A Study to Evaluate Pazopanib in Comparison to Pemetrexed in Maintenance Setting in Non-progressing Subjects With Metastatic Stage IVA and IVB Non-squamous Non-small Cell Lung Cancer (NSCLC) Population
Condition: Lung Cancer, Small Cell
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Small Cell Lung Carcinoma
Intervention: pazopanib; pemetrexed
Intervention description: oral agent, administered at 800 mg daily (400 mg tablets x 2). Dose can be reduced, interrupted or discontinued due to adverse events or intolerance; pemetrexed IV 500 mg/m2 once every 3 weeks
Intervention MeSH terms: Pemetrexed
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: GW786034; non-small cell lung cancer; NSCLC; pemetrexed; pazopanib

Summary:

      This is a Phase II, randomized, open-label, multi-center study in advanced (Stage IVA and IVB
      subjects per the International Association for the Study of Lung Cancer (IASLC) 2009 Lung
      cancer staging schema) non-squamous NSCLC subjects comparing pazopanib relative to pemetrexed
      in the maintenance setting. Subjects should have completed 4-6 cycles of induction therapy
      with carboplatin + pemetrexed or cisplatin + pemetrexed and have had Stable Disease (SD),
      Partial Response (PR) or Complete Response (CR) as the best response to be enrolled into the
      study. The primary objective is to estimate the hazard ratio of progression free survival
      (PFS) in advanced NSCLC subjects given maintenance therapy of pazopanib (Arm A) relative to
      pemetrexed (Arm B). The secondary objectives are: overall survival, response rates, safety
      and tolerability. A total of approximately 200 subjects will be enrolled and randomized in a
      1:1 ratio. Safety and efficacy assessments will be regularly performed on all subjects.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Signed written Informed Consent.

          -  Subjects must complete 4 to 6 cycles of chemotherapy with carboplatin + pemetrexed or
             cisplatin + pemetrexed and have had SD, PR or CR at the time of screening/enrolment as
             the best response.

          -  Prior surgery and/or localized irradiation for NSCLC is permitted as long as it was a
             minimum of 4 weeks before entering the study. Subjects with recurrence after previous
             NSCLC that has been treated with surgery and adjuvant chemotherapy or a
             radio-chemotherapy regimen with curative intent are eligible, provided 1 year has
             passed since this treatment ended.

          -  Histologically or cytologically confirmed diagnosis of predominantly non-squamous cell
             Stage IVA Wet (with cytology positive Malignant Pleural Effusion (MPE)) or Stage IVB
             (metastatic) NSCLC.

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

          -  Life expectancy of at least 12 weeks.

          -  Must have measurable disease per Response Evaluation Criteria In Solid Tumors
             (RECIST). A measurable lesion is defined as a lesion that can be accurately measured
             in at least one dimension with the longest diameter ≥ 20 mm using conventional
             techniques, or ≥ 10 mm with spiral computed tomography (CT) scan.

          -  Able to swallow and retain oral medication.

          -  Adequate organ system function.

          -  Women of childbearing potential must have a negative pregnancy test within <= 7 days
             prior to administration or dispensing of study treatment and agree to use effective
             contraception.

          -  Age ≥ 18 years of legal age of consent if different from 18 years.

        Exclusion Criteria:

          -  History of active or any other malignancy other than lung cancer in the 2 yrs prior to
             the first dose of study drug other than NSCLC. Exception: Subjects with a history of
             completely resected non-melanomatous skin carcinoma or successfully treated in situ
             carcinoma are eligible.

          -  History or clinical evidence of central nervous system (CNS) metastases or
             leptomeningeal carcinomatosis, except for individuals who have previously-treated CNS
             metastases, are asymptomatic, and have had no requirement for steroids or anti-
             seizure medications for 4 months prior to first dose of study drug. Screening with CNS
             imaging studies (computed tomography [CT] or magnetic resonance imaging [MRI]) is
             required only if clinically indicated or if the subject has a history of CNS
             metastases.

          -  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

          -  Clinically significant gastrointestinal abnormalities that may affect absorption of
             investigational product including, but not limited to:

        Malabsorption syndrome Major resection of the stomach or small bowel

          -  Presence of uncontrolled infection.

          -  Corrected QT interval (QTc) > 480 msecs using Bazett's formula

          -  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).

        - 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. Blood pressure (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.

          -  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.

          -  Prior major surgery or trauma within 28 days prior to first dose of study drug and/or
             presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
             placement not considered to be major).

          -  Evidence of active bleeding or bleeding diathesis.

          -  Recent hemoptysis (>=½ teaspoon of red blood within 8 weeks before first dose of study
             drug).

          -  Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels (Note:
             tumor abutting the vessel is acceptable, but contiguous tumor and vessel is not; CT
             with contrast is strongly recommended to evaluate such lesions).

          -  Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
             would make the subject inappropriate for study participation including any serious
             condition that could interfere with subject's safety, provision of informed consent,
             or compliance to study procedures.

          -  Use of any prohibited medication within the timeframes listed in the protocol.

          -  Prior use of an investigational agent within 28 days or 5 half-lives, whichever is
             longer, prior the first dose of study drug.

          -  Any ongoing toxicity from prior anti-cancer therapy that is >Grade 1 (except the value
             for hemoglobin; see Table 1) and/or that is progressing in severity, except alopecia.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to pazopanib and/or pemetrexed.

          -  Inability to interrupt aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs)
             2 days before, the day of, and 2 days after the dose of pemetrexed. If a subject is
             taking an NSAID (COX-2 inhibitors included) or salicylate with a long half-life (e.g.

        naproxen, piroxicam, diflusinal, nabumetone, rofecoxib, or celecoxib) it should not be
        taken 5 days before, the day of, and 2 days after the dose of pemetrexed.

          -  Inability or unwillingness to take folic acid, vitamin B12 supplementation, or
             dexamethasone.

          -  Have clinically significant third-space fluid collections (e.g., ascites or pleural
             effusions) that cannot be controlled by drainage or other procedures prior to Day 1,
             Cycle 1.

          -  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