Ecteinascidin 743 in Treating Children With Refractory Solid Tumors

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Ecteinascidin 743 may be an effective treatment for solid tumors. PURPOSE: Phase I trial to study the effectiveness of ecteinascidin 743 in treating children who have refractory solid tumors.

Detailed Description
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OBJECTIVES: I. Determine the maximum tolerated dose and dose-limiting toxicity of ecteinascidin 743 in pediatric patients with refractory solid tumors. II. Determine the pharmacokinetics of this drug in these patients. III. Determine the antitumor activity of this drug in this patient population. OUTLINE: This is a dose escalation, multicenter study. Patients are stratified according to pretreatment (pretreated vs less heavily pretreated). Patients receive ecteinascidin 743 IV over 3 hours on day 1. Treatment continues every 3 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of ecteinascidin 743 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicities. PROJECTED ACCRUAL: A total of 3-20 patients will be accrued for this study within 2 years.

Official Title
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Phase I Study of ET-743 in Pediatric Refractory Solid Tumors

Conditions
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Unspecified Childhood Solid Tumor, Protocol Specific

Intervention / Treatment
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* Drug: ECTEINASCIDIN 743


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed malignant solid tumor at original diagnosis Refractory to standard treatment or no curative therapy available No CNS tumor No bone marrow metastases (for less heavily pretreated stratum only) PATIENT CHARACTERISTICS: Age: At least 365 days to 17 years Performance status: Karnofsky 50-100% (for patients older than 10 years) Lansky 50-100% (for patients 10 years and younger) Life expectancy: At least 8 weeks Hematopoietic: Absolute neutrophil count at least 1,500/mm3 Platelet count at least 100,000/mm3 (transfusion independent) Hemoglobin at least 8.0 g/dL (RBC transfusion allowed) Hepatic: Bilirubin no greater than normal SGPT no greater than 2.5 times normal Albumin at least 2 g/dL Alkaline phosphatase normal Gamma glutamyl transferase less than 2.5 times normal Renal: Creatinine no greater than 1.5 times normal OR Creatinine clearance or GFR at least lower limit of normal Other: Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception Creatine phosphokinase less than 2 times normal No uncontrolled infection Seizure disorder allowed if well controlled on anticonvulsants No CNS toxicity greater than grade II PRIOR CONCURRENT THERAPY: Biologic therapy: At least 1 week since prior biologic therapy and recovered At least 1 week since prior growth factor therapy At least 6 months since prior peripheral blood stem cell transplantation and no evidence of graft-vs-host disease For less heavily pretreated stratum: No prior peripheral blood stem cell transplantation Chemotherapy: At least 4 weeks since prior myelosuppressive chemotherapy (6 weeks for nitrosoureas) and recovered No prior ecteinascidin 743 For less heavily pretreated stratum: No more than 2 prior chemotherapy regimens Endocrine therapy: Not specified Radiotherapy: At least 2 weeks since prior local palliative radiotherapy (small port) At least 6 weeks since prior substantial bone marrow radiotherapy At least 6 months since prior craniospinal radiotherapy or radiotherapy to 50% or greater of pelvis For less heavily pretreated stratum: No prior craniospinal irradiation of 18Gy or greater No prior irradiation to greater than 50% of pelvis Recovered from toxic effects of prior radiotherapy Surgery: Not specified Other: No concurrent foods or medication that interferes with P-450 metabolism Anticonvulsants allowed

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapy ECTEINASCIDIN 743 (1100 ug/m2 )<br> | Drug: ECTEINASCIDIN 743<br> <br> * Other names: IND 50,286;|
| Experimental: ECTEINASCIDIN 743 (1300 ug/m2)<br> | Drug: ECTEINASCIDIN 743<br> <br> * Other names: IND 50,286;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival |  | Length of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Limiting Toxicity | To determine the maximum tolerated dose (MTD) of vincristine, when used in combination with irinotecan, and the dose-limiting toxicity (DLT) of this combination; irinotecan will be administered IV over 1 hour x 5 days, q 21 days, with vincristine IVP days 1, 8, 15, 22, 29, every 42 days, to children with refractory solid tumors. |  | 
| Determine a safe and tolerable dose of vincristine, when administered with irinotecan | To determine a safe and tolerable dose of vincristine, when administered with irinotecan, for future evaluation in phase II clinical trials. |  | 
| Determine the pharmacokinetics of vincristine and irinotecan | To determine the pharmacokinetics of vincristine and irinotecan (and its active metabolite SN-38) when administered in combination to children with refractory cancer. | Length of study | 
| Determine the incidence and severity of other toxicities | To determine the incidence and severity of other toxicities of this combination. | Length of study | 
| Seek preliminary evidence of anti-tumor activity of irinotecan plus vincristine | To seek preliminary evidence of anti-tumor activity of irinotecan plus vincristine against recurrent solid tumors. | Length of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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unspecified childhood solid tumor, protocol specific