Protocol Number: 03-C-0062

Title:

A Phase I Study of ZD1839 (Iressa™ (Trademark)), An Oral Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Children with Refractory Solid Tumors

Number:

03-C-0062

Summary:

This study will determine 1) the highest dose of the experimental drug Iressa that can safely be given to children and adolescents with cancer, 2) the side effects of the drug in these patients, and 3) how the child's body handles (metabolizes) the drug over time. Iressa binds to epidermal growth factor receptor (EGFR) proteins. These proteins are found on the surface of some cancer cells and some normal cells and may help tumor cells grow and spread to other parts of the body. Iressa may block the effects of these growth factors as well as the growth of new blood vessels that nourish tumors.

Patients under 22 years of age with a solid tumor cancer for whom no satisfactory standard therapy is available may be eligible for this study. Participants will have the following tests and procedures:

- Iressa treatment: Patients will take one Iressa tablet daily in 28-day cycles.

- Physical examinations: at least once weekly during the first 28-day cycle and periodically throughout the course of treatment.

- Eye examinations: twice during the first treatment cycle and periodically throughout the course of treatment.

- Blood tests: weekly during the first treatment cycle and periodically throughout the course of treatment. In addition, special blood tests will be done: before beginning treatment and on days 10 and 28 of the first treatment cycle to examine the effect of Iressa on VEGF, MMP-2, and MMP-9 - proteins in the blood that may reflect tumor growth and spread and formation of new tumor blood vessels; before beginning treatment to study the genes that control drug metabolism.

- X-rays, CT scans, MRI scans: periodically throughout the course of treatment.

- Pharmacology test: on days 10, 21 and 28 of the first course of treatment and day 28 of subsequent cycles. On day 10 of treatment cycle 1, eight blood samples of 1 teaspoon each will be drawn over 24 hours to measure blood levels of the drug. On the other test days, only one blood sample will be drawn. If possible, the blood will be collected through the child's permanent intravenous catheter (Hickman line or port-a-cath) or a heparin lock to avoid multiple needle sticks.

- Buccal swab: before starting Iressa and on day 28 of the first treatment cycle. Cells are scraped from the inside of the cheek to examine the effect of Iressa on normal cells.

- Test for the presence of EGFR receptor proteins on the surface of cancer cells. This test will be done on tissue samples that were stored after a prior surgery or biopsy, if available.

Patients may continue to receive Iressa unless their tumor continues to grow during treatment, they develop unacceptable side effects, or other reason determined by the study doctor.

Sponsoring Institute:

National Cancer Institute (NCI)

Recruitment Detail

Type: Active Accrual Of New Subjects

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

Age: Patients must be less than 22 years of age at the time of study entry.

Histologic Diagnosis: Patients must have had histologic verification of solid tumor malignancy at original diagnosis.

Patient's disease must be considered refractory to conventional therapy or for which no conventional therapy exists.

Performance Status: Karnofsky greater than or equal to 50% for patients greater than 10 years of age and Lansky Play-Performance Scale greater than or equal to 50 for children less than or equal to 10 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair will be considered ambulatory for the purpose of assessing the performance score.

Life Expectancy: Must be greater than or equal to 8 weeks.

Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.

a. Myelosuppressive chemotherapy: Must not have received within 2 weeks of entry onto this study (4 weeks if prior nitrosourea).

b. Biologic (anti-neoplastic agent): At least 7 days since the completion of therapy with a biologic agent.

c. XRT: Greater than or equal to 2 wks for local palliative XRT (small port); greater than or equal to 6 months must have elapsed if prior craniospinal XRT or if greater than or equal to 50% radiation of pelvis; greater than or equal to 6 wks must have elapsed if other substantial BM radiation.

d. Stem Cell Transplant (SCT): No evidence of active graft vs. host disease. For allogeneic SCT, greater than or equal to 6 months must have elapsed.

Growth factor(s): Must not have received within 1 week of entry onto this study.

Study Specific: Patients on enzyme activating anticonvulsants will not be allowed on this study. ZD1839 should not be administered with drugs with known corneal toxicity (e.g., tamoxifen, chlorpromazine, amiodarone, chloroquine).

Adequate Bone Marrow Function Defined As: For patients with solid tumors including status post Stem Cell Transplant (SCT):

- Peripheral absolute neutrophil count (ANC) greater than or equal to 1000/microL.

- Platelet count greater than or equal to 50,000/miciroL (transfusion independent)

- Hemoglobin greater than or equal to 8.0 gm/dL (may receive RBC transfusions).

Patients with solid tumors metastatic to bone marrow who have granulocytopenia, anemia, and/or thrombocytopenia are eligible provided they meet criteria, but will not be evaluable for hematological toxicity.

Adequate Renal Function Defined As: An age-adjusted normal serum creatinine (see below) or a GFR greater than or equal to 70 ml/min/1.73m(2).

Age less than or equal to 5 years, Maximum Serum Creatine (mg/dL) 0.8.

Age greater than or equal to 5 and less than or equal to 10 years, Maximum Serum Creatinine (mg/dL) 1.0.

Age greater than 10 and less than or equal to 15 years, Maximum Serum Creatinine (mg/dL) 1.2.

Age greater than 15 years, Maximum Serum Creatinine (mg/dL) 1.5.

Adequate Liver Function Defined As:

- Total bilirubin less than or equal to 1.5 x institutional upper limit of normal for age, and

- SGPT (ALT) less than or equal to 3 x institutional upper limit of normal for age and albumin greater than or equal to 2 g/dL.

EXCLUSION CRITERIA:

Pregnancy or Breast-Feeding: No information is available regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.

Patients who have an uncontrolled infection.

Patients on enzyme activating anticonvulsants will not be allowed on this study.

Patients with primary central nervous system tumors or known metastases to the central nervous system.

Special Instructions: Currently Not Provided

Keywords:

EGFR Inhibitor

Pharmacokinetics

Pharmacogenomics

Recruitment Keywords:

None

Conditions:

Tumors

Investigational Drug(s):

Gefitnib/Iressa

Investigational Device(s):

None

Contacts:

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citations:

Salomon DS, Brandt R, Ciardiello F, Normanno N. Epidermal growth factor-related peptides and their receptors in human

malignancies. Crit Rev Oncol Hematol. 1995 Jul;19(3):183-232. Review. No abstract available.

PMID: 7612182

Woodburn JR. The epidermal growth factor receptor and its inhibition in cancer therapy.

Pharmacol Ther. 1999 May-Jun;82(2-3):241-50. Review.

PMID: 10454201

Meyers MB, Shen WP, Spengler BA, Ciccarone V, O'Brien JP, Donner DB, Furth

ME, Biedler JL.

Increased epidermal growth factor receptor in multidrug-resistant human

neuroblastoma cells.

J Cell Biochem. 1988 Oct;38(2):87-97.

PMID: 2464605

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