Clinical trial NCT00070473: Pemetrexed Disodium in Treating Young Patients With Recurrent Solid Tumors
Official title: A Phase I Study of Pemetrexed (LY231514, Alimta) in Children and Adolescents With Recurrent Solid Tumors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Unspecified Childhood Solid Tumor, Protocol Specific
Keywords: unspecified childhood solid tumor, protocol specific
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2003-10-07
Enrollment: 33
Sex: ALL
Minimum age (years): 1
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as pemetrexed disodium, use different ways to stop tumor cells from dividing so they stop growing or die. Pemetrexed disodium may stop the growth of tumor cells by blocking the enzymes necessary for their growth.

PURPOSE: This phase I trial is studying the side effects and best dose of pemetrexed disodium in treating young patients with recurrent solid tumors.

Detailed description: OBJECTIVES:

Primary

* Determine the maximum tolerated dose of pemetrexed disodium in children and adolescents with refractory solid tumors.
* Determine the dose-limiting toxic effects of this drug in these patients.
* Determine the pharmacokinetics of this drug in these patients.

Secondary

* Determine, preliminarily, the antitumor activity of this drug in these patients.
* Correlate the presence of the C677T polymorphism of the methylenetetrahydrolate reductase gene, the presence of a polymorphism in the enhancer region of the thymidylate synthase (TS) gene promoter (2R and 3R tandem repeats), the presence of a polymorphism within one of those repeats, and the presence of a functional polymorphism in the 3'-untranslated region with toxicity in patients treated with this drug.
* Correlate homocysteine and methylmalonic acid levels at study entry with toxicity in patients treated with this drug.
* Correlate various gene expression profiles with response in patients treated with this drug.

OUTLINE: This is a dose-escalation study.

Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of pemetrexed disodium 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 toxicity.

PROJECTED ACCRUAL: A total of 3-36 patients will be accrued for this study within 1 year.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Histologically confirmed solid tumor for which there is no known curative therapy or therapy that is known to prolong survival with acceptable quality of life

  * Histologic requirement waived for intrinsic brain stem tumors
* No pleural effusion or ascites
* Neurological deficits from CNS tumors must have been relatively stable for at least 1 week prior to study entry

PATIENT CHARACTERISTICS:

Age

* 1 to 21

Performance status

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

Life expectancy

* At least 8 weeks

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

* Bilirubin no greater than 1.5 times upper limit of normal (ULN)
* ALT no greater than 2.5 times ULN
* Albumin at least 2 g/dL

Renal

* Creatinine clearance or radioisotope glomerular filtration rate at least 70 mL/min OR
* Creatinine based on age as follows:

  * No greater than 0.8 mg/dL (age 5 and under)
  * No greater than 1.0 mg/dL (age 6 to 10)
  * No greater than 1.2 mg/dL (age 11 to 15)
  * No greater than 1.5 mg/dL (age 16 and over)

Pulmonary

* No evidence of dyspnea at rest
* No exercise intolerance

Other

* Not pregnant or nursing
* Negative pregnancy test
* Fertile patients must use effective contraception
* No evidence of Approved-not yet active graft-versus-host disease
* No uncontrolled infection
* Seizure disorder allowed provided it is well-controlled with anticonvulsants
* CNS toxicity no greater than grade 1

PRIOR CONCURRENT THERAPY:

Biologic therapy

* Recovered from prior immunotherapy
* At least 7 days since prior antineoplastic biologic therapy
* At least 6 months since prior allogeneic stem cell transplantation
* More than 1 week since prior growth factors
* No concurrent biologic therapy
* No concurrent immunotherapy
* No concurrent prophylactic growth factor support during course 1

Chemotherapy

* No prior pemetrexed disodium
* More than 3 weeks since prior myelosuppressive chemotherapy (4 weeks for nitrosoureas) and recovered
* No other concurrent chemotherapy

Endocrine therapy

* Concurrent dexamethasone for CNS tumors allowed provided dose has been stable or decreasing for at least 1 week prior to study entry

Radiotherapy

* Recovered from all prior radiotherapy
* At least 2 weeks since prior local palliative radiotherapy
* At least 6 months since prior craniospinal radiotherapy
* At least 6 months since prior radiotherapy to 50% or more of the pelvis
* At least 6 weeks since prior substantial bone marrow radiotherapy
* No concurrent radiotherapy

Surgery

* Not specified

Other

* No trimethoprim or sulfa within 2 days before and after study drug administration
* No concurrent nonsteroidal anti-inflammatory agents (e.g., ibuprofen and aspirin)
* No other concurrent anticancer or investigational agents

Primary outcomes:
measure: Event Free Survival
timeFrame: Length of study
Secondary outcomes:
measure: Dose Limiting Toxicity
timeFrame: Length of study
measure: Maximum Tolerated Dose
timeFrame: Length of study
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center at Stanford University Medical Center
state: California
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Indianapolis
country: United States
facility: Indiana University Cancer Center
state: Indiana
city: Bethesda
country: United States
facility: NCI - Pediatric Oncology Branch
state: Maryland
city: Boston
country: United States
facility: Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: Fairview University Medical Center - University Campus
state: Minnesota
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: New York
country: United States
facility: Herbert Irving Comprehensive Cancer Center at Columbia University
state: New York
city: Syracuse
country: United States
facility: SUNY Upstate Medical University Hospital
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Portland
country: United States
facility: Cancer Institute at Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
state: Texas
city: Houston
country: United States
facility: Baylor University Medical Center - Houston
state: Texas
city: Seattle
country: United States
facility: Children's Hospital and Regional Medical Center - Seattle
state: Washington
city: Toronto
country: Canada
facility: Hospital for Sick Children
state: Ontario
city: Montreal
country: Canada
facility: Hopital Sainte Justine
state: Quebec
Study officials:
affiliation: OHSU Knight Cancer Institute
name: H. Stacy Nicholson, MD, MPH
role: STUDY_CHAIR
affiliation: Doernbecher Children's Hospital at Oregon Health and Science University
name: Linda C. Stork, MD
role: STUDY_CHAIR
References:
citation: Malempati S, Nicholson HS, Reid JM, Blaney SM, Ingle AM, Krailo M, Stork LC, Melemed AS, McGovern R, Safgren S, Ames MM, Adamson PC; Children's Oncology Group. Phase I trial and pharmacokinetic study of pemetrexed in children with refractory solid tumors: the Children's Oncology Group. J Clin Oncol. 2007 Apr 20;25(12):1505-11. doi: 10.1200/JCO.2006.09.1694.