Clinical trial NCT00513981: High-Dose Methotrexate in Treating Young Patients With Solid Tumors
Official title: Study to Determine the Maximum Tolerated Time of Infusion for High-Dose Methotrexate, Administered as a Continuous Intravenous Infusion at a Dose of 6g/m² Per 24 Hours of Infusion Time
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Brain and Central Nervous System Tumors
Sarcoma
Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: unspecified childhood solid tumor, protocol specific
recurrent osteosarcoma
recurrent childhood soft tissue sarcoma
recurrent childhood ependymoma
untreated childhood brain stem glioma
recurrent childhood brain stem glioma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2007-08-09
Enrollment: 36
Sex: ALL
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as high-dose methotrexate work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Chemoprotective drugs, such as leucovorin calcium, may protect normal cells from the side effects of chemotherapy.

PURPOSE: This phase I trial is studying the side effects, best way to give, and best dose of high-dose methotrexate in treating patients with solid tumors.

Detailed description: OBJECTIVES:

* To determine the maximum tolerated time to exposure to high-dose methotrexate when administered as a continuous infusion at a dose of 6 g/m² per 24 hours.
* To relate the methotrexate schedules investigated to the magnitude and duration of changes in plasma homocysteine and methionine.
* To relate evidence of the systemic effect of methotrexate through changes in plasma homocysteine and methionine to any hepatic, neurological, or antiproliferative toxicity observed in the study group.

OUTLINE: Patients receive a continuous infusion of high-dose methotrexate IV over 24, 30, 36, or 42 hours depending on time of study entry. Beginning at hour 42 or 48, patients receive leucovorin calcium IV every 6 hours for 3 days or until plasma methotrexate concentration is \< 0.2 µM. Treatment repeats every 2 weeks in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study and analyzed for pharmacodynamic effects on plasma homocysteine and methionine by gas chromatography/mass spectrometry techniques.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically proven malignancy, including but not limited to, any of the following:

  * Patients with MRI findings in keeping with a diffuse intrinsic pontine glioma will be eligible without histological confirmation of tumor type

    * Patients with a diagnosis of diffuse intrinsic pontine glioma who are not eligible for the erlotinib hydrochloride phase I study (CCLG-NAG-2005-09)
  * Patients with relapsed ependymoma following the CCLG phase II study of intravenous etoposide (CCLG-CNS-2001-4) or prior to this are eligible at the discretion of the physician
  * Patients with relapsed osteogenic sarcoma, other soft tissue sarcomas, or other solid tumors may be suitable for this study at the discretion of the physician
* Radiologically evaluable disease without bone marrow involvement

PATIENT CHARACTERISTICS:

Inclusion criteria:

* Lansky performance status (PS) 30-100% (for patients ≤ 12 years of age)
* ECOG PS ≤ 2 (for patients ≥ 13 years of age)
* Life expectancy ≥ 9 weeks
* ANC \> 1,000/mm³
* Platelet count \> 100,000/mm³
* Hemoglobin \> 9 g/dL
* Serum creatinine ≤ 1.5 times upper limit of normal (ULN) for age
* Serum total bilirubin normal
* AST or ALT ≤ 2 times ULN
* Glomerular filtration rate ≥ 60 mL/min
* Negative pregnancy test
* Fertile patients must use effective contraception

Exclusion criteria:

* Poor medical risk because of nonmalignant systemic disease or uncontrolled infection
* Concurrent malignancies at other sites

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

* Prophylactic trimethoprim-sulfamethoxazole must be stopped 1 week prior to methotrexate administration

Exclusion criteria:

* Received chemotherapy or biologic therapy within the past 4 weeks
* Received radiotherapy within the past 6 weeks

Primary outcomes:
measure: Maximum tolerated infusion time for high-dose methotrexate
Secondary outcomes:
measure: Plasma biochemical evidence of the systemic effect of methotrexate in terms of changes in plasma homocysteine and methionine
Other outcomes:
Locations:
city: Dublin
country: Ireland
facility: Our Lady's Hospital for Sick Children Crumlin
city: Birmingham
country: United Kingdom
facility: Birmingham Children's Hospital
state: England
city: Bristol
country: United Kingdom
facility: Bristol Royal Hospital for Children
state: England
city: Cambridge
country: United Kingdom
facility: Addenbrooke's Hospital
state: England
city: Leeds
country: United Kingdom
facility: Leeds Cancer Centre at St. James's University Hospital
state: England
city: Leicester
country: United Kingdom
facility: Leicester Royal Infirmary
state: England
city: Liverpool
country: United Kingdom
facility: Royal Liverpool Children's Hospital, Alder Hey
state: England
city: London
country: United Kingdom
facility: University College Hospital
state: England
city: London
country: United Kingdom
facility: Great Ormond Street Hospital for Children
state: England
city: Manchester
country: United Kingdom
facility: Royal Manchester Children's Hospital
state: England
city: Newcastle-Upon-Tyne
country: United Kingdom
facility: Sir James Spence Institute of Child Health
state: England
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
state: England
city: Oxford
country: United Kingdom
facility: Oxford Radcliffe Hospital
state: England
city: Sheffield
country: United Kingdom
facility: Children's Hospital - Sheffield
state: England
city: Southampton
country: United Kingdom
facility: Southampton General Hospital
state: England
city: Sutton
country: United Kingdom
facility: Royal Marsden - Surrey
state: England
city: Belfast
country: United Kingdom
facility: Royal Belfast Hospital for Sick Children
state: Northern Ireland
city: Aberdeen
country: United Kingdom
facility: Royal Aberdeen Children's Hospital
state: Scotland
city: Edinburgh
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Glasgow
country: United Kingdom
facility: Royal Hospital for Sick Children
state: Scotland
city: Cardiff
country: United Kingdom
facility: Childrens Hospital for Wales
state: Wales
Study officials:
affiliation: Royal Manchester Children's Hospital
name: Eddy J. Estlin
role: PRINCIPAL_INVESTIGATOR
References: