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Home > "T" Clinical Trials Conditions > Temozolomide and O6-Benzylguanine for Treating Childhood Cancers  Temozolomide and O6-Benzylguanine for Treating Childhood Cancers
Temozolomide and O6-Benzylguanine for Treating Childhood Cancers
For Condition: Embryonal Neoplasm,Brain Neoplasm,Osteosarcoma,Germ Cell Neoplasm,Sarcoma,Nephroblastoma,Liver Neoplasm,Ewing's Sarcoma,Rhabdomyosarcoma
Status: Recruiting
Sponsor(s): National Cancer Institute (NCI) ,
Synopsis: This study will investigate the combined use of temozolomide (TMZ) and O6-benzylguanine (O6BG) for treating cancer. TMZ is an anti-cancer drug approved to treat certain brain tumors in adults. TMZ loses its effectiveness over time because a protein called AGT makes the tumor resistant to the drug. O6BG inactivates AGT and, therefore, may prolong TMZ's effectiveness. Children and young adults under age 21 with various types of cancer (brain, liver, bone and others) for whom standard treatment was not successful may be eligible for this study. Participants will receive TMZ capsules by mouth and an intravenous (through a vein) infusion of O6BG 5 days in a row every month for up to 12 months. Blood will be drawn on days 3 and 5 of the first course of treatment to measure AGT levels. Also on day 5 of the first treatment course, 16 blood samples (1 teaspoon each) will be taken over a 48-hour period to study how the two drugs work in the body. If possible, a heparin lock will be placed in the vein to avoid having multiple needle sticks. A tissue biopsy (removal of a small piece of tumor) may be taken if the tumor is close to the skin and not near a vital organ. The sample will be used to evaluate the effect of O6BG on AGT levels. A doctor will see the patients weekly. Routine blood tests will be done twice a week. MRI or CT scans will be done before treatment begins and every 1 to 2 months during treatment to measure the size of the tumor. Patients with a brain tumor will also have a magnetic resonance spectroscopic test (similar to MRI) every 1 to 2 months to measure chemicals in the tumor. Patients will complete a Quality of Life Assessment questionnaire about the effect of the illness on the patient's behavior and everyday activities. Potential benefits to patients in this study are tumor shrinkage and symptom improvement, such as pain relief. Because this is an experimental therapy, however, the likelihood of tumor shrinkage cannot be predicted.
Details: Temozolomide is a prodrug that spontaneously degrades to the active metabolite, MTIC, under physiologic conditions. MTIC is an alkylating agent that preferentially methylates the O(6)-position on guanine. The DNA repair protein, O(6)-alkylguanine-DNA alkyltransferase (AGT) removes the methyl group from the O(6)-position of guanine, repairing the lesion produced by MTIC. AGT is expressed in many tumors and has been associated with tumor resistance and poor clinical response to methylating agents, such as the nitrosoureas and temozolomide. O(6)-Benzylguanine (O(6)BG) is an AGT substrate that permanently inactivates AGT. O(6)BG depletes tumor AGT, blocks repair of the lesion produced by temozolomide and thereby enhances its cytotoxicity. A pediatric phase I trial using the combination of temozolomide and O(6)BG on a daily times 5 days schedule every 4 weeks will be conducted in children with refractory solid tumors and brain tumors to determine the maximum tolerated dose (MTD) of temozolomide when given in combination with a biologically active dose of O(6)BG. Pharmacokinetic studies of O(6)BG and temozolomide will also be performed.
Eligibility:
Study Type: Interventional, Treatment, Safety
Minimum Age/Maximum Age: /
Genders: Both
Protocol Entry Criteria: INCLUSION CRITERIA: 1. Age: Patients must be less than or equal to 21 years of age. 2. Histological diagnosis: Patients must have a histologically confirmed solid tumor, which may include, but is not limited to, rhabdomyosarcoma and other soft tissue sarcomas, Ewing's family tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors or primary brain tumor. For patients with brainstem gliomas or optic gliomas, the requirement for histological confirmation may be waived. 3. Prior therapy: 3.1 The patient's tumor must be refractory to standard treatment. Patients must have no known potentially curative therapy available to them. Curative therapy may include surgery, radiation therapy, chemotherapy, or any combination of these modalities. 3.2 Patients must have had their last dose of limited-field radiation therapy at least four weeks prior to study entry. Patients who have received extensive prior radiation therapy (craniospinal radiation, total body radiation, or radiation to more than half of the pelvis) must be at least 4 months post-completion of radiation therapy. Patients must have received their last dose of chemotherapy at least three weeks prior to study entry (four weeks for nitrosoureas), and their last investigational therapy at least four weeks prior to study entry. 3.3 Patients must have recovered from the toxic effects of all prior therapy prior to entry onto this trial. 3.4 Patients with brain tumors who are receiving corticosteroids for the control of tumor-associated edema must be on a stable or decreasing dose for at least 1 week prior to study enrollment. 3.5 Patients who have previously received temozolomide are eligible if they have not received the drug in the past 3 months and they did not experience severe toxicities during their previous course of therapy with temozolomide. Severe toxicity is defined as any grade 4 non-hematologic toxicity or failure to recover (to grade less than or equal to 1 level) from any non-hematologic or hematologic toxicity within six weeks of receiving temozolomide. Patients who received temozolomide in combination with other agents that were designed to inactivate AGT are not eligible for this trial. 3.6 Patients should be off colony stimulating factors such as G-CSF, GM-CSF, and Epo for at least one week prior to study entry. 4. Measurable/Evaluable disease: Patients must have measurable or evaluable disease. There must be evidence of progressive disease on prior chemotherapy or radiation therapy or persistent disease after surgery. 5. Performance status: Patients should have an ECOG performance status of 0, 1, or 2 and a life expectancy of at least eight (8) weeks. Patients who are unable to walk because of paralysis, but who are up in a wheel chair will be considered ambulatory for the purpose of calculating the performance score. 6. Hematological function: Patients must have adequate bone marrow function defined as a peripheral absolute granulocyte count of greater than 1500/mm(3), hemoglobin greater than 8 gm/dL, and platelet count greater than 100,000/mm(3). 7. Hepatic function: Patients must have adequate liver function, defined as bilirubin within normal limits and SGPT less than 2 times the upper limit of normal. 8. 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). 9. Patients must be able to swallow capsules. 10. Informed consent: All patients or their legal guardians (if the patient is less than 18 years old) must sign a document of informed consent indicating their understanding of the investigational nature and their risks of this study before any protocol related studies are performed. When appropriate, pediatric patients will be included in all discussions in order to obtain verbal assent. 11. Durable Power of Attorney (DPA): Assignment of a DPA to a family member or guardian should be offered to all patients 18 to 21 years of age who have a brain tumor. EXCLUSION CRITERIA: 1. Patients currently receiving other investigational chemotherapeutic agents. 2. Patients with a history of myeloablative therapy requiring bone marrow or stem cell transplantation within the previous 4 months. 3. Pregnant or breast-feeding females are excluded. 4. Clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction) which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate this therapy or are likely to interfere with the study procedures or results. 5. Patients with a history of hypersensitivity to dacarbazine, temozolomide, or polyethylene glycol (PEG).
Total Enrollment: 48
Location and Contact Information:
National Cancer Institute (NCI) *Recruiting*
Bethesda, Maryland, 20892
United States
Recruiting Katherine Warren 3014026298
Additional Information:
Study ID Numbers: 000105; 00-C-0105
Study Start Date: April 4, 2000
Record last reviewed: March 1, 2004
Additional information available at: clinicaltrials.gov
Clinicaltrials.gov Reference link: NCT00005019
Other Germ Cell Neoplasm Studies:
1. Temozolomide and O6-Benzylguanine for Treating Childhood Cancers
2. A Pilot Study of Tumor-Specific Peptide Vaccination and IL-2 with or without Autologous T Cell Transplantation in Recurrent Pediatric Sarcomas
3. Studying Genetic Changes in Ewing Sarcoma Tumors
4. Evaluation, Treatment, and Natural History of Children with Cancer
5. P-glycoprotein Antagonist, Tariquidar, in Combination with Doxorubicin (Adriamycin), Vinorelbine (Navelbine), or Docetaxel to Treat Children with Solid Tumors
Related Studies:
Other Germ Cell Neoplasm Clinical Trials
Other Maryland Clinical Trials
Other Bethesda Clinical Trials
Temozolomide and O6-Benzylguanine for Treating Childhood Cancers
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