Back to resultsTrabectedin in Treating Young Patients With Recurrent or Refractory Soft Tissue Sarcoma or Ewing's Family of Tumors
Primary Purpose
Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma
Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
trabectedin
pharmacological study
Sponsored by
About this trial
This is an interventional treatment trial for Previously Treated Childhood Rhabdomyosarcoma
Eligibility Criteria
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
Sites / Locations
- University of Arkansas for Medical Sciences
- Children's Hospital Central California
- Childrens Memorial Hospital
- Roswell Park Cancer Institute
- New York University Langone Medical Center
- Columbia University Medical Center
- Wake Forest University Health Sciences
- Nationwide Children's Hospital
- St. Jude Children's Research Hospital
- University of Vermont
- Seattle Children's Hospital
- Chedoke-McMaster Hospitals
- Hospital for Sick Children
- Hospital Sainte-Justine
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm Type
Experimental
Experimental
Experimental
Experimental
Experimental
Arm Label
Trabectedin 1.3 mg/m2 to assess feasibility in all patients
Trabectedin 1.5 mg/m2 to assess feasibility in all patients
Trabectedin at 1.5 mg/m2 to assess efficacy in Ewing sarcoma
Trabectedin at 1.5 mg/m2 - assess efficacy in rhabdomyosarcoma
Trabectedin 1.5 mg/m2 - assess efficacy in nonrhabdomyosarcoma
Arm Description
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.
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
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.
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.
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.
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.
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.
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.
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.
Secondary Outcome Measures
Full Information
NCT ID
NCT00070109
First Posted
October 3, 2003
Last Updated
August 13, 2018
Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
1. Study Identification
Unique Protocol Identification Number
NCT00070109
Brief Title
Trabectedin in Treating Young Patients With Recurrent or Refractory Soft Tissue Sarcoma or Ewing's Family of Tumors
Official Title
A Phase II Study Of Trabectedin (ET-743, Yondelis®) in Children With Recurrent Rhabdomyosarcoma, Ewing Sarcoma, or Nonrhabdomyosarcomatous Soft Tissue Sarcomas
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
January 2008 (undefined)
Primary Completion Date
October 2010 (Actual)
Study Completion Date
December 2013 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Children's Oncology Group
Collaborators
National Cancer Institute (NCI)
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Previously Treated Childhood Rhabdomyosarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Recurrent Ewing Sarcoma, Peripheral Primitive Neuroectodermal Tumor
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Trabectedin 1.3 mg/m2 to assess feasibility in all patients
Arm Type
Experimental
Arm Description
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.
Arm Title
Trabectedin 1.5 mg/m2 to assess feasibility in all patients
Arm Type
Experimental
Arm Description
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.
Arm Title
Trabectedin at 1.5 mg/m2 to assess efficacy in Ewing sarcoma
Arm Type
Experimental
Arm Description
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.
Arm Title
Trabectedin at 1.5 mg/m2 - assess efficacy in rhabdomyosarcoma
Arm Type
Experimental
Arm Description
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.
Arm Title
Trabectedin 1.5 mg/m2 - assess efficacy in nonrhabdomyosarcoma
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
trabectedin
Other Intervention Name(s)
Ecteinascidin, ET 743, Yondelis
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
pharmacological study
Other Intervention Name(s)
pharmacological studies
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
Response (Complete Response [CR] and Partial Response [PR])
Description
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.
Time Frame
Twenty-six (26) cycles of chemotherapy or termination of protocol therapy, whichever occurs first.
Title
Number of Patients With Dose-Limiting Toxicity (DLT)
Description
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.
Time Frame
1 Cycle
Title
Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Maximum Plasma Concentration (Cmax) of Trabectedin
Description
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.
Time Frame
From baseline up to168 hours after trabectedin infusion in course 1
Title
Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Apparent Volume at Steady State (Vss) of Trabectedin
Description
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.
Time Frame
From baseline up to168 hours after trabectedin infusion in course 1
Title
Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Half-life of Trabectedin
Description
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.
Time Frame
From baseline up to168 hours after trabectedin infusion in course 1
Title
Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Area Under the Curve (AUC) of Trabectedin
Description
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.
Time Frame
From baseline up to168 hours after trabectedin infusion in course 1
Title
Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Clearance of Trabectedin
Description
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.
Time Frame
From baseline up to168 hours after trabectedin infusion in course 1
10. Eligibility
Sex
All
Minimum Age & Unit of Time
12 Months
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sylvain Baruchel, MD
Organizational Affiliation
Children's Oncology Group
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Arkansas for Medical Sciences
City
Little Rock
State/Province
Arkansas
ZIP/Postal Code
72205
Country
United States
Facility Name
Children's Hospital Central California
City
Madera
State/Province
California
ZIP/Postal Code
93636-8762
Country
United States
Facility Name
Childrens Memorial Hospital
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60614
Country
United States
Facility Name
Roswell Park Cancer Institute
City
Buffalo
State/Province
New York
ZIP/Postal Code
14263
Country
United States
Facility Name
New York University Langone Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Columbia University Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Wake Forest University Health Sciences
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Facility Name
Nationwide Children's Hospital
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43205
Country
United States
Facility Name
St. Jude Children's Research Hospital
City
Memphis
State/Province
Tennessee
ZIP/Postal Code
38105
Country
United States
Facility Name
University of Vermont
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05401
Country
United States
Facility Name
Seattle Children's Hospital
City
Seattle
State/Province
Washington
ZIP/Postal Code
98105
Country
United States
Facility Name
Chedoke-McMaster Hospitals
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8S 4L8
Country
Canada
Facility Name
Hospital for Sick Children
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 1X8
Country
Canada
Facility Name
Hospital Sainte-Justine
City
Montreal
State/Province
Quebec
ZIP/Postal Code
H3T 1C5
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
22088484
Citation
Baruchel S, Pappo A, Krailo M, Baker KS, Wu B, Villaluna D, Lee-Scott M, Adamson PC, Blaney SM. A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: a report from the Children's Oncology Group. Eur J Cancer. 2012 Mar;48(4):579-85. doi: 10.1016/j.ejca.2011.09.027. Epub 2011 Nov 14.
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Trabectedin in Treating Young Patients With Recurrent or Refractory Soft Tissue Sarcoma or Ewing's Family of Tumors
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