ZD 1839 ( Iressa )

Iressa (gefitinib) is a drug for the treatment of non-small-cell lung cancer.

Precision tumor-killers promise to be the next wave of cancer treatment. Chemotherapy has proven less effective than desired in both ability to kill tumor cells and ability to salvage healthy cells necessary for survival. In recent years, Aventis Pharmaceuticals, AG, developed Taxotere (docetaxel), one of the earlier treatments to eliminate tumor cells while sparing healthy somatic cells from most of the toxic effects inherent in most other anti-tumor medication. For many treating physicians, researchers and patients, however, Taxotere too closely resembles traditional chemotherapy in its administration (an IV drip), its side effects (nausea and hair loss among others) and its rate of success. Researchers are continuing the quest for more effective treatments and believe a promising new field may lie in two new areas: angiogenesis inhibitors and epidermal growth factor-tyrosine kinase inhibitors (EGFR-TKIs).

These two new possibilities in treatment are similar in their alleged precision and their manipulation of enzymes to halt tumor growth. However, while angiogenesis inhibitors target the blood network of tumors, EGFR-TKIs instead target another factor crucial to tumor growth and survival - cell division. One EGFR-TKI is ZD 1839, also known as Iressa. Manufactured by AstraZeneca Plc, Iressa is taken in pill form and has been tested widely in the United States, Japan and elsewhere.

Iressa is currently in test phase for mesothelioma, but has already been clinically tested and seems to be relatively effective for treatment of non-small cell lung cancer (NSCLC) and breast cancer according to reports in the Philadelphia Business Journal, abstracts from the American Society of Clinical Oncology (ASCO) and Epsicom Business Intelligence online. Additionally, updates from ASCO's proceedings at its May 2001 conference support that Iressa has shown greater efficacy than herceptin in treating breast cancer and that herceptin combined with Iressa shows a higher rate of success than Iressa alone. Additionally, ASCO abstracts present evidence that Iressa may prove an effective treatment against tamoxifen-resistant breast cancer. The drug is currently in Phase II clinical trials for breast, colorectal, gastric and prostate cancers through different organizations, as well as the trials for mesothelioma being run by the Cancer and Leukemia Group B, according to AstraZeneca's Website and the National Institutes of Health National Cancer Institute (NCI).

AstraZeneca is promoting Iressa as an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). In order for a tumor to grow, tumor cell receptors must be able to link with certain enzymes, one of them being tyrosine kinase. Iressa blocks tyrosine kinase before it can join with the cell, thereby shutting down growth according to the pharmaceutical company's Website and ASCO abstracts.

AstraZeneca submitted data from two clinical trials of Iressa being used to treat NSCLC to the Food and Drug Administration (FDA) on December 28, 2001. The data from these two Phase II trials worldwide tested the efficacy of the drug at two different dosages: 250mg/day and 500 mg/day. No other therapy was administered to the patients while they were taking ZD 1839. Patients included in the studies had been treated with one or two chemotherapy regimens previously - including at least one platinum-based regimen - and had still exhibited tumor progression. ZD 1839 produced responses or disease stabilization in more than 50 percent of patients and was generally well tolerated by them with a minimum of side effects.

In the first study, the tumor response rate was 18.7%. Disease control was 52.9%, and 34% of the study group showed no signs of progression after four months of treatment. Additionally, symptoms of disease were relieved in 38.7% of patients, and the median time to at least partial alleviation of symptoms was eight days. No detailed results for the second trial were yet available to the public.

In a report from CancerEdge online, commenting on the success of the drug at the AACR-NCI-EORTC International Conference, José Baselga, MD, stated: "It is almost unprecedented to see such a high response rate with a new drug in such a difficult-to-treat subset of patients. The overall response rate of 18.7% is much higher than with standard chemotherapy, and the side effects are minimal." According to abstracts of studies of patients with NSCLC treating with Iressa, many had already tried regimens of chemotherapy and been discontinued due to a failure of chemotherapy to reduce tumor size.

After submitting their trial data to the FDA on December 28, 2001, AstraZeneca requested fast-track approval of Iressa by mid-2002. AstraZeneca released a statement on March 15, 2002, stating that they would be unable to present all clinical data at May's annual conference of the American Society of Clinical Oncology (ASCO), but Iressa would still be ready for market by the second half of 2002.

According to released data from AstraZeneca and ASCO regarding various clinical trials of the drug, the most commonly observed side effects of Iressa include the following:

• Diarrhea
• Rash
• Acne

The released reports also go on to say that loss of blood platelets and nausea, common in other cancer therapies, were seen less frequently at the lower 250/mg doses. A lowered platelet level and nausea, however, were seen more frequently in other clinical tests of Iressa that employed dosages of the drug as high as 500mg/day and going up to 800mg/day. Anorexia was also observed.

For more information regarding Iressa, its results in testing and pertinent press releases regarding its submission to the FDA for approval, please visit the AstraZeneca website at: www.astrazeneca.com or visit the American Society of Clinical Oncologists (ASCO) website at: www.asco.org.

-Sources consulted for this story include the Doctor's Guide from the P\S\L Group, Epsicom Business Intelligence online, the Philadelphia Business Journal, CancerEdge online, the National Institutes of Health National Cancer Institute Website and press releases from Yahoo!'s Business Wire, as well as information provided by AstraZeneca Plc, and the American Society of Clinical Oncology.

As was mentioned above, clinical trials to determine the success of Iressa against mesothelioma are being conducted by the Cancer and Leukemia Group B. Clinical Trial enrollment, qualification data and contact information is below.

Phase II Study of ZD 1839 in Patients With Malignant Mesothelioma (Summary Last Modified 11/2001)

Protocol Ids: CLB-30101

Protocol Type: treatment

Sponsorship: NCI cooperative group program, NCI-sponsored

Status: Active

Age Range: Over 18

OBJECTIVES

I. Determine the activity of ZD 1839, in terms of failure-free survival, in patients with malignant mesothelioma.

II. Determine the response rate in patients treated with this drug.

III. Determine the toxicity of this drug in these patients.

IV. Determine the overall survival of patients treated with this drug.

V. Determine whether overexpression of epidermal growth factor receptor and expression of cyclo-oxygenase-2 can predict the effectiveness of this drug in these patients.

ENTRY CRITERIA

--Disease Characteristics--

• Histologically confirmed malignant mesothelioma that is not amenable to curative surgery or radiotherapy
• Epithelial, sarcomatoid, or mixed subtype
• Any site of origin (including, but not limited to, the pleura, peritoneum, pericardium, or tunica vaginalis) allowed
• Measurable disease, defined as lesions that can be accurately measured in at least 1 dimension (longest diameter) as at least 20 mm with conventional techniques or at least 10 mm with spiral CT scan
• Must be outside prior radiation port
• Lesions not considered measurable include the following: Bone lesions, Leptomeningeal disease, Ascites, Pleural/pericardial effusion, Inflammatory breast disease, Lymphangitis cutis/pulmonis, Abdominal masses not confirmed and followed by imaging techniques, Cystic lesions
• No known brain metastases
• Epithelial, sarcomatoid, or mixed subtype

--Prior/Concurrent Therapy--

• Biologic therapy:No prior epidermal growth factor receptor-inhibitor therapy
• Epithelial, sarcomatoid, or mixe
• Chemotherapy:Prior intrapleural cytotoxic or sclerosing agents (including bleomycin) allowed
• No prior systemic cytotoxic chemotherapy for malignant mesothelioma
• No concurrent chemotherapy
• Endocrine therapy:
• At least 1 week since prior CYP3A4 inducers (e.g., dexamethasone, glucocorticoids, progesterone)
• No concurrent CYP3A4 inducers (e.g., dexamethasone)
• No concurrent hormonal therapy (e.g., tamoxifen) except steroids for adrenal failure or hormones for nondisease-related conditions (e.g., insulin for diabetes)

Radiotherapy:

• See Disease Characteristics
• At least 4 weeks since prior radiotherapy
• No concurrent radiotherapy, including for palliation

Surgery:

• See Disease Characteristics
• At least 2 weeks since prior major surgery

Other:

• See Disease Characterist
• At least 1 week since other prior CYP3A4 inducers (e.g., carbamazepine, ethosuximide, griseofulvin, nafcillin, nelfinavir mesylate, nevirapine, oxcarbazepine, phenobarbital, phenylbutazone, phenytoin, primidone, rifabutin, rifampin, rofecoxib, St. John's Wort, sulfadimidine, sulfinpyrazone, or troglitazone)
• No other concurrent CYP3A4 inducers
• No concurrent CYP3A4 substrates or inhibitors
• No other concurrent investigational agent
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent chlorpromazine, amiodarone, or chloroquine

--Patient Characteristics--

• Age: Over 18
• Performance status: 0-1
• Life expectancy: Not specified
• Hematopoietic: Granulocyte count at least 1,500/mm3;Platelet count at least 100,000/mm3
• Hepatic: Bilirubin no greater than 1.5 times upper limit of normal (ULN)
• SGOT no greater than 2.5 times ULN
• Renal: Creatinine no greater than 1.5 times ULN
• Cardiovascular: No symptomatic congestive heart failure
• No unstable angina pectoris
• No cardiac arrhythmia
• Other: Not pregnant or nursing
• Fertile patients must use effective contraception
• No other concurrent active malignancy except nonmelanomatous skin cancer
• Disease considered not currently active if completely treated with less than a 30% risk for relapse
• No other concurrent uncontrolled illness
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance

OUTLINE

• This is a multicenter study.
• Patients receive oral ZD 1839 once daily on days 1-21. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
• Patients are followed every 2 months for 1 year and then every 6 months for up to 3 years.

STRATIFICATION

• Not abstracted

SPECIAL STUDY PARAMETERS

• Not abstracted

END POINTS

• Not abstracted

PROJECTED ACCRUAL

• A total of 40 patients will be accrued for this study within 7-10 months.

WARNING

The purpose of most clinical trials listed in this database is to test new cancer treatments, or new methods of diagnosing, screening, or preventing cancer. Because all potentially harmful side effects are not known before a trial is conducted, dose and schedule modifications may be required for participants if they develop side effects from the treatment or test. The therapy or test described in this clinical trial is intended for use by clinical oncologists in carefully structured settings, and may not prove to be more effective than standard treatment. A responsible investigator associated with this clinical trial should be consulted before using this protocol.

DOSAGE SCHEDULE

• Not abstracted

DOSAGE FORMS

• Not abstracted

PARTICIPATING ORGANIZATIONS/STUDY CONTACTS

• Ramaswamy Govindan, Chair Ph: 314-362-4819

• Cancer and Leukemia Group B

STUDY CONTACTS

Alabama -- California -- Delaware -- District of Columbia -- Florida -- Illinois -- Indiana -- Iowa -- Maine -- Maryland -- Massachusetts -- Minnesota -- Missouri -- Nebraska -- Nevada -- New Hampshire -- New York -- North Carolina -- Ohio -- Pennsylvania -- Rhode Island -- South Carolina -- Tennessee -- Vermont -- Virginia

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*** POSTED APRIL 17, 2002 ***