It was unlikely that the primary endpoint would be reached based on the fifth interim analysis results.

Drugs used in chemotherapy, such as docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Gefitinib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Combining docetaxel with gefitinib may kill more tumor cells. It is not yet known whether docetaxel is more effective with or without gefitinib in treating head and neck cancer. This randomized phase III trial is studying docetaxel and gefitinib to see how well they work compared to docetaxel alone in treating patients with metastatic or locally recurrent head and neck cancer.

PRIMARY OBJECTIVES:

I. To determine the survival of poor prognosis patients with recurrent/metastatic squamous cell carcinoma of the head and neck treated with docetaxel with or without ZD1839 (Iressa, gefitinib).

SECONDARY OBJECTIVES:

I. To determine the time to progression and response rate in poor prognosis patients with recurrent/metastatic squamous cell carcinoma of the head and neck treated with docetaxel with or without ZD1839 (Iressa, gefitinib).

II. To correlate the expression and activation status of the epidermal growth factor receptor (EGFR) signaling pathway with clinical outcome in the above patient population. The following specific biomarkers will be measured by immunohistochemistry on paraffin-embedded tumor tissue: EGFR, p-EGFR, AKT, p-AKT, Transforming growth factor (TGF)-alpha, Ki-67, extracellular-signal-regulated kinase (ERK), p-ERK, p70s6, p- p70s6 , and p27.

III. To evaluate the frequency of common polymorphisms of Cytochrome P450 3A (CYP3A) and EGFR in this study population and the impact of these polymorphisms on survival, time to progression, response rate, and toxicities.

IV. To analyze docetaxel and ZD1839 (Iressa, gefitinib) pharmacokinetics and to correlate polymorphisms with pharmacokinetic variability, response, toxicity, and other endpoints.

V. To evaluate disease-related symptoms and overall quality of life among patients receiving docetaxel only to those receiving docetaxel and ZD1839 (Iressa, gefitinib).

VI. To evaluate whether additional clinical benefit associated with ZD1839 (Iressa, gefitinib) can be detected as an improvement in patient-reported symptoms on the FACT Head and Neck Symptom Index (FHNSI)-10 and GP5.

OUTLINE: This is a randomized, placebo-controlled, double-blind, multicenter study. Patients are stratified according to treatment with prior chemotherapy (pretreated vs untreated), Eastern Cooperative Oncology Group (ECOG) performance status (0 vs 1 vs 2), weight loss within the past 6 months (< 5% vs ≥ 5%), and prior cetuximab treatment (yes or no). Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive docetaxel intravenously (IV) over 30-60 minutes on days 1, 8, and 15 and oral placebo once daily on days 1-28.

Arm II: Patients receive docetaxel as in arm I and oral gefitinib once daily on days 1-28.

In both arms, courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients in arm I who have disease progression may receive single-agent oral gefitinib once daily until further disease progression (which is called step 2 in the study).

Quality of life is assessed at baseline, on days 15 and 28 of course 1, on day 28 of all subsequent courses, and at 2-4 weeks after completion of study treatment.

Patients are followed every 3 months for 2 years and then every 6 months for 3 years.

PROJECTED ACCRUAL: A total of 330 patients (165 per treatment arm) will be accrued for this study within 31.5 months.

Inclusion Criteria:

• Histologically or cytologically confirmed squamous cell carcinoma of the head and neck; patient must not have nasopharyngeal carcinoma of histologic types World Health Organization (WHO) 2 and 3

• Metastatic or locally recurrent carcinoma of the head and neck that is considered incurable by local therapies

• Any number of prior chemotherapy or biologic/targeted therapy regimens is allowed

• No prior systemic EGFR inhibitors, such as ZD1839 (Iressa, gefitinib)/Iressa (AstraZeneca), ABX-EBX (Abgenix), MDX-447 (Medarex/Merck), OSI-774/Tarceva (OSI pharmaceuticals), C225/Cetuximab (ImClone), PKI166 (Novartis), CI-1033 (Parke-Davis), EKB-569 (Wyeth Ayerst); treatment with paclitaxel is allowed if the patient did not progress while on paclitaxel

  • NOTE: the use of cetuximab given concurrently with radiation or chemoradiotherapy for up to 9 total weekly doses, as part of initial potentially curative therapy is allowed, if completed > 6 months prior to registration

• Patients must not receiving any other investigational agent while on the study

• Patients must have either:

  • Strata A:

    • Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 (in bed 50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities; up and about more than 50% of waking hours), AND no prior chemotherapy for recurrent metastatic head and neck cancer OR

  • Strata B

    • PS 0-2 AND prior chemotherapy (i.e. one or more prior chemotherapy regimens (without docetaxel)) for locally recurrent/metastatic disease or exposure to prior chemotherapy (without docetaxel) as part of primary curative therapy < 6 months prior to randomization; patients who receive chemotherapy as part of potentially curative therapy of primary disease within 6 months of randomization will be considered as having prior chemotherapy for recurrent/metastatic disease, whereas patients who received chemotherapy as part of potentially curative therapy of disease > 6 months of randomization will be considered as having no prior chemotherapy for recurrent/metastatic disease

• Patients must have fully recovered from the effects of any prior surgery, chemotherapy, or radiation therapy

  • A minimum time period of 3 weeks must elapse between the completion of radiation therapy and randomization to the study
  • A minimum period of 4 weeks must elapse between the last administration of any prior chemotherapy and randomization to the study
  • At least 2 weeks must elapse between the last administration of biologic/targeted therapy and randomization to the study
  • Patients must be > 3 weeks since major surgery, or significant traumatic injury prior to randomization

• Absolute neutrophil count (ANC) >= 1500 /mm^3

• Platelets >= 100,000 /mm^3

• Hemoglobin >= 8.0 g/dl

• Bilirubin within normal limits

• Creatinine < 2.0 or creatinine clearance of > 60 ml/min

• All females of childbearing potential must have a blood test or urine study within 2 weeks prior to randomization to rule out pregnancy

• Women of childbearing potential and sexually active males must use an accepted and effective method of contraception while on treatment and for three months after the completion of treatment

• Patients must have measurable or non-measurable disease based on Response Evaluation Criteria In Solid Tumors (RECIST); baseline measurements and evaluations must be obtained < 4 weeks of randomization; all areas of disease should be recorded and mapped out in order to assess response and uniformity of response to therapy; disease in previously irradiated sites is considered measurable if there has been unequivocal disease progression or biopsy-proven residual carcinoma following radiation therapy; persistent disease after radiotherapy must be biopsy proven at least 8 weeks after completion of radiation therapy

  • Radiographic findings are acceptable providing that clear-cut measurements can be made

• Patients with a prior history of squamous cell or basal carcinoma of the skin or in situ cervical cancer must have been curatively treated. Patients with a history of other prior malignancy must have been treated with curative intent and must have remained disease-free for 5 years post diagnosis

• Drugs that are Cytochrome P450 3A4 (CYP3A4) inhibitors should be generally avoided and if possible, discontinued, 1 week prior to initiating study drug; however, if medically necessary, they can be taken with caution after consulting with the study chair

• From patients consenting to participate in the correlative studies:

  • Tissues must be submitted as outlined in Section 10; if tissue cannot be submitted, written justification must be submitted to the ECOG Pathology Coordinating Office

Exclusion criteria:

• Prior therapy with docetaxel at any time (even if part of prior curative treatment)
• Unstable systemic disease, including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, or serious arrhythmia requiring medication
• Hypercalcemia related to head and neck cancer
• Brain metastasis
• Current peripheral neuropathy >= grade 2 at time of randomization
• Patients have co-existing condition that would preclude full compliance with the study
• Known hypersensitivity to ZD1839 (Iressa, gefitinib) or any excipients of this product; prior history of severe hypersensitivity reaction to Docetaxel or other drugs formulated with polysorbate 80
• HIV positive patient's receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with ZD1839 (Iressa, gefitinib)
• Patients have had tumor-related hemorrhagic events in the previous three months that required as major medical intervention, such as surgery or embolization
• Patients are on therapeutic anticoagulation or have tumors that are unequivocally invading major vessels (e.g. carotid artery)
• Females are pregnant or breast feeding because chemotherapy may be harmful to the fetus or the nursing infant; also, the effects of ZD1839 (Iressa, gefitinib) on the developing human fetus are unknown

The primary population was eligible and treated patients in the study. All study results were based on the primary population except for adverse event results. In total, 136 patients enrolled on arm I, but 19 patients were ineligible/no protocol therapy. 134 patients entered arm II, 12 of them were not eligible/not starting protocol therapy.

Assessed every cycle (1 cycle = 4 weeks) while on treatment and for the 30 days following the last dose of protocol drug (which was included in the form for the last cycle).

Prior to diagnosis of progression / relapse or after start of non-protocol therapy, severe (Grade ≥ 3) long term toxicity that has not been previously reported was included in the report as well.