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Home > "P" Clinical Trials Conditions > Phase I Study of Depsipeptide in Children with Cancer  Phase I Study of Depsipeptide in Children with Cancer
Phase I Study of Depsipeptide in Children with Cancer
For Condition: Neoplasms
Status: Recruiting
Sponsor(s): National Cancer Institute (NCI) ,
Synopsis: This study will examine the safety and side effects of the experimental drug depsipeptide in children and adolescents with solid tumor cancers. Depsipeptide has killed cancer cells grown in laboratory test tubes and has reduced the size of tumors in some animal models. This study will determine: - The side effects of depsipeptide in children and adolescents with cancer; - The highest dose of depsipeptide that can be safely given to children and adolescents with cancer; - The pharmacology of depsipeptide (how the body handles the drug); - The effects of depsipeptide on white blood cells, tumor cells, or bone marrow; - Whether depsipeptide can inhibit the growth of childhood tumors. Patients between 1 and 21 years of age who have a solid tumor that no longer responds to standard treatment may be eligible for this study. Participants will receive infusions of depsipeptide in 4-week treatment cycles. The drug will be infused over 4 hours through a catheter (thin plastic tube) in a vein once a week for 3 weeks (days 1, 8, and 15) of each 4-week cycle. Treatment will continue unless unacceptable side effects occur, the tumor continues to grow, a better therapy becomes available, the patient asks to stop treatment, or the patient can no longer keep appointments or take the study medication as instructed. During the first course of treatment (first 28 days), patients will have the following tests and procedures: - Holter monitoring to monitor heart rate and rhythm continuously for 28 days; - Electrocardiograms (EKGs) before and after depsipeptide is given on days 1 and 8 to check heart beat and rhythm; - Weekly physical examinations and routine blood tests. After the first treatment course, patients will have the following tests and procedures periodically: - Physical examinations; - Electrocardiograms to check heart beat or rhythm; - MUGA or echocardiogram: MUGA is a nuclear medicine heart scan; an echocardiogram is an ultrasound test of heart function; - Routine blood tests; - Routine imaging tests, such as x-rays, CT scans, and MRI scans to monitor the response to treatment. In addition, patients may agree to undergo the following optional procedures: - Blood tests to study the pharmacology of depsipeptide. This requires drawing 11 blood samples on day 1 of the treatment and another 11 samples on day 3. The samples will be collected through an indwelling catheter to avoid multiple needle sticks. - White blood cell testing for the effects of depsipeptide during treatment cycle 1. This requires taking blood samples during treatment cycle at intervals of 1 before the depsipeptide fusion, 2 hours after the start of the infusion, the end of the 4-hour infusion, and 2, 4, and 20 hours after the infusion ends. - Tests on tumor tissue or bone marrow, if biopsy tissue is available from a prior surgery or biopsy. Additional surgery or biopsies will not be done to obtain tissue samples for this test.
Details: Depsipeptide is a novel histone deacetylase (HDAC) inhibitor isolated from the soil organism, Chromobacterium violaceum. Inhibitors of HDACs relieve transcriptional repression which can result in reactivation of tumor suppressor or death pathway genes that were abnormally silenced during the generation of the malignant phenotype. In vitro and in vivo, depsipeptide can produce cell cycle arrest, induction of apoptosis, and differentiation. In vitro, depsipeptide has potent anti-tumor activity against many human tumor cell lines (including neuroblastoma) with IC(50)'s less than 10 nM and no toxicity against human fibroblasts. In vivo. depsipeptide inhibits growth of many human solid tumor murine xenografts. Two phase I trials in adult patients with refractory solid tumors have been completed. Depsipeptide administered intravenously on day 1 and 5 of a 21 day cycle was generally well tolerated. The maximum tolerated dose (MTD) was 17.8 mg/m(2) and dose limiting toxicities (DLTs) were nausea, vomiting and fatigue. Nonspecific ECG changes were reported at all dose levels above 3.5 mg/m(2) and one patient treated at the 24.9 mg/m(2) dose level experienced dose limiting atrial fibrillation. In the other study, depsipeptide was administered on day 1, 8, and 15 of a 28 day cycle. This regimen was well tolerated with DLTs of fatigue and thrombocytopenia. No cardiac toxicities were documented. The MTD was 13.3 mg/m(2). In this pediatric study, depsipeptide will be administered as a 4 hour IV infusion on days 1, 8, and 15 of a 28 day cycle. The objectives of this study are to determine the MTD and DLT of depsipeptide in pediatric patients with refractory solid tumors, to characterize the pharmacokinetics of depsipeptide in the pediatric population, to determine whether patients with refractory or recurrent leukemia will tolerate depsipeptide at the MTD established for children with refractory or recurrent solid tumors, to preliminarily define the antitumor activity of depsipeptide in children with refractory solid tumors, and to assess the biological activity of depsipeptide by measuring histone deacetylase inhibition in peripheral mononuclear cells (PBMC) during cycle 1.
Eligibility:
Study Type: Interventional, Treatment, Safety
Minimum Age/Maximum Age: /
Genders: Both
Protocol Entry Criteria: INCLUSION CRITERIA: IMPORTANT NOTE: The eligibility criteria listed below are interpreted literally and cannot be waived. Planned start of treatment must be within 7 days of fulfilling all eligibility criteria, unless otherwise specified. Patient must be less than 22 years of age at the time of study entry. Patients with solid tumors, either extracranial solid tumors or brain tumors, are eligible. Patients must have had histologic verification of the diagnosis of malignancy at the time of initial diagnosis, with the exception of patients with brain stem or optic pathway tumors, for whom the requirement for histologic verification is waived. Patients with recurrent or refractory leukemia will not be eligible for the dose escalation part of the study. Once an MTD is reached, however, 6 patients with recurrent or refractory leukemia, in cohorts of 3, will be enrolled at the solid tumor MTD to assess tolerability in patients with leukemia. Patient's disease must be considered refractory to conventional therapy, or no effective conventional therapy must exit. Karnofsky greater than or equal to 60% for patients greater 10 years of age and Lansky greater than or equal to 60 for children less than or equal to 10 years of age. Neurologic deficits in patients with CNS tumors must have been relatively stable for a minimum of 2 weeks prior to study entry. Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score. Life expectancy must be greater than or equal to 8 weeks. Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. Myelosuppressive chemotherapy and biologic: Must not have received within 3 weeks of entry onto this study (4 weeks if prior nitrosourea). XRT: greater than or equal to 2 weeks for local palliative XRT (small port); greater than or equal to 6 months must have elapsed if prior craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 weeks must have elapsed if other substantial BM radiation. Stem Cell Transplant (SCT): No evidence of active graft vs. host disease. For allogeneic SCT, greater than or equal to 6 months must have elapsed. Patients must show evidence of full recovery from acute toxic effects of all prior chemotherapy or radiotherapy prior to study entry. Concomitant Medications Growth factor(s): Must not have received within 1 week of entry onto this study. Steroids: Patients with CNS tumors who are receiving dexamethasone must be on a stable or decreasing dose for at least 1 week prior to study entry. Anticonvulsants: Must not be receiving enzyme-inducing anticonvulsant drugs. Patients cannot be on medications associated with prolongation of QTc interval. Depsipeptide may be administered after a 5 half-life washout period elapses following the use of these drugs. Organ Function Requirements Adequate Bone Marrow Function Defined As: For all patients including those post SCT: Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microL Platelet count greater than or equal to 100,000/microL (transfusion independent) Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions) Adequate Renal Function Defined As: An age-adjusted normal serum creatinine: Less than or equal to 5 years---Maximum Serum Creatinine 0.8 mg/dL Greater than 5 and less than or equal to 10 yrs---Maximum Serum Creatinine 1.0 mg/dL Greater than 10 and less than or equal to 15 yrs---Maximum Serum Creatinine 1.2 mg/dL Greater than 15 years---Maximum Serum Creatinine 1.5 mg/dL OR A GFR greater than or equal to 70 ml/min/1.73m(2). Adequate Liver Function Defined As: Total bilirubin less than or equal to 1.5 X institutional upper limit of normal for age, SGPT (ALT) less than or equal to 5 X institutional upper limit of normal for age, and Albumin greater than or equal to 2 g/dL. Adequate Cardiac Function Defined As: Shortening fraction of greater than or equal to 27% by echocardiogram, or Ejection fraction of greater than or equal to 50% by gated radionuclide study. Adequate Pulmonary Function Defined As: No evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry greater than 94% if there is clinical indication for determination. Central Nervous System Function Defined As: Patients with seizure disorder may be enrolled if well controlled and not on enzyme-inducing anti-convulsants. Adequate serum calcium, magnesium and potassium concentrations Serum total calcium (or ionized calcium if hypoalbuminemia), magnesium and potassium must exceed the institutional lower limit of normal for age (with or without supplementation). EXCLUSION CRITERIA: There is no available information regarding human fetal or teratogenic toxicities of depsipeptide. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. Lactating women must agree not to breast-feed. Patients who have an uncontrolled infection. Patients with leukemia will be excluded from the dose escalation component of the trial. However, once the dose finding component of the trial is completed, and the MTD is established in patients with refractory or recurrent solid tumor, 6 patients with relapsed or refractory leukemia will be enrolled at the MTD to assess tolerability. Patients who have previously received depsipeptide. Patients with symptoms of congestive heart failure, uncontrolled cardiac rhythm disturbance, or a QTC that is greater than or equal to 450 msec. All patients and/or their parents or legal guardians must sign a written informed consent. All institutional, FDA, and NCI requirements for human studies must be met.
Total Enrollment: 36
Location and Contact Information:
National Cancer Institute (NCI) *Recruiting*
Bethesda, Maryland, 20892
United States
Recruiting Patient and Public Liaison Office 1-800-411-1222
Additional Information:
Study ID Numbers: 030307; 03-C-0307
Study Start Date: September 25, 2003
Record last reviewed: September 15, 2003
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00069771
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2. Relationship Between Personality and Coping Styles in Bone Marrow Transplant Candidates
3. Massage for the Treatment of Cancer-Related Pain
4. A Phase I Trial of 5-Flouroucacil Given with 776C85 (GW776) and Low-Dose Leucovorin in Adult Patients with Solid Tumors
5. Anemia in Patients with a Non-Myeloid Malignancy
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Phase I Study of Depsipeptide in Children with Cancer
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