GW786034 in Patients With Non Small Cell Lung Cancer 3rd Line
Condition: Non Small Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Pazopanib (GW786034)
Intervention description: Pazopanib 800 mg daily x 12 weeks, (Cycle = 21 days) up to 24 months
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Lung Cancer Non Small Cell

Summary:

      Lung Cancer is the most common cause of cancer death in the United States with an estimated
      mortality in excess of 160,000, more than the combined mortality seen with prostate, breast,
      colorectal cancers(1). Most patients with Lung Cancer have Non-Small Cell Lung Cancers(
      NSCLC) and only 25-30% of patients with NSCLC (Non Small Cell Lung Cancer) have resectable
      disease( Stage I or II) at the time of diagnosis.

      The vast majority of patients with advanced NSCLC (Non Small Cell Lung Cancer) are not
      curable and overall five year survival is 11%-14%1.

      Chemotherapy is beneficial for patients with locally advanced and metastatic disease.
      Numerous phase III studies have determined the superiority of systemic chemotherapy over best
      supportive care. Platinum based chemotherapy has been widely accepted as the standard of care
      for the initial treatment of advanced NSCLC.

      However first line chemotherapy is modest at best. A randomized trial comparing four of the
      most commonly used chemotherapy regimens in the United States not only failed to show a
      clearly superior arm but also confirmed the dismal prognosis of these patients. The response
      rate for all 1207 patients was 18.6% with a median survival of eight months and one year
      survival of 33.5 % and a two year survival of 12%5. Clearly a different paradigm is needed
      for the treatment of this disease.
    

Eligibility criteria:

        Inclusion Criteria:

        Required Characteristics 3.1. Subjects must provide written informed consent prior to
        performance of study-specific procedures or assessments, and must be willing to comply with
        treatment and follow up. Procedures conducted as part of the subject's routine clinical
        management (e.g., blood count, imaging study) and obtained prior to signing of informed
        consent may be utilized for screening or baseline purposes provided these procedures are
        conducted as specified in the protocol.

        Note: It is not necessary that informed consent be obtained within the protocol-specified
        screening window.

        3.11 ≥18 years of age.

        3.12 ≥2 prior systemic therapies for Non Small Cell Lung Cancer.

        3.13 Histologic or cytologic diagnosis of stage IV Non Small Cell Lung cancer

        . 3.14 Measurable disease. For patients having only lesions measuring ≥1 cm to ≤2 cm per
        RECIST criteria must use spiral CT imaging for both pre- and post-treatment tumor
        assessments.

        3.15 Laboratory values obtained ≤14 days prior to registration: Hematologic Absolute
        neutrophil count (ANC) 1.5 X 109/L Hemoglobin1 9 g/dL (5.6 mmol/L) Platelets 100 X 109/L
        Prothrombin time (PT) or international normalized ratio (INR) 1.2 X upper limit of normal
        (ULN) Partial thromboplastin time (PTT) 1.2 X ULN Hepatic2 Total bilirubin 1.5 X ULN AST
        and ALT 2.5 X ULN Renal Serum creatinine 1.5 mg/dL (133 µmol/L)

        Or, if greater than 1.5 mg/dL:

        Calculated creatinine clearance 50 mL/min

        Urine Protein to Creatinine Ratio (UPC)3 < 1

          1. Subjects may not have had a transfusion within 7 days of screening assessment.

          2. Concomitant elevations in bilirubin and AST/ALT above 1.0 x ULN are not permitted

          3. If UPC >/= 1, then a 24-hour urine protein must be assessed. Subjects must have a
             24-hour urine protein value <1g to be eligible.

             3.16 ECOG Performance Score 0, or 1.

             3.17 Negative pregnancy test done ≤ 7 days prior to registration, for women of
             childbearing potential only.

             A female is eligible to enter and participate in this study if she is of:
             Non-childbearing potential (i.e., physiologically incapable of becoming pregnant),
             including any female who has had:

               -  A hysterectomy

               -  A bilateral oophorectomy (ovariectomy)

               -  A bilateral tubal ligation

               -  Is post-menopausal

             Subjects not using hormone replacement therapy (HRT) must have experienced total
             cessation of menses for ≥ 1 year and be greater than 45 years in age, OR, in
             questionable cases, have a follicle stimulating hormone (FSH) value >40 mIU/mL and an
             estradiol value < 40pg/mL (<140 pmol/L).

             Subjects using HRT must have experienced total cessation of menses for >= 1 year and
             be greater than 45 years of age OR have had documented evidence of menopause based on
             FSH and estradiol concentrations prior to initiation of HRT

             Childbearing potential, including any female who has had a negative serum pregnancy
             test within 1 week prior to the first dose of study treatment, preferably as close to
             the first dose as possible, and agrees to use adequate contraception. GSK acceptable
             contraceptive methods, when used consistently and in accordance with both the product
             label and the instructions of the physician, are as follow:

               -  An intrauterine device with a documented failure rate of less than 1% per year.

               -  Vasectomized partner who is sterile prior to the female subject's entry and is
                  the sole sexual partner for that female.

               -  Complete abstinence from sexual intercourse for 14 days before exposure to
                  investigational product, through the dosing period, and for at least 21 days
                  after the last dose of investigational product.

               -  Double-barrier contraception (condom with spermicidal jelly, foam suppository, or
                  film; diaphragm with spermicide; or male condom and diaphragm with spermicide).

               -  Oral contraceptives

               -  Female subjects who are lactating should discontinue nursing prior to the first
                  dose of study drug and should refrain from nursing throughout the treatment
                  period and for 14 days following the last dose of study drug

             3.18 Ability and willingness to provide informed consent.

             3.19 Life expectancy ≥12 weeks.

             -

             Exclusion Criteria:

             3.21 Any of the following as this regimen may be harmful to a developing fetus or
             nursing child.

             • Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential or their sexual partners who are unwilling
                  to employ adequate contraception.

             3.22 Any abnormal serum calcium, magnesium, and potassium levels

             3.23 Clinically significant hemoptysis, cerebral hemorrhage, or gastrointestinal
             hemorrhage in the past 6 months

             3.24 Any patient currently on an antiarrhythmics or other medications that are know to
             prolong the QT interval.

             3.25 Uncontrolled infection.

             3.26 Poorly controlled hypertension [defined as systolic blood pressure (SBP) of ≥140
             mmHg or diastolic blood pressure (DBP) of ≥ 90mmHg].

             Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to
             study entry. BP must be re-assessed on two occasions that are separated by a minimum
             of 1 hour; on each of these occasions, the mean (of 3 readings) SBP / DBP values from
             each BP assessment must be <140/90 mmHg in order for a subject to be eligible for the
             study

             3.27 Any condition (e.g., gastrointestinal tract disease resulting in an inability to
             take oral medication or a requirement for IV alimentation, prior surgical procedures,
             affecting absorption, or active peptic ulcer disease) that impairs their ability to
             swallow and retain pazopanib tablets.

               -  Malabsorption syndrome

               -  Major resection of the stomach or small bowel. 3.28 Clinically significant
                  gastrointestinal abnormalities that may increase the risk for gastrointestinal
                  bleeding including, but not limited to:

               -  Active peptic ulcer disease

               -  Known intraluminal metastatic lesion/s with risk of bleeding

               -  Inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease), or other
                  gastrointestinal conditions with increased risk of perforation

               -  History of abdominal fistula, gastrointestinal perforation, or intra abdominal
                  abscess within 28 days prior to beginning study treatment.

             3.29 Known endobronchial lesions and or lesions infiltrating major pulmonary vessels.

             3.30 Cavitary lesions deemed to be at increased risk of bleeding.

             3.31 Any other severe underlying diseases that are, in the judgment of the
             investigator, inappropriate for entry into this study.

             3.32 Second primary malignancy except for carcinoma in situ of the cervix or
             nonmelanomatous skin cancer, unless that prior malignancy was diagnosed and
             definitively treated ≥5 years previously with no subsequent evidence of recurrence.
             Patients with a history of low-grade (Gleason score ≤6) localized prostate cancer will
             be eligible even if diagnosed <5 years prior to registration.

             3.33 Any ancillary therapy considered investigational (utilized for a non-FDA approved
             indication and in the context of a research investigation) ≤4 weeks prior to
             registration.

             3.34 Other concurrent chemotherapy, immunotherapy, radiotherapy.

             3.35a. History of allergic reactions attributed to compounds of similar chemical or
             biologic composition to pazopanib or other agents used in the study.

             b. Medications that act through the CYP450 system. Some medications that act through
             the cytochrome P450 system are specifically prohibited in patients receiving
             pazopanib. Certain other agents should be used with caution. (A list of medications
             that are specifically prohibited or that should be used with caution during this trial
             of pazopanib will be provided with the full study protocol as Appendix 1. A list of
             selected agents that could affect pazopanib will be listed in Appendix I. ) c. Any of
             the following concurrent severe and/or uncontrolled medical conditions:

             • Serious or non-healing wound, ulcer, or bone fracture

             • History of abdominal fistula, diverticulosis, gastrointestinal perforation, or
             intra-abdominal abscess ≤28 days prior to registration

               -  Any history of cerebrovascular accident (CVA) ≤6 months prior to registration

               -  History of any one or more of the following cardiovascular conditions within the
                  past 6 months:

               -  Cardiac angioplasty or stenting

               -  Myocardial infarction

               -  Unstable angina

               -  Coronary artery bypass graft surgery

               -  Symptomatic peripheral vascular disease

               -  Class III or IV congestive heart failure, as defined by the New York Heart
                  Association (NYHA)

               -  History of venous thrombosis ≤12 weeks prior to registration.

               -  Class III or IV heart failure as defined by the NYHA functional classification
                  system .History of Class II heart failure and is asymptomatic on treatment may be
                  considered eligible.

               -  Poorly controlled diabetes.

               -  Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the
                  lung.

               -  QTc prolongation (defined as a QTc interval ) > 480 msecs using Bazett's formula)
                  or other significant ECG abnormalities d. Symptomatic, untreated, or uncontrolled
                  CNS metastases or seizure disorder. Patients with CNS metastases treated with
                  whole brain radiation (WBRT)or gamma knife may be enrolled after completion of
                  WBRT or gamma knife. Patients may begin chemotherapy as early as the next day
                  after completion of WBRT or gamma knife.

                  e. Uncontrolled intercurrent illness including, but not limited to, ongoing or
                  active infection or psychiatric illness/social situations that would limit
                  compliance with study requirements.

                  f. HIV-positive patients on combination antiretroviral therapy because of the
                  potential for pharmacokinetic interactions with pazopanib. In addition, these
                  patients are at increased risk of lethal infections when treated with marrow
                  suppressive therapy

                  g. Any of the following prior therapies:

               -  Major surgery (i.e., laparotomy), open biopsy, or significant traumatic injury ≤4
                  weeks prior to registration. Minor surgery ≤4 weeks prior to registration.
                  Insertion of a vascular access device is not considered major or minor surgery in
                  this regard.

               -  Treatment with any of the following anti-cancer therapies:

               -  radiation therapy, surgery or tumor embolization within 14 days prior to the
                  first dose of Pazopanib OR

               -  chemotherapy, immunotherapy, biologic therapy, investigational therapy or
                  hormonal therapy within 14 days or five half-lives of a drug (whichever is
                  longer) prior to the first dose of pazopanib

             Patients with progressive disease inside of the radiation field are not eligible.

             3.36 History of cerebrovascular accident including transient ischemic attack (TIA),
             pulmonary embolism or untreated deep venous thrombosis (DVT) within the past 6 months.

             Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulating
             agents for at least 6 weeks are eligible

             3.37 Evidence of active bleeding or bleeding diathesis.

             3.38 Hemoptysis within 6 weeks of first dose of study drug.

             3.39 Unable or unwilling to discontinue use of prohibited medications for at least 14
             days or five half-lives of a drug (whichever is longer) prior to the first dose of
             study drug and for the duration of the study.

             3.40 Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 and/or that
             is progressing in severity, except alopecia.

             3.41 Other Eligibility Criteria Considerations To assess any potential impact on
             subject eligibility with regard to safety, the investigator must refer to the
             following document(s) for detailed information regarding warnings, precautions,
             contraindications, adverse events, and other significant data pertaining to the
             investigational product(s) being used in this study: Clinical Investigator's Brochure
             for pazopanib.[Investigator Brochure]

             -