- To compare overall survival in patients with incurable stage III or IV non-small cell lung cancer receiving PF-00299804 versus placebo after failure of standard therapy for advanced metastatic disease.
- To compare overall survival in KRAS-WT patients between the two arms.
- To compare overall survival in EGFR-mutant patients between the two arms.
- To compare progression-free survival between arms.
- To compare objective response rates between arms.
- To estimate time to response and response duration in these patients.
- To evaluate the nature, severity, and frequency of toxicities between arms.
- To compare quality of life between arms.
- To determine the incremental cost-effectiveness and cost-utility ratios for PF-00299804.
- To correlate the expression of tumor and blood markers (at diagnosis) with outcomes and response.
OUTLINE: This is a multicenter study. Patients are stratified according to center, performance status (0 or 1 vs 2 or 3), tobacco use (never vs past or present), best response to prior EGFR tyrosine kinase inhibitor (progressive disease vs other), weight loss (< 5% vs ? 5% or unknown), and ethnicity (East Asian vs other). Patients are randomized to 1 of 2 treatment arms.
- Arm I: Patients receive oral PF-00299804 once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
- Arm II: Patients receive oral placebo once daily. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
Blood, serum, plasma, and tissue samples are collected and examined for biomarkers and gene mutations, and may be banked for future studies.
Patients complete quality-of-life questionnaires EORTC QLQ-C30 and other questionnaires at baseline and then periodically during and after completion of study treatment.
Cost effectiveness and cost utility of PF-00299804 is assessed via the Health Utilities Index (EQ-5D) and the Resource Utilization Assessment periodically.
After completion of study treatment, patients are followed at 4 weeks and then every 12 weeks thereafter.
- Histologically confirmed diagnosis of non-small cell carcinoma of the lung. Patients must have an adequate histopathology or cytology specimen must consent to release of all specimens for this protocol, and the centre/pathologist must have agreed to submission of the specimens.
- Patients must have evidence of disease, but measurable disease is not mandatory. To be considered evaluable for complete or partial response assessment, patients must have at least one measurable lesion as follows:
X-ray ? 20 mm Spiral CT scan or physical exam ? 10 mm (lymph nodes must be ? 15 mm in the short axis); Measurable lesions must be outside a previous radiotherapy field if they are the sole site of disease, unless disease progression has been documented.
- Male or female, 18 years of age or older.
- ECOG performance status of 0, 1, 2 or 3. Patients with performance status of 3 are eligible providing that the investigator attests that the patient has a reasonable life expectancy (? 6 weeks).
- Adequate renal and hepatic functions as defined by the following required laboratory values obtained within 14 days prior to randomization. If anemic, patients should be asymptomatic and should not be decompensated.
Creatinine <1.5 upper limit of normal Total bilirubin < 1.5 upper limit of normal ALT (SGPT) < 2.5 times the upper limit of normal. Note: If clearly attributable to liver metastasis, ALT (SGPT) values < 5 times the upper limit of normal are permitted.
- Previous Therapy Failure of a treatment regimen is defined as the inability to continue a regimen for any reason including, but not limited to, progressive disease, toxicity, or patient request. Up to a maximum of three lines of chemotherapy for advanced/metastatic disease (defined below) and at least one of erlotinib or gefitinib for advanced/ metastatic disease (defined below) should have failed.
Exchange of one chemotherapy agent for another within a combination chemotherapy regimen is not considered a new regimen in the following circumstances
- carboplatin is substituted for cisplatin due to nephrotoxicity
- one agent in the combination regimen is changed due to hypersensitivity occurring in the first cycle.
Chemotherapy for Advanced/Metastatic Disease:
Patients must have recovered from any reversible toxic effects and at least 21 days must have elapsed from the last dose and prior to randomization (14 days from the last dose for chemotherapy regimens administered on a weekly schedule). Further palliative cytotoxic chemotherapy must not be planned.
Patients < 70 years:
? Must have received 1 and up to a maximum of 3prior chemotherapy regimens (at least one of the three must have been a combination regimen and at least one must have contained platinum).
Patients ? 70 years (generally accepted as being at the time of the administration of the first regimen of chemotherapy for advanced disease):
? Must have received 1 and up to a maximum of 3 prior chemotherapy regimens for their disease. These may have been single agent chemotherapy regimens and a platinum agent is not required in keeping with current standards of practice.
Adjuvant Chemotherapy: Patients may ALSO have had prior adjuvant therapy for completely resected disease, providing completed at least 12 months prior to randomization. Adjuvant regimens < 12 months prior to randomization and combined chemotherapy/radiation regimens for irresectable locally advanced stage III disease (irrespective of timing), are considered to be for advanced/metastatic disease and constitute one of the 3 permissible regimens. Patients must have recovered from any reversible treatment related toxicities prior to randomization.
EGFR Inhibitor Therapy: Patients may only be enrolled after failure of prior gefitinib or erlotinib for advanced or metastatic disease. Patients who have received adjuvant gefitinib or erlotinib for completely resected NSCLC and who have recurred < 12 months after discontinuing erlotinib or gefitinib are eligible. Patients who received gefitinib or erlotinib for neoadjuvant therapy only are not eligible. EGFR inhibitor therapy must have been discontinued at least 21 days prior to randomization. Patients who discontinued prior gefitinib or erlotinib therapy for severe or life threatening organ toxicity are not eligible. Patients may also have received other EGFR active agents (such as reversible oral agents or monoclonal antibodies or vaccines) in addition to erlotinib or gefitinib but may not have received ANY prior irreversible EGFR inhibitor such as BIBW2992, HKI-272 (neratinib).
Maintenance Therapy: The same chemotherapy or agent/s continued for longer than 4-6 cycles for the purposes of 'maintenance' is considered one regimen; if another chemotherapy agent is given with 'maintenance' intent, it is considered a second regimen providing that 'failure' is documented. Patients who received erlotinib or gefitinib with 'maintenance' intent after completion of 1st line chemotherapy are eligible providing that 'failure' is documented.
Radiation: Patients may have had prior radiation therapy provided that a minimum of 14 days has elapsed between the end of radiotherapy and randomization onto the study. (Exceptions may be made however, for low dose, non-myelosuppressive radiotherapy. Patients must have recovered from any acute toxic effects from radiation prior to randomization.
Previous Surgery: Previous surgery is permitted provided that wound healing has occurred and at least 14 days have elapsed (major surgery).
- Patient able (i.e. sufficiently fluent) and willing to complete the quality of life questionnaires. The baseline assessment must already have been completed. Inability (illiteracy, loss of sight, or other equivalent reason) to complete the questionnaires will not make the patient ineligible for the study. However, ability but unwillingness to complete the questionnaires will make the patient ineligible.
- Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate.
- Patients must be accessible for treatment and follow-up. All randomized patients must be followed and treated at participating centres. Investigators must assure themselves the patients randomized on this trial will be available for complete documentation of the treatment, adverse events, and follow-up.
- In accordance with NCIC CTG policy, protocol treatment is to begin within 2 working days of patient randomization.
Patients who fulfill any of the following criteria are not eligible for admission to the study: