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

• ClinicalTrials.gov Identifier: NCT00070109
• Recruitment Status: Completed
• First Posted: October 7, 2003
• Results First Posted: January 27, 2014
• Last Update Posted: September 14, 2018
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

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:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• 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: January 2008
• Actual Primary Completion Date: October 2010
• Actual Study Completion Date: December 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 Name: 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 Name: 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 Name: 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 Name: 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 Name: pharmacological studies

Outcome Measures

Primary Outcome Measures :

1. Response (Complete Response [CR] and Partial Response [PR]) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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

• Ages Eligible for Study: 12 Months to 50 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Arkansas

University of Arkansas for Medical Sciences

Little Rock, Arkansas, United States, 72205

United States, California

Children's Hospital Central California

Madera, California, United States, 93636-8762

United States, Illinois

Childrens Memorial Hospital

Chicago, Illinois, United States, 60614

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

New York University Langone Medical Center

New York, New York, United States, 10016

Columbia University Medical Center

New York, New York, United States, 10032

United States, North Carolina

Wake Forest University Health Sciences

Winston-Salem, North Carolina, United States, 27157

United States, Ohio

Nationwide Children's Hospital

Columbus, Ohio, United States, 43205

United States, Tennessee

St. Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Vermont

University of Vermont

Burlington, Vermont, United States, 05401

United States, Washington

Seattle Children's Hospital

Seattle, Washington, United States, 98105

Canada, Ontario

Chedoke-McMaster Hospitals

Hamilton, Ontario, Canada, L8S 4L8

Hospital for Sick Children

Toronto, Ontario, Canada, M5G 1X8

Canada, Quebec

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

More Information

Publications of Results:

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.

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT00070109
• Other Study ID Numbers: ADVL0221; NCI-2009-00357 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); CDR0000329999 ( Other Identifier: Clinical Trials.gov ); COG-ADVL0221 ( Other Identifier: Children's Oncology Group ); U10CA098543 ( U.S. NIH Grant/Contract )
• First Posted: October 7, 2003
• Results First Posted: January 27, 2014
• Last Update Posted: September 14, 2018
• Last Verified: August 2018

Additional relevant MeSH terms:

Sarcoma; Rhabdomyosarcoma; Sarcoma, Ewing; Neuroectodermal Tumors; Neuroectodermal Tumors, Primitive; Rhabdomyosarcoma, Embryonal; Neuroectodermal Tumors, Primitive, Peripheral; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Myosarcoma; Neoplasms, Muscle Tissue; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplasms, Neuroepithelial; Neoplasms, Glandular and Epithelial; Trabectedin; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents