FOR THE NEW.......................................
Post# of 72440
FOR THE NEW..............................................
A Safety, Pharmacokinetic and Pharmacodynamic Study of Kevetrin in Patients With Advanced Solid Tumors
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 |
- 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.
- 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: | April 2014 |
| Estimated Primary Completion Date: | October 2013 (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 |
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.
Contacts and Locations | United States, Massachusetts | |
| Dana-Farber / Harvard Cancer Center | Recruiting |
| Boston, Massachusetts, United States, 02215 | |
| Contact: Geoffrey Shapiro, MD PhD 617-632-4942 geoffrey_shapiro@dfci.harvard.edu | |
| Principal Investigator: Geoffrey Shapiro, MD PhD | |
| Sub-Investigator: Daniel Cho, MD | |
| Sub-Investigator: Shuchi Pandya, MD | |
More Information No publications provided
| Responsible Party: | Cellceutix Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT01664000 History of Changes |
| Other Study ID Numbers: | CTIX 12-01, 12-151 |
| Study First Received: | August 2, 2012 |
| Last Updated: | October 18, 2012 |
| Health Authority: | United States: Food and Drug Administration |
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