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A Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin in Patients With Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2014 by Cellceutix Corporation
Sponsor:
Information provided by (Responsible Party):
Cellceutix Corporation
ClinicalTrials.gov Identifier:
NCT01664000
First received: August 2, 2012
Last updated: July 7, 2014
Last verified: July 2014
  Purpose

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.


Condition Intervention Phase
Solid Tumors
Drug: thioureidobutyronitrile
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Cellceutix Corporation:

Primary Outcome Measures:
  • Maximum Tolerated Dose (MTD) of Kevetrin [ Time Frame: up to 6 months ] [ Designated as safety issue: Yes ]

    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.


  • Dose Limiting Toxicities (DLT) of Kevetrin. [ Time Frame: up to 4 weeks ] [ Designated as safety issue: Yes ]

    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.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: No ]

    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.


  • 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 ] [ Designated as safety issue: No ]

    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.


  • Change in tumor size [ Time Frame: baseline and 2 months ] [ Designated as safety issue: No ]
    Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging

  • Change in tumor size [ Time Frame: baseline and 4 months ] [ Designated as safety issue: No ]
    Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging

  • Change in tumor size [ Time Frame: baseline and 6 months ] [ Designated as safety issue: No ]
    Change in tumor size based on RECIST criteria version 1.1. using MRI, CT scan, and/or standard of care imaging

  • Decrease in serum tumor marker [ Time Frame: baseline and 1 month ] [ Designated as safety issue: No ]
    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.

  • Decrease in serum tumor marker [ Time Frame: baseline and 2 months ] [ Designated as safety issue: No ]
    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.

  • Decrease in serum tumor marker [ Time Frame: baseline and 3 months ] [ Designated as safety issue: No ]
    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.

  • Decrease in serum tumor marker [ Time Frame: baseline and 4 months ] [ Designated as safety issue: No ]
    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.

  • Decrease in serum tumor marker [ Time Frame: baseline and 5 months ] [ Designated as safety issue: No ]
    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.

  • Decrease in serum tumor marker [ Time Frame: baseline and 6 months ] [ Designated as safety issue: No ]
    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.

  • Changes in the biomarker p21 in peripheral blood lymphocytes [ Time Frame: baseline and 7 hours ] [ Designated as safety issue: No ]
    For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.

  • Changes in the biomarker p21 in peripheral blood lymphocytes [ Time Frame: baseline and 24 hours ] [ Designated as safety issue: No ]
    For biomarker analysis, p21 expression, assayed by qPCR, in peripheral blood lymphocytes after Kevetrin administration.


Estimated Enrollment: 40
Study Start Date: October 2012
Estimated Study Completion Date: November 2014
Estimated Primary Completion Date: September 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Kevetrin
thioureidobutyronitrile intravenous once/week for 3 weeks/ cycle
Drug: thioureidobutyronitrile
Kevetrin (thioureidobutyronitrile)
Other Name: Kevetrin

Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Males or females, greater than or equal to 18 years of age, of any race or ethnicity, who can provide written Informed Consent.
  • Patients with a life expectancy of at least 3 months.
  • Pathologically confirmed solid tumor, locally advanced or metastatic, either refractory after standard therapy, or for which no effective curative or surgical treatment options are available
  • Must have measurable disease on baseline imaging (e.g., CT scan, PET, MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to meet eligibility.
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1
  • Acceptable liver function:
  • Bilirubin less than or equal to 1.5 times the upper limit of normal
  • Aspartate aminotransferase (AST, SGOT), alanine amino transferase (ALT, SGPT) less than or equal to 2.5 times the upper limit of normal, less than 5 times the upper limit if there are liver metastases.
  • Acceptable renal function:
  • Serum creatinine within normal limits.
  • Acceptable hematologic status:
  • Absolute neutrophil count greater than or equal to 1500 cells/mm3.
  • Platelet count greater than or equal to 100,000/mm3.
  • Hemoglobin greater than or equal to 9 g/dL
  • Acceptable coagulation status:
  • Coagulation Prothrombin time less than or equal to 1.5 times the upper limit
  • Partial thromboplastin time less than or equal to 1.5 times the upper limit
  • All males in the study must agree to use condoms during sex to prevent spillage of semen for the duration of the study and for 3 months after the patient leaves the study.
  • All females in the study must not be pregnant or breast feeding and not planning to become pregnant or breast feed for the duration of the study, and for at least three months after study completion.
  • All women of childbearing potential must commit to using a double barrier method of contraception, an intrauterine device, or sexual abstinence for the duration of the study and for at least three months after study completion.
  • Serum pregnancy test for women of child bearing potential must be negative at entry into study.
  • Written voluntary informed consent: the patient is capable of complying with the requirements of the written Informed Consent Form (ICF) and complying with protocol requirements.

Exclusion Criteria:

  • History of significant disease that in the Investigator's opinion would put the patient at high risk on the trial.
  • Cognitive impairment sufficient to render the patient incapable of giving informed consent.
  • History of clinically significant psychiatric illness that would prevent the patient from providing a valid ICF and complying with protocol requirements.
  • Unwillingness or inability to comply with procedures required in this protocol.
  • History or presence of alcoholism or drug abuse within the past 2 years.
  • Patients who have had a major surgical procedure within the past 6 weeks.
  • History of HIV, hepatitis B, or hepatitis C.
  • Active, uncontrolled bacterial, viral, or fungal infections requiring systemic therapy.
  • Women of childbearing potential who are lactating, pregnant or there is the likelihood of becoming pregnant within the coming 12 months; a positive serum beta-human chorionic gonadotropin test at time of screening for entry into study.
  • New York Heart Association Class III or IV, cardiac disease, myocardial infarction within the past 6 months, unstable arrhythmia, or evidence of ischemia on ECG.
  • Patients with a mean QTc interval greater than 480ms are excluded. Avoid concomitant administration of agents that prolong the QT interval, except at the discretion of the investigator. If advised, patients should discontinue the use of these agents at least 2 weeks before the study begins. No uncontrolled arrhythmias.
  • Patients who are currently receiving other investigational agents.
  • Participation in a study of an investigational drug within 4 weeks prior to the planned first day of study drug administration.
  • Patients who have undergone radiation within the past 4 weeks.
  • Treatment with molecularly targeted agents within the past 3 weeks prior to planned first study drug administration. Patients who were receiving standard chemotherapy or experimental therapies must wait 4 weeks from their last dose prior to the planned first study drug administration. Patients treated with nitrosoureas or mitomycin C must wait 6 weeks from their last dose prior to the planned first study drug administration.
  • Patients with known brain metastases may be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients may be eligible if scans show limited disease or repeat scans show stable disease in the opinion of the investigator and patients have no ill effect from the metastases.
  • Herbal supplements are prohibited 1 week prior to the planned first study drug administration, during the clinical study, and up to the time that the patient is discharged from the study.
  • Patients who have been exposed to medications, herbal preparations, or foods known to be predominant Cytochrome P450 2C9, 2C19, 2D6, 3A4/5 substrates, strong inhibitors or inducers within 7 days of planned first study treatment day
  • Patients who in the opinion of the Investigator would not be able to provide reliable study data or be available for study follow-up.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01664000

Locations
United States, Massachusetts
Dana-Farber / Beth Israel Deaconess Medical Center / Harvard Cancer Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Andrew Wolanski    617-632-6623    awolanski@partners.org   
Principal Investigator: Geoffrey Shapiro, MD PhD         
Sub-Investigator: James W Mier, MD         
Sub-Investigator: Sara Tolaney, MD         
Sub-Investigator: Nicole Chau, MD         
Sub-Investigator: Leena Gandhi, MD         
Sub-Investigator: John Hilton, MD         
Sub-Investigator: Andrea Bullock, MD         
Sub-Investigator: James Butrynski, MD         
Sub-Investigator: Jason Luke, MD         
Sub-Investigator: James Cleary, MD, PhD         
Sponsors and Collaborators
Cellceutix Corporation
Investigators
Study Director: Krishna Menon, PhD VMD Cellceutix Corporation
  More Information

No publications provided

Responsible Party: Cellceutix Corporation
ClinicalTrials.gov Identifier: NCT01664000     History of Changes
Other Study ID Numbers: CTIX 12-01, 12-151
Study First Received: August 2, 2012
Last Updated: July 7, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Cellceutix Corporation:
Tumors
carcinoma
apoptosis
p53
p21
Caspase3
PARP
MDM2
PUMA

Additional relevant MeSH terms:
Neoplasms

ClinicalTrials.gov processed this record on November 19, 2014