Pemetrexed Disodium in Treating Young Patients With Recurrent Solid Tumors

A Phase I Study of Pemetrexed (LY231514, Alimta) in Children and Adolescents With Recurrent Solid Tumors

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.

Study Overview

• Status: Completed
• Conditions: Unspecified Childhood Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: pemetrexed disodium

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.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada
      • Hospital for Sick Children
  • Quebec
    • Montreal, Quebec, Canada
      • Hopital Sainte Justine
• United States
  • California
    • Los Angeles, California, United States, 323669
      • Children's Hospital Los Angeles
    • Stanford, California, United States, 94305
      • Stanford Cancer Center at Stanford University Medical Center
  • District of Columbia
    • Washington, District of Columbia, United States, 20010-2970
      • Children's National Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Cancer Center
  • Maryland
    • Bethesda, Maryland, United States, 301496
      • NCI - Pediatric Oncology Branch
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Dana-Farber/Harvard Cancer Center at Dana Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Fairview University Medical Center - University Campus
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
  • Mississippi
    • Jackson, Mississippi, United States, 39216-4505
      • University of Mississippi Medical Center
  • New York
    • New York, New York, United States, 10032
      • Herbert Irving Comprehensive Cancer Center at Columbia University
    • Syracuse, New York, United States, 13210
      • SUNY Upstate Medical University Hospital
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Oregon
    • Portland, Oregon, United States, 97239-3098
      • Cancer Institute at Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 215590
      • Children's Hospital of Philadelphia
    • Pittsburgh, Pennsylvania, United States, 15213
      • Children's Hospital of Pittsburgh
  • Texas
    • Dallas, Texas, United States, 75390
      • Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas
    • Houston, Texas, United States, 832822
      • Baylor University Medical Center - Houston
  • Washington
    • Seattle, Washington, United States, 206987
      • Children's Hospital and Regional Medical Center - Seattle

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 21 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Event Free Survival	Length of study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Limiting Toxicity	Any patient who experiences DLT at any time during protocol therapy will be considered evaluable for toxicity. Patients not experiencing DLT must complete a full cycle of therapy to be considered potentially evaluable for toxicity. Patients who are not evaluable for toxicity will be replaced.	Length of study
Maximum Tolerated Dose	The MTD will be that dose at which fewer than one-third of patients experience DLT	Length of study

Collaborators and Investigators

• Sponsor: Children's Oncology Group
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Linda C. Stork, MD, Doernbecher Children's Hospital at Oregon Health and Science University; Study Chair: H. Stacy Nicholson, MD, MPH, OHSU Knight Cancer Institute

Publications and helpful links

General Publications

• 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. Erratum In: J Clin Oncol. 2008 Jan 1;26(1):165.

Study record dates

Study Major Dates

• Study Start: October 1, 2003
• Primary Completion (Actual): March 1, 2006
• Study Completion (Actual): June 1, 2008

Study Registration Dates

• First Submitted: October 3, 2003
• First Submitted That Met QC Criteria: October 6, 2003
• First Posted (Estimate): October 7, 2003

Study Record Updates

• Last Update Posted (Estimate): February 20, 2014
• Last Update Submitted That Met QC Criteria: February 19, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Keywords: unspecified childhood solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Folic Acid Antagonists; Pemetrexed
• Other Study ID Numbers: ADVL0311; NCI-04-C-0261 (Other Identifier: NCI Trial Identifier); CDR0000334572 (Other Identifier: Clinical Trials.gov); COG-ADVL0311 (Other Identifier: Children's Oncology Group)