PF-00299804 in Stage IIIB or Stage IV Non-Small Cell Lung Cancer Not Responding to Standard Therapy for Advanced or Metastatic Cancer
Condition: Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: PF-00299804; Placebo
Intervention description: PF-804 45 mg PO, daily; Placebo 45 mg PO, daily
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 720.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stage IIIB non-small cell lung cancer; stage IV non-small cell lung cancer; recurrent non-small cell lung cancer

Summary:

      RATIONALE: PF-00299804 may stop the growth of tumor cells by blocking some of the enzymes
      needed for cell growth. It is not yet known whether PF-00299804 is more effective than a
      placebo in treating patients with advanced non-small cell lung cancer.

      PURPOSE: This randomized phase III trial is studying PF-00299804 to see how well it works
      compared with a placebo in treating patients with stage IIIB or stage IV non-small cell lung
      cancer that has not responded to standard therapy for advanced or metastatic cancer.
    

Eligibility criteria:

        Eligibility Criteria

          -  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.

        Ineligibility Criteria

        Patients who fulfill any of the following criteria are not eligible for admission to the
        study:

          -  Patients receiving concurrent treatment with other experimental drugs or anti-cancer
             therapy.

          -  Patients who have experienced untreated and/or uncontrolled cardiovascular conditions
             and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart
             failure, myocardial infarction within the previous year or cardiac ventricular
             arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular
             conduction defects). Patients with a significant cardiac history, even if controlled,
             should have a LVEF > 50%.

          -  Patients with untreated brain or meningeal metastases are not eligible (CT scans are
             not required to rule this out unless there is a clinical suspicion of CNS disease).
             Patients with treated CNS disease who have radiologic or clinical evidence of stable
             brain metastases, with no evidence of cavitation or hemorrhage in the brain lesion,
             are eligible providing that they are asymptomatic and do not require corticosteroids
             (must have discontinued steroids at least 1 week prior to randomization).

          -  Patients with active or uncontrolled infections, or with serious illnesses or medical
             conditions which would not permit the patient to be managed according to the protocol,
             including

               -  Severe dry eye syndrome

               -  Keratoconjunctivitis sicca

               -  Sjogren's syndrome

               -  Severe exposure keratopathy

               -  Disorders that might increase the risk for epithelium-related complications
                  (e.g., bullous keratopathy, aniridia, severe chemical burns, neutrophilic
                  keratitis)

               -  Uncontrolled inflammatory gastrointestinal diseases (Crohn's, ulcerative colitis
                  etc.)

               -  Prior pneumonitis/ILD secondary to EGFR inhibitors

          -  Mean QTc with Bazetts correction > 470msec in screening ECG or history of familial
             long QT syndrome.

          -  Drugs that are highly dependent on CYP2D6 for metabolism are prohibited, since PF-804
             is a potent CYP2D6 inhibitor in in vitro assays. These inhibitors or inducers are
             prohibited from 7 days prior to the first dose until the end of treatment with PF-804.
             These include: S-metoprolol, propafenone, timolol, amitriptyline, clomipramine,
             desipramine, imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine,
             flecainide, mexilletine, tamoxifen, venlafaxine. Lidocaine may be used with clinical
             monitoring (including telemetry). Opiates such as morphine, oxycodone, dihydrocodeine,
             hydrocodone, and tramadol can be used as substitutes to replace codeine. Use of these
             opiates should be monitored for altered analgesia during treatment with PF-804 as they
             may be partly metabolized by CYP2D6. If PF-804 is administered with drugs which are
             P-glycoprotein (P-gp) substrates and have a narrow therapeutic index, monitoring for
             exaggerated effect and/or toxicities is recommended.

          -  Pregnancy or inadequate contraception. Women must be post-menopausal, surgically
             sterile, or use two reliable forms of contraception. Women of child-bearing potential
             must have a pregnancy test taken and proven negative within 7 days prior to
             randomization. Men must be surgically sterile or use a barrier method of
             contraception.