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

Phase 2
Completed
Conditions
Recurrent Ewing Sarcoma
Previously Treated Childhood Rhabdomyosarcoma
Recurrent Childhood Rhabdomyosarcoma
Recurrent Childhood Soft Tissue Sarcoma
Peripheral Primitive Neuroectodermal Tumor
Interventions
Drug: trabectedin
Other: pharmacological study
Registration Number
NCT00070109
Lead Sponsor
Children's Oncology Group
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.

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
50
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

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Exclusion Criteria

Not provided

Read More

Study & Design

Study Type
INTERVENTIONAL
Study Design
SINGLE_GROUP
Arm && Interventions
GroupInterventionDescription
Trabectedin at 1.5 mg/m2 to assess efficacy in Ewing sarcomapharmacological studyPatients 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 1.3 mg/m2 to assess feasibility in all patientspharmacological studyPatients 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 1.5 mg/m2 - assess efficacy in nonrhabdomyosarcomapharmacological studyPatients 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 1.5 mg/m2 to assess feasibility in all patientspharmacological studyPatients 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 at 1.5 mg/m2 - assess efficacy in rhabdomyosarcomapharmacological studyPatients 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 1.3 mg/m2 to assess feasibility in all patientstrabectedinPatients 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 1.5 mg/m2 to assess feasibility in all patientstrabectedinPatients 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 at 1.5 mg/m2 to assess efficacy in Ewing sarcomatrabectedinPatients 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 at 1.5 mg/m2 - assess efficacy in rhabdomyosarcomatrabectedinPatients 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 1.5 mg/m2 - assess efficacy in nonrhabdomyosarcomatrabectedinPatients 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.
Primary Outcome Measures
NameTimeMethod
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.

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.

Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Maximum Plasma Concentration (Cmax) of TrabectedinFrom 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.

Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Apparent Volume at Steady State (Vss) of TrabectedinFrom 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.

Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Half-life of TrabectedinFrom 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.

Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Area Under the Curve (AUC) of TrabectedinFrom 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.

Pharmacokinetics by a Miniaturized Liquid Chromatography/Tandem Mass Spectrometry Method : Clearance of TrabectedinFrom 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.

Secondary Outcome Measures
NameTimeMethod

Trial Locations

Locations (14)

Childrens Memorial Hospital

🇺🇸

Chicago, Illinois, United States

Nationwide Children's Hospital

🇺🇸

Columbus, Ohio, United States

Hospital for Sick Children

🇨🇦

Toronto, Ontario, Canada

Children's Hospital Central California

🇺🇸

Madera, California, United States

New York University Langone Medical Center

🇺🇸

New York, New York, United States

Roswell Park Cancer Institute

🇺🇸

Buffalo, New York, United States

Columbia University Medical Center

🇺🇸

New York, New York, United States

Seattle Children's Hospital

🇺🇸

Seattle, Washington, United States

Chedoke-McMaster Hospitals

🇨🇦

Hamilton, Ontario, Canada

St. Jude Children's Research Hospital

🇺🇸

Memphis, Tennessee, United States

Hospital Sainte-Justine

🇨🇦

Montreal, Quebec, Canada

University of Vermont

🇺🇸

Burlington, Vermont, United States

Wake Forest University Health Sciences

🇺🇸

Winston-Salem, North Carolina, United States

University of Arkansas for Medical Sciences

🇺🇸

Little Rock, Arkansas, United States

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