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A Phase 1, Open-Label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin (Thioureidobutyronitrile) Administered Intravenously, in Patients With Advanced Solid Tumors


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Solid Tumors

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Trial Information

A Phase 1, Open-Label, Dose-Escalation, Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin (Thioureidobutyronitrile) Administered Intravenously, in Patients With Advanced Solid 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.


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 which is locally advanced or metastatic, and
either refractory after standard therapy for the disease, or for which no effective
curative or surgical treatment options are available

- Must have evaluable or measurable disease on baseline imaging (e.g., CT scan, PET,
MRI) per RECIST 1.1 criteria to meet eligibility.

- 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

- AST (SGOT), 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, or calculated creatinine clearance greater
than or equal to 60 mL/min/1.73m2 by the Cockcroft and Gault equation or 24 hour
urine creatinine clearance.

- Acceptable hematologic status:

- ANC greater than or equal to 1500 cells/mm3. For patients to be eligible for a new
treatment cycle, ANC must be greater than or equal to 1000 cells/mm3

- Platelet count greater than or equal to 100,000/mm3. For patients to be eligible for
a new treatment cycle, platelet count must be greater than or equal to 75,000 /mm3.

- Hemoglobin greater than or equal to 9 g/dL

- Acceptable coagulation status:

- PT less than or equal to 1.5 times the upper limit

- PTT less than or equal to 1.5 times the upper limit

- All males in the study must agree to always 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.

- If the patient is female, she 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 (e.g., diaphragm and condom), an intrauterine device (IUD), or sexual
abstinence for the duration of the study and for at least three months after study
completion.

- A 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 ICF and complying with protocol requirements.

Exclusion Criteria:

- History of clinically significant psychiatric illness that would prevent the patient
from providing a valid ICF and complying with protocol requirements.

- History of significant disease that in the Investigator's opinion would put the
patient at high risk on the trial.

- 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.

- Active, uncontrolled bacterial, viral, or fungal infections requiring systemic
therapy.

- 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 who have undergone radiation within the past 4 weeks.

- 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.

- Patients who have had a major surgical procedure within the past 6 weeks.

- Unwillingness or inability to comply with procedures required in this protocol.

- History of HIV, hepatitis B, or hepatitis C.

- History or presence of alcoholism or drug abuse within the past 2 years.
Participation in a study of an investigational drug within 4 weeks prior to the
planned first day of study drug administration.

- Patients who are currently receiving any other investigational agents. Cognitive
impairment sufficient to render the patient incapable of giving informed consent.

- 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-hCG test at time of screening for entry into study.

- Herbal supplements, e.g., Saint John's Wort, Milk Thistle, 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. Use of Senekot is
permitted.

- Patients who have been exposed to medications, herbal preparations, or foods known to
be predominant CYP450 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.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Maximum Tolerated Dose (MTD) of Kevetrin

Outcome 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.

Outcome Time Frame:

up to 6 months

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

CTIX 12-01

NCT ID:

NCT01664000

Start Date:

October 2012

Completion Date:

April 2014

Related Keywords:

  • Solid Tumors
  • Tumors
  • carcinoma
  • apoptosis
  • p53
  • p21
  • Caspase3
  • PARP
  • MDM2
  • PUMA
  • Neoplasms

Name

Location

Dana-Farber / BIDMC / Harvard Cancer CenterBoston, Massachusetts  02215