Trabectedin in Treating Young Patients With Recurrent or Refractory Soft Tissue Sarcoma or Ewing's Family of Tumors

Study Overview
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Brief Summary
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This phase II trial is studying how well trabectedin works in treating young patients with recurrent or refractory soft tissue sarcoma or Ewing's family of tumors. Drugs used in chemotherapy such as trabectedin use different ways to stop tumor cells from dividing so they stop growing or die.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the response rate in pediatric patients with recurrent or refractory soft tissue sarcomas or Ewing's sarcoma family of tumors treated with ecteinascidin 743 (trabectedin). II. Determine the toxicity of this drug in these patients. III. Determine the pharmacokinetics of this drug in these patients. OUTLINE: Patients receive trabectedin IV over 3 hours on day 1. Treatment repeats every 21days for up to 26 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up for up to 5 years.

Official Title
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A Phase II Study Of Trabectedin (ET-743, Yondelis®) in Children With Recurrent Rhabdomyosarcoma, Ewing Sarcoma, or Nonrhabdomyosarcomatous Soft Tissue Sarcomas

Conditions
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Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma, Peripheral Primitive Neuroectodermal Tumor

Intervention / Treatment
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* Drug: trabectedin
* Other: pharmacological study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must be greater than or equal to 12 months of age at the time of study entry and no more than 21 years of age when initially diagnosed with the malignancy to be treated on this protocol Histologically confirmed recurrent or refractory sarcoma tumors, including the following: Rhabdomyosarcoma Nonrhabdomyosarcomatous soft tissue sarcoma Ewing's sarcoma Measurable disease by imaging studies Lesions assessable only by radionuclide scans are not considered measurable If the only measurable lesion has been previously irradiated, then that lesion must have shown evidence of an interim increase in size No significant amount of metastatic liver disease, defined as the following: Lesions occupying more than 25% of the liver by imaging and abnormal liver function tests or abnormal synthetic liver function Performance status - Lansky 50-100% (10 years of age and under) Performance status - Karnofsky 50-100% (over 10 years of age) Absolute neutrophil count at least 1,000/mm^3 Platelet count at least 100,000/mm^3 (transfusion independent) Hemoglobin at least 8.0 g/dL (transfusion allowed) No concurrent CYP3A4 inhibitors, including the following: Grapefruit juice Erythromycin Azithromycin Clarithromycin Rifampin and its analogs Fluconazole Ketoconazole Itraconazole Cimetidine Cannabinoids (marijuana or dronabinol) Leukotriene inhibitors used in asthma (e.g., zafirlukast, montelukast, or zileuton) Bilirubin no greater than upper limit of normal (ULN) Total alkaline phosphatase no greater than ULN Hepatic fraction alkaline phosphatase and 5 nucleotidase no greater than ULN SGOT and SGPT ≤ 2.5 times ULN Albumin ≥ 2.5 g/dL Gamma-glutamyl transferase < 2.5 times ULN Maximum creatinine based on age as follows: 0.8 mg/dL (5 years of age and under) 1.0 mg/dL (6 to 10 years of age) 1.2 mg/dL (11 to 15 years of age) 1.5 mg/dL (over 15 years of age) Creatinine clearance or radioisotope glomerular filtration rate (GFR) at least 70 mL/min No uncompensated congestive heart failure within the past 6 months Not pregnant or nursing Fertile patients must use effective contraception during and for 2 months after study participation No active uncontrolled infection Weight ≥ 15 kilograms More than 1 week since prior growth factors that support platelet or white blood cell number or function At least 7 days since prior biologic agents and recovered No prior allogeneic stem cell transplantation No other concurrent immunomodulating agents More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered No more than 2 prior multi-agent chemotherapy regimens No other concurrent anticancer chemotherapy Concurrent steroids allowed At least 6 weeks since prior since prior extended radiotherapy and recovered No prior total body radiotherapy Concurrent radiotherapy to localized painful lesions allowed provided at least 1 measurable lesion is not irradiated* At least 7 days since prior enzyme-inducing anticonvulsants (e.g., carbamazepine, phenobarbital, or phenytoin) No concurrent enzyme-inducing anticonvulsants No other concurrent investigational agents

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trabectedin 1.3 mg/m2 to assess feasibility in all patients<br>Patients receive trabectedin over 3 hours on day 1. Treatment repeats every 21 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. A cohort of 6 patients will be enrolled at the 1.3 mg/m2 dose level. | Drug: trabectedin<br>* Given IV<br>* Other names: Yondelis;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Trabectedin 1.5 mg/m2 to assess feasibility in all patients<br>Patients receive trabectedin over 3 hours on day 1. Treatment repeats every 21 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. Six toxicity-evaluable patients are assigned this treatment. | Drug: trabectedin<br>* Given IV<br>* Other names: Yondelis;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Trabectedin at 1.5 mg/m2 to assess efficacy in Ewing sarcoma<br>Patients receive trabectedin over 3 hours on day 1. Treatment repeats every 21 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. | Drug: trabectedin<br>* Given IV<br>* Other names: Yondelis;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Trabectedin at 1.5 mg/m2 - assess efficacy in rhabdomyosarcoma<br>Patients receive trabectedin over 3 hours on day 1. Treatment repeats every 21 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. | Drug: trabectedin<br>* Given IV<br>* Other names: Yondelis;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|
| Experimental: Trabectedin 1.5 mg/m2 - assess efficacy in nonrhabdomyosarcoma<br>Patients receive trabectedin over 3 hours on day 1. Treatment repeats every 21 days for up to 26 courses in the absence of disease progression or unacceptable toxicity. | Drug: trabectedin<br>* Given IV<br>* Other names: Yondelis;Other: pharmacological study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response (Complete Response [CR] and Partial Response [PR]) | Any patient who is enrolled and receives at least one dose of trabectedin will be considered evaluable for response if the individual receives at least one dose of trabectedin and: (1) is removed from protocol therapy because of progressive disease where progressive disease is documented either by imaging studies or clinical progression; or (2) has at least one radiographic evaluation of disease status after the start of protocol therapy and is not electively removed from protocol therapy with stable disease or is not lost to follow-up with stable disease. Patients who achieve a complete response (CR) - disappearance of all target lesions or partial response (PR) - >=30% decrease in the sum of the longest diameter of target lesions according to the RECIST criteria will be considered responders for the study design. All other patients who are evaluable for response will be considered non-responders for the study. | Twenty-six (26) cycles of chemotherapy or termination of protocol therapy, whichever occurs first. | 
| Number of Patients With Dose-Limiting Toxicity (DLT) | Any Grade 3 or Grade 4 non-hematologic toxicity attributable to the Investigational drug with the specific exclusion of: Grade 3 nausea and vomiting; Grade 3 transaminase (AST/ALT) elevation that return to less than or equal to Grade 1 or baseline prior to the time for the next treatment cycle; Grade 3 fever or infection; Alopecia; Grade 4 neutropenia of > 7 days duration or Grade 4 thrombocytopenia of > 7 days duration, which requires transfusion therapy on greater than 2 occasions in 7 days, or which causes a delay of more than 14 days beyond the planned interval between treatment cycles. | 1 Cycle | 
| Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Maximum Plasma Concentration (Cmax) of Trabectedin | The plasma concentrations at each time point were determined by miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method. The plasma concentration-versus-time data of trabectedin were estimated using non-compartmental methods. Individual time points were not available, so one estimated Cmax was derived for each patient. | From baseline up to168 hours after trabectedin infusion in course 1 | 
| Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Apparent Volume at Steady State (Vss) of Trabectedin | The plasma concentrations at each time point were determined by miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method. The plasma concentration-versus-time data of trabectedin were estimated using non-compartmental methods. Individual time points were not available, so one estimated Vss was derived for each patient. | From baseline up to168 hours after trabectedin infusion in course 1 | 
| Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Half-life of Trabectedin | The plasma concentrations at each time point were determined by miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method. The plasma concentration-versus-time data of trabectedin were estimated using non-compartmental methods. Individual time points were not available, so one estimated Half-life was derived for each patient. | From baseline up to168 hours after trabectedin infusion in course 1 | 
| Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Area Under the Curve (AUC) of Trabectedin | The plasma concentrations at each time point were determined by miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method. The plasma concentration-versus-time data of trabectedin were estimated using non-compartmental methods. Individual time points were not available, so one estimated AUC was derived for each patient. | From baseline up to168 hours after trabectedin infusion in course 1 | 
| Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Clearance of Trabectedin | The plasma concentrations at each time point were determined by miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method. The plasma concentration-versus-time data of trabectedin were estimated using non-compartmental methods. Individual time points were not available, so one estimated Clearance was derived for each patient. | From baseline up to168 hours after trabectedin infusion in course 1 |