Tabectedin to Treat Children and Adolescents With Cancer
Mo kle
Abstrè
Deskripsyon
Background:
Trabectedin (ET-743) is a natural product derived from the marine tunicate Ecteinascidia turbinata. It binds to the minor groove of DNA and interacts with various transcription factors resulting in cell cycle arrest. It also inhibits transcription coupled nucleotide excision repair system inducing lethal DNA strand breaks.
In preclinical and clinical studies, trabectedin has been found to be active in many soft tissue sarcomas including leiomyosarcoma, synovial cell sarcoma, neuroblastoma, rhabdomyosarcoma, melanoma, breast, ovarian, non-small cell lung, renal and prostate carcinoma.
In adult phase I and phase II studies, trabectedin has been well-tolerated up to dose levels of 1.9mg/m(2)/dose with the most common toxicities being fatigue, neutropenia, and reversible transaminase elevations. Objective responses were seen at doses equal to or greater than 1.5mg/m(2)/dose. Trabectedin 1.5mg/m(2) administered as a 24-hour continuous intravenous infusion is the recommended dose and schedule in adults.
A pediatric phase I study of trabectedin administered as a 3-hour infusion has been completed in the Children's Oncology Group. The maximum tolerated dose was 1.1 mg/m(2). Dose limiting toxicity was reversible elevation of hepatic transaminases.
Objectives:
Determine the maximum tolerated dose (MTD) of trabectedin administered as a 24-hour continuous infusion in children and adolescents with relapsed or refractory solid tumors.
Define the toxicity profile of trabectedin administered as a 24-hr infusion in children and adolescents.
Describe the pharmacokinetics of trabectedin administered as a 24-hr infusion in children and adolescents.
Quantify double strand DNA breaks in peripheral blood mononuclear cells of patients receiving trabectedin.
Evaluate archival formalin fixed paraffin embedded tumor tissue, when available from prior biopsies or surgical procedures, for the expression of the nucleotide excision repair proteins and genomic instability markers (histone gamma-H2AX, phospho-ATM, phospho-Chk2) by immunohistochemistry
Molecular characterization of DNA repair genes and correlation to outcome using mRNA isolated from microdissected archival formalin fixed, paraffin embedded tumor sections.
Study the pharmacogenetics of host DNA repair proteins and drug metabolizing enzymes to explore the impact of host factors on trabectedin toxicity.
Eligibility:
Children greater than or equal to 4 years and less than 17 years of age with relapsed or refractory solid tumors.
Design:
Patients will receive trabectedin as a 24-hour continuous infusion repeated every 21 days. The starting dose level is 1.1mg/m(2)/dose with escalations to 1.5mg/m(2)/dose and 1.7mg/m(2)/dose.
All patients will receive dexamethasone pretreatment and growth factor support with filgrastim or pegfilgrastim.
The definition of dose-limiting hepatic toxicity will be identical to the definition used in phase I trials in adults on the same dosing schedule.
Pharmacokinetic analysis will be performed on days 1, 2, 3, 4, 5 and 7 of the first treatment cycle.
Three to six patients will be enrolled at the first dose level and up to 6 patients will be enrolled on subsequent dose levels. Dose escalation will be based on tolerability of trabectedin at the prior dose level. For patients enrolled at dose level 1 (1.1mg/m(2)), intrapatient dose escalation to dose level 2 (1.5mg/m(2)) will be allowed with subsequent cycles if no dose limiting toxicities occurred at the lower dose level. Total accrual will be up to 24 patients.
Dat
| Dènye verifye: | 04/03/2012 |
| Premye Soumèt: | 09/30/2011 |
| Enskripsyon Estimasyon Soumèt: | 10/11/2011 |
| Premye afiche: | 10/16/2011 |
| Dènye Mizajou Soumèt: | 06/29/2017 |
| Dènye Mizajou afiche: | 07/01/2017 |
| Dat aktyèl kòmanse etid la: | 12/19/2006 |
| Dat Estimasyon Prensipal Estimasyon an: | 10/10/2011 |
| Dat estime fini etid la: | 10/10/2011 |
Kondisyon oswa maladi
Entèvansyon / tretman
Drug: Trabectedin (ecteinascidin-743, ET-743, YONDELIS [R])
Faz
Kritè kalifikasyon yo
| Laj ki kalifye pou etid | 4 Years Pou 4 Years |
| Sèks ki kalifye pou etid | All |
| Aksepte Volontè Healthy | Wi |
| Kritè | - INCLUSION CRITERIA: AGE: greater than or equal to 4 years and less than 17 years of age. DIAGNOSIS: Histologically confirmed solid tumors, which may include but are not limited to rhabdomyosarcoma and other soft tissue sarcomas, Ewing's sarcoma family of tumors, osteosarcoma, neuroblastoma, Wilms' tumor, hepatic tumors, germ cell tumors, and brain tumors with the exception that histologic confirmation is not required for patients with optic or brainstem gliomas. MEASURABLE/EVALUABLE DISEASE: Patients must have measurable or evaluable disease. PRIOR THERAPY: The patient's cancer must have relapsed after or failed to respond to frontline curative therapy and there must not be other potentially curative treatment options available. - Patients must have fully recovered to less than or equal to grade 1 from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study. - Myelosuppressive chemotherapy: The last dose of all myelosuppressive anticancer drugs must be at least 3 weeks prior to study entry. - Growth factors: The last dose of growth factors such as filgrastim and epoetin must be at least one week prior to study entry, the last dose of long-acting colony stimulating factors, such as pegfilgrastim, must be 2 weeks prior to study entry. - Investigational anti-cancer agents: The last dose of all investigational agents must be at least 30 days prior to study entry. - Biologic anti-cancer agents: The last dose of non-myelosuppressive biologic agents for the treatment of the patient's cancer (example, retinoids) must be at least 7 days prior to study entry. - Radiation therapy: The last dose of radiation to more than 25% of marrow containing bones (pelvis, spine, skull) must be at least 4 weeks prior to study entry, TBI and craniospinal radiation must be completed at least 4 months prior to study entry. The last dose of all other local palliative radiation must be at least 2 weeks prior to study entry. - Stem Cell Transplantation. Patients must be at least 2 months post-autologous transplant and recovered from treatment-related toxicities. Patients who have received an allogeneic transplant are excluded. CONCOMITANT MEDICATIONS: -Patients with brain tumors must be on a stable or tapering dose of corticosteroids for 7 days prior to the date of the baseline scan performed for the purpose of assessing response to therapy on this study. PERFORMANCE STATUS: Patients must have a Lansky (less than or equal to 10 years old) or Karnofsky (greater than 10 years old) score of greater than or equal to 60%. HEMATOLOGIC FUNCTION: Peripheral absolute neutrophil count greater than or equal to 1,500/microliter and a platelet count greater than or equal to 75,000/microliter independent of transfusion, and a hemoglobin of greater than or equal to 8 gm/dl (transfusion permitted to achieve this level). HEPATIC FUNCTION: - ALT (SGPT) and AST (SGOT) must be less than or equal to 2.5 x the upper limit of normal (ULN). - Bilirubin must be less than or equal to ULN. If the patient has Gilbert's syndrome, normal bilirubin is not required but should be discussed with the PI or study chair. - Alkaline phosphatase must be less than or equal to ULN for age and sex or if alkaline phosphatase greater than ULN then 5' nucleotidase must be less than or equal to ULN or the gamma-glutamyl transpeptidase (GGT) must be less than or equal to 2.5 times the ULN to be eligible. Normal Values for Alkaline Phosphatase at the NIH Clinical Center (U/L): Age between 4 to 6 years with a normal value (U/L) in Males 93 to 309 and a normal value (U/L) in Females 96 to 297. Age between 7 to 9 years with a normal value (U/L) in Males 86 to 315 and a normal value (U/L) in Females 69 to 325. Age between 10 to 12 years with a normal value (U/L) in Males 42 to 362 and a normal value (U/L) in Females 51 to 332. Age between 13 to 15 years with a normal value (U/L) in Males 74 to 390 and a normal value (U/L) in Females 50 to 162. Age between 16 to 18 years with a normal value (U/L) in Males 52 to 171 and a normal value (U/L) in Females 47 to 119. OTHER: creatine kinase less than or equal to 2.5 times the ULN. RENAL FUNCTION: Age-adjusted serum creatinine OR a creatinine clearance greater than or equal to 60 mL/min/1.73 m(2). Age less than or equal to 5 with a serum creatinine less than or equal to 0.8 (mg/dl). Age greater than 5 years and less than or equal to 10 with a serum creatinine of less than or equal to 1.0 (mg/dl). Age greater than 10 and less than or equal to 15 with a serum creatinine less than or equal to 1.2 (mg/dl). Age greater than 15 with a serum creatinine less than or equal to 1.5 (mg/dl). EXCLUSION CRITERIA: Patients with severe uncontrolled infections or other unrelated systemic illnesses, which in the judgment of the Principal or Associate Investigator would compromise the patient's ability to tolerate trabectedin or are likely to interfere with the study procedures or results. Patients with known history of xeroderma pigmentosum or other diseases with reduced DNA repair. Pregnant or breast-feeding females. Sexually active patients must be willing to use an effective form of birth control. Patients currently receiving other investigational agents. Patients who have received allogeneic stem cell transplants. Patients who have had prior therapy with trabectedin (ET-743, Yondelis). |
