined for all patients enrolled in the study on Day 1 of Cycle 1 and Day 15 of Cycle 2. Blood samples will be obtained before dosing, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion.
The pharmacokinetic profile will be analyzed by standard noncompartmental methods to provide estimated values of the pharmacokinetic parameters and associated variables, such as area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of Kevetrin. Associations between pharmacokinetic variables and drug-related toxicities will be evaluated.
measure: Pharmacokinetic Profile of Kevetrin
time frame: Day 15 Pre-dose, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion
description: The pharmacokinetics (PK) of Kevetrin will be determined for all patients enrolled in the study on Day 1 of Cycle 1 and Day 15 of Cycle 2. Blood samples will be obtained before dosing, 30 minutes after starting the infusion, 1 hr, 1 hr 10 min, 1 hr 20 min, 1 hr 30 min, 1 hr 45 min, 2 hr, 2 hr 30 min, 3 hr, 4 hr, 5 hr, 7 hr, and 24 hr after the initiation of the infusion.
The pharmacokinetic profile will be analyzed by standard noncompartmental methods to provide estimated values of the pharmacokinetic parameters and associated variables, including area under the plasma concentration versus time curve (AUC) and peak plasma concentration (Cmax) of Kevetrin. Associations between pharmacokinetic variables and drug-related toxicities will be evaluated.
measure: Change in tumor size
time frame: baseline and 2 months
description: Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging
measure: Change in tumor size
time frame: baseline and 4 months
description: Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging
measure: Change in tumor size
time frame: baseline and 6 months
description: Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging
measure: Decrease in serum tumor marker
time frame: baseline and 1 month
description: A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.
measure: Decrease in serum tumor marker
time frame: baseline and 2 months
description: A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.
measure: Decrease in serum tumor marker
time frame: baseline and 3 months
description: A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.
measure: Decrease in serum tumor marker
time frame: baseline and 4 months
description: A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.
measure: Decrease in serum tumor marker
time frame: baseline and 5 months
description: A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.
measure: Decrease in serum tumor marker
time frame: baseline and 6 months
description: A decrease in a tumor marker in the serum may also suggest evidence of anti-tumor efficacy. The following tumor markers will be evaluated: Carcinoembryonic antigen (CEA), Cancer Antigen 125 (CA125), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 15-3 (CA15-3), Prostate Specific Antigen (PSA), or other appropriate markers. The choice of the individual tumor markers will be based on the type of tumor of the patient and the testing that has preceded the patient's participation in this study.
measure: Changes in the biomarker p21 in peripheral blood lymphocytes
time frame: baseline and 7 hours
description: For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.
measure: Changes in the biomarker p21 in peripheral blood lymphocytes
time frame: baseline and 24 hours
description: For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.
arm group label: Kevetrin
arm group type: Experimental
description: thioureidobutyronitrile intravenous once/week for 3 weeks/ cycle
intervention type: Drug
intervention name: thioureidobutyronitrile
description: Kevetrin (thioureidobutyronitrile)
arm group label: Kevetrin
other name: Kevetrin
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Geoffrey Shapiro, MD PhD
role: Principal Investigator
affiliation: Dana-Farber Cancer Institute
facility: 
country: United States
responsible party type: Sponsor
mesh term: Neoplasms
sharing ipd: Yes