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Bone and Soft Tissue Tumors

ADVL0221: A Phase II Study of Trabectedin (ET-743, Yondelis® ) in Children with Recurrent Rhabdomyosarcoma, Ewing Sarcoma, or Non-rhabdomyosarcomatous Soft Tissue Sarcomas

Type of TrialStatus of TrialAge Range (yrs.)Sponsor of TrialProtocol ID
Treatment Active 1 to 21 years COG ADVL0221

Outline

This is a multicenter study.

Patients are stratified according to disease (Ewing's sarcoma family of tumors vs rhabdomyosarcoma vs nonrhabdomyosarcomatous soft tissue sarcoma).

Patients receive ecteinascidin 743 IV over 3 hours on day 1. Treatment repeats every 21 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

Patients are followed at 30 days.

Objectives

  • 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.
  • Determine the toxicity of this drug in these patients.
  • Determine the pharmacokinetics of this drug in these patients.

Projected Accrual

A total of 30-60 patients (10-20 per stratum) will be accrued for this study within 2 years.

Mechanism of Action

Trabectedin (Ecteinascidin-743, YONDELIS™) is a new anti-tumor agent of marine origin, derived from the colonial tunicate (sea squirt) Ecteinascidia turbinata, which is found in the Mediterranean and Caribbean seas. The compound has a unique and complex mechanism of anti-tumor action that is not yet fully elucidated. Among its multiple effects are: promoter-selective inhibition of transcriptional activation of key genes, including oncogenes involved in cell proliferation and drug resistance; inhibition of transcription-dependent nucleotide excision repair pathways; and inhibition of cell cycle progression,resulting in p53-independent apoptosis. Trabectedin displays anti-proliferative activity against a variety of human solid-tumor cell lines, including soft-tissue sarcoma, breast, ovarian, non-small cell lung, prostate and renal cancers, and melanomas. Of these, soft-tissue sarcoma cell lines appear to be particularly sensitive to the cytotoxic action of the drug.

Entry Criteria

Disease Characteristics:

· Histologically confirmed recurrent or refractory sarcomas, 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

Patient Characteristics:

Age

  • 21 and under (at time of diagnosis)

Performance status

  • Lansky 50-100% (10 years of age and under)
  • Karnofsky 50-100% (over 10 years of age)

Life expectancy

  • Not specified

Hematopoietic

  • 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)

Hepatic

  • See Disease Characteristics
  • Bilirubin no greater than upper limit of normal (ULN)
  • Total alkaline phosphatase no greater than ULN OR
  • Hepatic fraction alkaline phosphatase and 5 nucleotidase no greater than ULN
  • SGOT and SGPT normal for age
  • Albumin at least 2.5 g/dL

Renal

· 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) OR
  • Creatinine clearance or radioisotope glomerular filtration rate (GFR) at least 70 mL/min

Cardiovascular

  • No uncompensated congestive heart failure within the past 6 months

Other

  • 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

Prior Concurrent Therapy:

Biologic therapy

  • 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

Chemotherapy

  • 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

Endocrine therapy

  • Concurrent steroids allowed

Radiotherapy

  • See Disease Characteristics
  • 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* NOTE: *Any irradiated lesion cannot be used to assess tumor response

Surgery

  • Not specified

Other

  • 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
  • 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)