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

• Sponsor: Children's Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00070109
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 50
• Locations: 14
• Arms: 5
• Duration (Months): 71
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Recurrent Ewing Sarcoma; Peripheral Primitive Neuroectodermal Tumor	Drug: trabectedin; Other: pharmacological study	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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).

2. 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study Of Trabectedin (ET-743, Yondelis®) in Children With Recurrent Rhabdomyosarcoma, Ewing Sarcoma, or Nonrhabdomyosarcomatous Soft Tissue Sarcomas
• Study Start Date: Jan 1, 2008
• Actual Primary Completion Date: Oct 1, 2010
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trabectedin 1.3 mg/m2 to assess feasibility in all patients 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; Given IV; Other Names: Ecteinascidin ET 743 Yondelis ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies
Experimental: Trabectedin 1.5 mg/m2 to assess feasibility in all patients 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; Given IV; Other Names: Ecteinascidin ET 743 Yondelis ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies
Experimental: Trabectedin at 1.5 mg/m2 to assess efficacy in Ewing sarcoma 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; Given IV; Other Names: Ecteinascidin ET 743 Yondelis ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies
Experimental: Trabectedin at 1.5 mg/m2 - assess efficacy in rhabdomyosarcoma 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; Given IV; Other Names: Ecteinascidin ET 743 Yondelis ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies
Experimental: Trabectedin 1.5 mg/m2 - assess efficacy in nonrhabdomyosarcoma 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; Given IV; Other Names: Ecteinascidin ET 743 Yondelis ; Other: pharmacological study; Correlative studies; Other Names: pharmacological studies

Outcome Measures

Primary Outcome Measures

1. Response (Complete Response [CR] and Partial Response [PR]) [Twenty-six (26) cycles of chemotherapy or termination of protocol therapy, whichever occurs first.]

   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.

2. Number of Patients With Dose-Limiting Toxicity (DLT) [1 Cycle]

   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.

3. Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Maximum Plasma Concentration (Cmax) of Trabectedin [From baseline up to168 hours after trabectedin infusion in course 1]

   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.

4. Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Apparent Volume at Steady State (Vss) of Trabectedin [From baseline up to168 hours after trabectedin infusion in course 1]

   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.

5. Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Half-life of Trabectedin [From baseline up to168 hours after trabectedin infusion in course 1]

   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.

6. Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Area Under the Curve (AUC) of Trabectedin [From baseline up to168 hours after trabectedin infusion in course 1]

   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.

7. Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Clearance of Trabectedin [From baseline up to168 hours after trabectedin infusion in course 1]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Months to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
2	Children's Hospital Central California	Madera	California	United States	93636-8762
3	Childrens Memorial Hospital	Chicago	Illinois	United States	60614
4	Roswell Park Cancer Institute	Buffalo	New York	United States	14263
5	New York University Langone Medical Center	New York	New York	United States	10016
6	Columbia University Medical Center	New York	New York	United States	10032
7	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
8	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
9	St. Jude Children's Research Hospital	Memphis	Tennessee	United States	38105
10	University of Vermont	Burlington	Vermont	United States	05401
11	Seattle Children's Hospital	Seattle	Washington	United States	98105
12	Chedoke-McMaster Hospitals	Hamilton	Ontario	Canada	L8S 4L8
13	Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
14	Hospital Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5

Sponsors and Collaborators

• Children's Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Sylvain Baruchel, MD, Children's Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00070109
• Other Study ID Numbers: ADVL0221; NCI-2009-00357; CDR0000329999; COG-ADVL0221; U10CA098543
• First Posted: Oct 7, 2003
• Last Update Posted: Sep 14, 2018
• Last Verified: Aug 1, 2018

• Additional relevant MeSH terms: Sarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Rhabdomyosarcoma, Embryonal; Neuroectodermal Tumors, Primitive, Peripheral; Recurrence; Trabectedin

Study Results

Participant Flow

Arm/Group Title	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/Group 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. trabectedin: Given IV pharmacological study: Correlative studies	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. trabectedin: Given IV	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. trabectedin: Given IV	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. trabectedin: Given IV	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. trabectedin: Given IV
Period Title: Overall Study
STARTED	8	6	8	20	8
COMPLETED	0	0	0	0	0
NOT COMPLETED	8	6	8	20	8

Baseline Characteristics

Arm/Group Title	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	Total
Arm/Group 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. trabectedin: Given IV pharmacological study: Correlative studies	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. trabectedin: Given IV	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. trabectedin: Given IV	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. trabectedin: Given IV	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. trabectedin: Given IV	Total of all reporting groups
Overall Participants	8	6	8	20	8	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	18.5	15.5	16	14.5	16	15.5
Sex: Female, Male (Count of Participants)
Female	1 12.5%	2 33.3%	3 37.5%	11 55%	2 25%	19 38%
Male	7 87.5%	4 66.7%	5 62.5%	9 45%	6 75%	31 62%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	1 16.7%	0 0%	3 15%	3 37.5%	7 14%
Not Hispanic or Latino	8 100%	5 83.3%	0 0%	16 80%	5 62.5%	34 68%
Unknown or Not Reported	0 0%	0 0%	8 100%	1 5%	0 0%	9 18%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 12.5%	1 5%	0 0%	2 4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	1 12.5%	0 0%	0 0%	5 25%	1 12.5%	7 14%
White	6 75%	6 100%	7 87.5%	12 60%	7 87.5%	38 76%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 12.5%	0 0%	0 0%	2 10%	0 0%	3 6%
Region of Enrollment (participants) [Number]
United States	5 62.5%	6 100%	5 62.5%	19 95%	8 100%	43 86%
Canada	3 37.5%	0 0%	3 37.5%	1 5%	0 0%	7 14%

Outcome Measures

1. Primary Outcome

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.

Outcome Measure Data

Analysis Population Description

No pts in Group 1 were evaluated for response. 1 pt in Group 3 is excluded because the pt was removed from protocol therapy after cycle 3 when a cardiac evaluation was missed. The pt was removed prior to disease assessment on protocol therapy. 1 pt enrolled in Group 4 was excluded because patient was removed from therapy prior to chemotherapy.

Arm/Group Title	Trabectedin 1.5 mg/m2- Feasibility in All Patients(Group 2)	Trabectedin 1.5 mg/m2- Efficacy in Ewing Sarcoma (Group 3)	Trabectedin 1.5 mg/m2- Efficacy in Rhabdomyosarcoma (Group 4)	Trabectedin 1.5 mg/m2-efficacy in Nonrhabdomyosarcoma(Group 5)
Arm/Group 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. trabectedin: Given IV	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. trabectedin: Given IV	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. trabectedin: Given IV	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. trabectedin: Given IV
Measure Participants	6	7	19	8
Number [participants]	1 12.5%	0 0%	0 0%	0 0%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Two pts in Group 1 and 1 pt in Group 2 were excluded because they were removed from therapy prior to the DLT evaluation period and no DLT had been observed. No patients in Groups 3, 4, or 5 were evaluated for DLT.

Arm/Group Title	Trabectedin 1.3 mg/m2- Feasibility in All Patients (Group 1)	Trabectedin 1.5 mg/m2- Feasibility in All Patients (Group 2)
Arm/Group 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. trabectedin: Given IV pharmacological study: Correlative studies	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. trabectedin: Given IV
Measure Participants	6	5
Number [participants]	1 12.5%	0 0%

3. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients for whom specimens were submitted to the pharmacokinetics laboratory with sufficient samples to calculate maximum plasma concentration of trabectedin. Group 1 and group 2 patients were excluded due to not submitting specimens.

Arm/Group Title	Trabectedin at 1.5 mg/m2- Efficacy in Ewing Sarcoma (Group 3)	Trabectedin 1.5 mg/m2- Efficacy in Rhabdomyosarcoma (Group 4)	Trabectedin 1.5 mg/m2-efficacy in Nonrhabdomyosarcoma(Group 5)
Arm/Group 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.	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.
Measure Participants	3	2	5
Mean (Standard Deviation) [ng/mL]	3.643333333 (4.08)	2.285 (0.191)	1.889 (1.26)

4. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients for whom specimens were submitted to the pharmacokinetics laboratory with sufficient samples to calculate apparent volume at steady state of trabectedin of trabectedin. Group 1 and group 2 patients were excluded due to not submitting specimens.

Arm/Group Title	Trabectedin at 1.5 mg/m2- Efficacy in Ewing Sarcoma (Group 3)	Trabectedin 1.5 mg/m2- Efficacy in Rhabdomyosarcoma (Group 4)	Trabectedin 1.5 mg/m2-efficacy in Nonrhabdomyosarcoma(Group 5)
Arm/Group 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.	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.
Measure Participants	3	2	2
Mean (Standard Deviation) [L]	1860.666667 (999.9)	1340.5 (439)	3269.5 (269.4)

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients for whom specimens were submitted to the pharmacokinetics laboratory with sufficient samples to calculate trabectedin half life. Group 1 and group 2 patients were excluded due to not submitting specimens.

Arm/Group Title	Trabectedin at 1.5 mg/m2- Efficacy in Ewing Sarcoma (Group 3)	Trabectedin 1.5 mg/m2- Efficacy in Rhabdomyosarcoma (Group 4)	Trabectedin 1.5 mg/m2-efficacy in Nonrhabdomyosarcoma(Group 5)
Arm/Group 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.	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.
Measure Participants	3	2	2
Mean (Standard Deviation) [hours]	47.4 (17.0)	49.5 (1.70)	63.4 (22.4)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients for whom specimens were submitted to the pharmacokinetics laboratory with sufficient samples to calculate trabectedin AUC. Group 1 and group 2 patients were excluded due to not submitting specimens.

Arm/Group Title	Trabectedin at 1.5 mg/m2- Efficacy in Ewing Sarcoma (Group 3)	Trabectedin 1.5 mg/m2- Efficacy in Rhabdomyosarcoma (Group 4)	Trabectedin 1.5 mg/m2-efficacy in Nonrhabdomyosarcoma(Group 5)
Arm/Group 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.	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.
Measure Participants	3	2	2
Mean (Standard Deviation) [ng/(mLxh)]	184.9 (193)	75.7 (43.3)	41.2 (18.7)

7. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Patients for whom specimens were submitted to the pharmacokinetics laboratory with sufficient samples to calculate trabectedin clearance. Group 1 and group 2 patients were excluded due to not submitting specimens.

Arm/Group Title	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/Group 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.	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.
Measure Participants	3	2	2
Mean (Standard Deviation) [L/hr]	20.5786891 (17.9)	18.11833775 (3.32)	63.8304367 (29.7)

Adverse Events

Adverse Event Reporting Description	1 patient in Group 4 was not included in the AE analysis as the patient never received treatment.
Arm/Group Title	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/Group 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. trabectedin: Given IV pharmacological study: Correlative studies		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. trabectedin: Given IV		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. trabectedin: Given IV		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. trabectedin: Given IV		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. trabectedin: Given IV
All Cause Mortality
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)		0/6 (0%)		1/8 (12.5%)		5/19 (26.3%)		3/8 (37.5%)
Eye disorders
Eye pain	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
General disorders
Death NOS	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		1/8 (12.5%)
Fever	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Infections and infestations
Infections and infestations - Other, specify	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Injury, poisoning and procedural complications
Vascular access complication	0/8 (0%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		1/8 (12.5%)
Investigations
Alanine aminotransferase increased	1/8 (12.5%)		0/6 (0%)		1/8 (12.5%)		1/19 (5.3%)		0/8 (0%)
Aspartate aminotransferase increased	1/8 (12.5%)		0/6 (0%)		1/8 (12.5%)		2/19 (10.5%)		0/8 (0%)
GGT increased	1/8 (12.5%)		0/6 (0%)		1/8 (12.5%)		1/19 (5.3%)		0/8 (0%)
Lymphocyte count decreased	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Metabolism and nutrition disorders
Dehydration	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Hyperglycemia	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Hyponatremia	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/8 (0%)		0/6 (0%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
Renal and urinary disorders
Acute kidney injury	0/8 (0%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		1/8 (12.5%)
Other (Not Including Serious) Adverse Events
	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
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/8 (75%)		4/6 (66.7%)		6/8 (75%)		15/19 (78.9%)		6/8 (75%)
Blood and lymphatic system disorders
Anemia	4/8 (50%)		2/6 (33.3%)		3/8 (37.5%)		5/19 (26.3%)		1/8 (12.5%)
Eye disorders
Blurred vision	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Eye disorders - Other, specify	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Gastrointestinal disorders
Abdominal distension	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Abdominal pain	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		1/8 (12.5%)
Constipation	0/8 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
Diarrhea	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Dry mouth	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Flatulence	0/8 (0%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		1/8 (12.5%)
Nausea	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		4/19 (21.1%)		0/8 (0%)
Upper gastrointestinal hemorrhage	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Vomiting	1/8 (12.5%)		1/6 (16.7%)		1/8 (12.5%)		4/19 (21.1%)		0/8 (0%)
General disorders
Fatigue	1/8 (12.5%)		1/6 (16.7%)		1/8 (12.5%)		1/19 (5.3%)		1/8 (12.5%)
Fever	1/8 (12.5%)		1/6 (16.7%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Non-cardiac chest pain	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		1/8 (12.5%)
Pain	0/8 (0%)		1/6 (16.7%)		1/8 (12.5%)		0/19 (0%)		1/8 (12.5%)
Infections and infestations
Bladder infection	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Infections and infestations - Other, specify	3/8 (37.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Mucosal infection	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		1/19 (5.3%)		1/8 (12.5%)
Injury, poisoning and procedural complications
Vascular access complication	0/8 (0%)		0/6 (0%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
Investigations
Activated partial thromboplastin time prolonged	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Alanine aminotransferase increased	3/8 (37.5%)		3/6 (50%)		1/8 (12.5%)		9/19 (47.4%)		3/8 (37.5%)
Alkaline phosphatase increased	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Aspartate aminotransferase increased	3/8 (37.5%)		3/6 (50%)		1/8 (12.5%)		6/19 (31.6%)		3/8 (37.5%)
Blood bilirubin increased	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
CPK increased	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Creatinine increased	0/8 (0%)		0/6 (0%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
GGT increased	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		5/19 (26.3%)		3/8 (37.5%)
Investigations - Other, specify	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Lymphocyte count decreased	1/8 (12.5%)		1/6 (16.7%)		1/8 (12.5%)		4/19 (21.1%)		2/8 (25%)
Neutrophil count decreased	4/8 (50%)		2/6 (33.3%)		2/8 (25%)		10/19 (52.6%)		2/8 (25%)
Platelet count decreased	0/8 (0%)		0/6 (0%)		2/8 (25%)		5/19 (26.3%)		0/8 (0%)
White blood cell decreased	3/8 (37.5%)		1/6 (16.7%)		2/8 (25%)		9/19 (47.4%)		2/8 (25%)
Metabolism and nutrition disorders
Acidosis	0/8 (0%)		0/6 (0%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
Anorexia	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		2/19 (10.5%)		0/8 (0%)
Hypercalcemia	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Hyperglycemia	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		3/19 (15.8%)		0/8 (0%)
Hypermagnesemia	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Hypoalbuminemia	1/8 (12.5%)		1/6 (16.7%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
Hypokalemia	1/8 (12.5%)		0/6 (0%)		1/8 (12.5%)		1/19 (5.3%)		0/8 (0%)
Hypophosphatemia	2/8 (25%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Buttock pain	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Myalgia	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Pain in extremity	2/8 (25%)		1/6 (16.7%)		1/8 (12.5%)		0/19 (0%)		0/8 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor Pain	2/8 (25%)		0/6 (0%)		1/8 (12.5%)		1/19 (5.3%)		0/8 (0%)
Nervous system disorders
Dizziness	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Dysgeusia	1/8 (12.5%)		0/6 (0%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Encephalopathy	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Neuralgia	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Peripheral sensory neuropathy	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Psychiatric disorders
Anxiety	0/8 (0%)		0/6 (0%)		0/8 (0%)		1/19 (5.3%)		0/8 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/8 (0%)		1/6 (16.7%)		0/8 (0%)		0/19 (0%)		0/8 (0%)
Dyspnea	0/8 (0%)		0/6 (0%)		0/8 (0%)		2/19 (10.5%)		0/8 (0%)
Vascular disorders
Phlebitis	0/8 (0%)		0/6 (0%)		1/8 (12.5%)		0/19 (0%)		1/8 (12.5%)

Limitations/Caveats

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Principal Investigators are NOT employed by the organization sponsoring the study.

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