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Home > "A" Clinical Trials Conditions > Arsenic Trioxide to Treat Children with Leukemia or Lymphoma  Arsenic Trioxide to Treat Children with Leukemia or Lymphoma
Arsenic Trioxide to Treat Children with Leukemia or Lymphoma
For Condition: Leukemia,Acute Promyelocytic Leukemia,Lymphoma
Status: Recruiting
Sponsor(s): National Cancer Institute (NCI) ,
Synopsis: Arsenic trioxide (As(2)O(3)) is an inorganic trivalent arsenical. Preclinical studies demonstrate a dose-dependent induction of apoptosis and partial differentiation in myeloid leukemia cell lines, and induction of apoptosis and cell cycle arrest in lymphoid neoplasms. The effects of As(2)O(3) are independent of the promyelocytic leukemia (PML) gene product and the specific fusion protein with the Retinoic Acid Receptor alpha (PML-RAR(alpha)) in acute promyelocytic leukemia (APL). Since 1971, As(2)O(3) has been used in the Northeastern region of China to treat more than one thousand adults with cancer. In clinical trials of adults with relapsed all trans retinoic acid (ATRA) resistant APL, durable clinical remission with minimal side effects was achieved in 70% of the patients. Pharmacokinetic analysis showed that daily intravenous administration of As(2)O(3) did not result in plasma accumulation of arsenic; tissue (hair and nail) arsenic content increased five to seven fold over pretreatment content but was still within reference range of normal individuals. A phase I trial and pharmacokinetic study of As(2)O(3) will be conducted in children. The spectrum of toxicity and the maximum tolerated dose will be defined in pediatric patients with refractory leukemia and lymphoma. Additionally, biological studies of cell cycle control parameters will be examined to further elucidate the effect of arsenicals in leukemia, lymphoma and in particular acute promyelocytic leukemia.
Details: Arsenic trioxide [As(2)O(3)] is an inorganic trivalent arsenical. Preclinical studies demonstrate a dose-dependent induction of apoptosis and partial differentiation in myeloid leukemia cell lines, and induction of apoptosis and cell cycle arrest in lymphoid neoplasms. The effects of As(2)O(3) are independent of the promyelocytic leukemia (PML) gene product and the specific fusion protein with the Retinoic Acid Receptor alpha (PML-RAR(alpha)) in acute promyelocytic leukemia (APL). Since 1971, As(2)O(3) has been used in the Northeastern region of China to treat more than one thousand adults with cancer. In clinical trials of adults with relapsed all trans retinoic acid (ATRA) resistant APL, durable clinical remission with minimal side effects was achieved in 70% of the patients. Pharmacokinetic analysis showed that daily intravenous administration of As(2)O(3) did not result in plasma accumulation of arsenic; tissue (hair and nail) arsenic content increased five to seven fold over pretreatment content but was still within reference range of normal individuals. In September 2000, arsenic trioxide was FDA approved for relapsed or refractory APL in patients greater than or equal to 5 years old. A phase I trial and pharmacokinetic study of As(2)O(3) will be conducted in children. The study will be conducted in two cohorts, APL and non-APL. In the non-APL cohort, the spectrum of toxicity and the maximum tolerated dose will be defined in pediatric patients with refractory non-APL leukemia and lymphoma using a fixed dose escalation scheme. In the APL cohort, the FDA approved dose (0.15 mg/kg/dose) will be administered to up to 18 children to further define the tolerance and pharmacokinetics. Additionally, biological studies of cell cycle control parameters will be examined in both cohorts to further elucidate the effect of arsenicals in leukemia, lymphoma and in particular acute promyelocytic leukemia.
Eligibility:
Study Type: Interventional, Treatment, Safety
Minimum Age/Maximum Age: /
Genders: Both
Protocol Entry Criteria: INCLUSION CRITERIA Age: Patients with APL must be greater than or equal to 2 years and less than or equal to 12 (twelve) years of age. Patients with non-APL leukemia or lymphoma must be greater than or equal 2 years and less than or equal to 21 (twenty one) years of age. Histological diagnosis: Patients must have a leukemia or lymphoma confirmed by morphologic analysis. The leukemia/lymphoma must be refractory to standard curative treatment regimens. Patients must have had their last dose of radiation therapy at least four weeks prior to study entry, their last dose of chemotherapy at least two weeks prior to study entry (four weeks for nitrosoureas), and their last dose of retinoids 7 days prior to study entry. Patients must have recovered from the toxic effects of all prior therapy before entry onto this trial. Patients should be off colony stimulating factors such as G-CSF, GM-CSF, and erythropoietin for at least one week prior to study entry. Measurable/Evaluable disease: Patients must have measurable or evaluable disease. Performance status: Patients should have an ECOG performance status of 0, 1, or 2. Hepatic function: Patients must have adequate liver function, defined as bilirubin within normal limits, SGPT less than 2x the upper limit of normal. Renal function: Patients must have an age-adjusted normal serum creatinine or a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2). Serum electrolytes: Potassium, magnesium and calcium must be equal to or greater than the lower limit of the normal range. Oral or intravenous supplementation may be used to normalize the serum electrolytes. EKG: A rate corrected QT interval (QTc) less than or equal to 0.48. Informed consent: All patients or their legal guardians (if the patient is less than 18) must sign a document of informed consent indicating their understanding of the investigational nature and the risks of this study before any protocol related studies are performed (this does not include routine laboratory tests or imaging studies required to establish eligibility). When appropriate, pediatric patients will be included in all discussions in order to obtain verbal assent. EXCLUSION CRITERIA Patients with meningeal leukemia/lymphomas (CSF WBC greater than 5/mm(3) and unequivocal confirmation of leukemic blasts in the CSF by morphologic demonstration on a CSF cytocentrifuge specimen). Patients with APL and meningeal disease may be entered following discussion with the PI or Protocol Chairman. Patients with persistent grade greater than or equal to 3 sensory or motor neuropathy. Patients with APL and persistent grade 3 or 4 neuropathy may be entered following discussion with the PI or Protocol Chairman. Patients with history of grand mal seizures (greater than or equal to grade 3) other than febrile seizures within the past 2 years. Patients must be off anticonvulsants for a minimum of 6 months. Patients with APL and history of seizures (greater than or equal to grade 3) may be entered following discussion with the PI or Protocol Chairman. Clinically significant unrelated systemic illness (serious infections or significant cardiac (including dysrhythmias), pulmonary, hepatic, renal or other organ dysfunction) which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate arsenic trioxide or are likely to interfere with the study procedures or results. Patients with cardiac disease including dysrhythmias. Patients with APL and history of cardiac disease may be entered following discussion with the PI or Protocol Chairman. Patients with normal serum potassium, magnesium, and calcium levels and have a QTc greater than 0.48 after discontinuation of medications that may prolong the QTc interval. Patients with known HIV infection or HIV related lymphoma or lymphoproliferative diseases are excluded from this trial due to unknown interaction of arsenic trioxide with antiretroviral medications and potential biological differences in lymphomas related to immune compromised states. Pregnant or breast feeding females are not eligible because arsenic trioxide may be harmful to the developing fetus or nursing child. Patients currently receiving other investigational agents. Patients who previously received arsenic trioxide.
Total Enrollment: 48
Location and Contact Information:
National Cancer Institute (NCI) *Recruiting*
Bethesda, Maryland, 20892
United States
Recruiting Clinical Support Center/NCI 1-888-624-1937
Additional Information:
Study ID Numbers: 000070; 00-C-0070
Study Start Date: January 31, 2000
Record last reviewed: October 1, 2003
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00004548
Other Lymphoma Studies:
1. Arsenic Trioxide to Treat Children with Leukemia or Lymphoma
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Arsenic Trioxide to Treat Children with Leukemia or Lymphoma
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