Protocol Number: 02-C-0303

Title:

Phase II Pilot Study of Clinical Activity and Proteomic Pathway Profiling of the EGFR Inhibitor, ZD1839 (Iressa; Gefitinib), In Patients With Epithelial Ovarian Cancer Or Cervical Cancer

Number:

02-C-0303

Summary:

This study will evaluate the safety and effectiveness of the experimental drug ZD1839 (also known as Iressa® (Registered Trademark) or gefitinib) for treating patients with advanced ovarian or cervical cancer with or without fallopian tube or primary peritoneal cancer. ZD1839 attacks a group of proteins called 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. In laboratory experiments, ZD1839 slowed the growth of certain cancers, and in preliminary studies in humans, a small number of women with ovarian cancer who took ZD1839 had no tumor growth for the period of time they received the drug. This study will determine whether ZD1839 can cause tumors to shrink or stabilize in some patients with ovarian or cervical cancer. It will also look for tumor characteristics that may indicate which ones are more likely to respond to treatment with ZD1839.

Women 18 years of age or older with ovarian or cervical cancer whose cancer persists or has relapsed after undergoing at least one operation and one course of chemotherapy or radiotherapy may be eligible for this study. Patients with fallopian tube or primary peritoneal cancer may also participate. Candidates will be screened with a medical history, physical examination, blood and urine tests, and a computerized tomography (CT) scan to locate the tumor and determine biopsy sites (see below).

Participants will take ZD1839 tablets by mouth once a day. They will keep a diary of when they take the medicine and record any side effects they may experience. In addition, they will have the following tests and procedures:

- CT scan before starting treatment and again every 8 weeks to monitor tumor size.

- Tumor biopsies before starting treatment and about 4 weeks into the study to look for characteristics unique to the patient's tumor that might make it more likely to respond to ZD1839. Tumor biopsies will be done using a needle or by direct visualization using laparoscopy. For the needle biopsy, the area of the procedure is anesthetized and a small needle is inserted through the skin into the tumor. A piece of tissue smaller than the size of a pin is withdrawn through the needle. The needle biopsy is done under CT guidance, allowing the radiologist to see exactly where to place the needle. Laparoscopy is a surgical procedure, performed under sedation or general anesthesia, that is done if the tumor is in a place that cannot be reached with a needle through the skin. It requires making two small holes in the skin through which tubes are inserted to locate the tumor and cut out a small piece of tissue.

- Skin biopsies before starting treatment and about 4 weeks into the study to determine the effect of ZD1839 on EGFR. The skin biopsies use a cookie cutter-like instrument to obtain two pieces of skin the size of a grain of rice.

- Follow-up visits every 4 weeks or more often, as needed, for a physical examination and blood tests, and review of laboratory studies and drug side effects.

Patients whose tumor stops growing or shrinks and who do not have serious drug side effects may continue to receive treatment. Those whose cancer worsens or who develop severe drug side effects will be taken off the study, referred back to their local physician, and counseled about other NCI trials for which they may be eligible or options outside NCI that may be available to them.

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:

All patients 18 years and older with biopsy-proven epithelial ovarian cancer or cervical cancer that is relapsed and/or refractory to prior therapy will be eligible. Patients with cancers of the fallopian tubes, primary peritoneum, or low malignant potential with an invasive recurrence will be included in the ovarian cancer cohort. For a first relapse of ovarian cancer, patients with a disease free interval greater than 12 months may be enrolled only after full informed consent outlining alternative treatment is completed.

Histopathologic diagnosis must be confirmed in the Laboratory of Pathology (LP), NCI. A block or re-cuts of the primary is required. If this is unavailable, a recent resection specimen of a metastatic site is required for entry.

All patients must have measurable disease (by RECIST criteria) and a sentinel lesion adequate for core biopsy either through percutaneous biopsy or laparoscopy to be eligible. All patients must be willing to undergo punch biopsies of unaffected skin.

Patients must have a performance status: ECOG &eq; 0, 1 or 2.

Patients must have good end organ function: WBC greater than 3000/mm(3), platelets greater than 100,000/mm(3), normal acute care panel with serum creatinine less than 1.5 mg/dl, liver function tests (AST and ALT) within 2.5 times the upper limit of normal, and bilirubin less than 1.5 mg/dl.

Patients must be at least 4 weeks from previous therapy (chemotherapy, hormonal therapy, and radiation therapy). Mitomycin and nitrosoureas must be stopped at least 6 weeks prior to enrollment. Date of last prior therapy will be reported in the research record.

All patients must have recovered from any toxicity related to prior therapy to NCI/CTEP grade 1.

The effects of ZD1839 on the developing human fetus are unknown. Women of childbearing age and potential must agree to use adequate contraception prior to study entry and during therapy and continue for 2 months after completion of therapy.

Patients must be able to give written informed consent.

All patients must be registered by calling the ORKAND Corporation at 301-402-1732 between the hours of 8:30 AM and 5:00 PM EST.

EXCLUSION CRITERIA:

Patients who have received other EGFR inhibitory agents such as OSI774, Cetuximab (IMC225), or Abgenics (anti-EGFR) will be excluded.

Evidence of CNS involvement (patients with abnormal clinical exam or history will require a head CT or MRI).

History of myocardial infarction or unstable dysrhythmia within six months of entry.

History of another invasive malignancy in the last five years. Noninvasive, non-melanoma skin cancers will be allowed.

Patients with active infection will not be eligible, but may be eligible once infection has resolved.

Pregnant women and those who are actively breast-feeding will be excluded because of possible risks to the fetus or infant.

There is limited data on drug interactions between ZD1839 and antiretroviral therapy. As such, patients requiring these medications are excluded from study because safety cannot be confirmed due to risk of drug interactions with ZD1839 or other agents administered during the study.

No concomitant use of complementary or alternative medication or other agents (investigational or anti-cancer agents) will be allowed without approval of a PI or AI. Every effort will be made to maximize patient safety and minimize changes in chronic medications. Medications altering metabolism of ZD1839 with potential toxicity will be allowed only at the PI's discretion. Patients receiving itraconazole, ketoconazole, erythromycin, verapamil, tamoxifen, chlorpromazine, amiodarone, and chloroquine will not be eligible for this study. Patients receiving concomitant drugs known to induce CYP3A4 enzymes, specifically phenytoin, carbamazepine, rifampicin, barbiturates, oxacarbazepine, rifapentine, or St. John's Wort will not be ineligible as studies have shown that plasma concentrations may be below those thought to be biologically active.

Patients with incomplete healing from previous oncologic or other major surgery and those with active ocular inflammation/infection will be ineligible.

Special Instructions: Currently Not Provided

Keywords:

Growth Factor

Tyrosine Kinase

Stabilization

Microarray

Recruitment Keywords:

Ovarian Cancer

Cervical Cancer

Conditions:

Ovarian Neoplasms

Cervix Neoplasms

Investigational Drug(s):

Gefitinib (Iressa, ZD1839)

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:

Fan Z, Masui H, Altas I, Mendelsohn J. Blockade of epidermal growth factor receptor function by bivalent and monovalent

fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies.

Cancer Res. 1993 Sep 15;53(18):4322-8.

PMID: 8364927

Ciardiello F. Epidermal growth factor receptor tyrosine kinase inhibitors as anticancer

agents.

Drugs. 2000;60 Suppl 1:25-32; discussion 41-2. Review.

PMID: 11129169

Wells A. EGF receptor. Int J Biochem Cell Biol. 1999 Jun;31(6):637-43. Review.

PMID: 10404636

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