Pazopanib As Pre-Surgical Therapy In Treatment-Naive Subjects With Non-Small Cell Lung Cancer
Condition: Non-Small Cell Lung Cancer; Lung Cancer, Non-Small Cell
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Pazopanib
Intervention description: Pazopanib is an oral, potent, multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, PDGFR-alpha and -beta and c-kit. Subjects were to receive 800 mg oral pazopanib daily for a minimum of 2 weeks to a maximum of 6 weeks.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: pazopanib; I-ELCAP; non-small cell lung cancer; antiangiogenesis; NSCLC; GW786034

Summary:

      This is a phase 2 open-label, multicenter, non-randomized study to evaluate the safety and
      efficacy of oral pazopanib as neoadjuvant treatment for patients with stage 1A, 1B, IIA or
      IIB (to T2) resectable Non-Small Cell Lung Cancer (NSCLC).
    

Eligibility criteria:

        Inclusion criteria:

          -  Signed, written informed consent provided prior to performing any study-specific
             procedures or assessments. Subject must be willing to comply with treatment and
             follow-up.

          -  Subjects ≥21 years of age with a life expectancy of ≥12 weeks

          -  The time between initial diagnosis and the scheduled surgery date allows for the
             subject to receive a minimum of 2 weeks or a maximum of 6 weeks treatment with
             pazopanib. Note: At least 4 weeks must be available between the diagnostic biopsy and
             surgery to allow for 1) one-week delay following the diagnostic biopsy prior to first
             dose of study drug, 2) minimum of 2 weeks on study drug, and 3) minimum of 1 week wash
             out prior to surgery.

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 or 1.

          -  Histologically- or cytologically-confirmed Stage IA, IB, IIA, or IIB (to T2) NSCLC
             according to the International Staging System [Mountain, 1997] and must be scheduled
             for surgical resection.

          -  Disease must consist of only a single lesion and must be measurable according to
             high-resolution CT scan-assisted volumetric measurement [Yankelevitz, 2000, Armato,
             2004]. In addition to the measurable single lesion, other small indeterminate nodules
             may also be present

          -  No approved or investigational anti-cancer therapy concurrently or in the 6 months
             prior to start of study drug, including surgery, tumor embolization, chemotherapy,
             radiation therapy, immunotherapy, hormone therapy, biologic therapy, or
             anti-angiogegneic therapy (e.g., inhibitors of VEGF or VEGFR).

          -  Fresh tumor biopsy for apoptosis and relevant biomarker analyses must be obtained
             within 30 to 8 days of first dose of study drug and must be available for all subjects
             prior to start of pazopanib treatment.

          -  System (Laboratory Values)

          -  Hematologic:Absolute neutrophil count (ANC)(≥ 1.5 X 109/L), Hemoglobin (≥9 g/dL),
             Platelets(≥100 X 109/L)

          -  Hepatic:Albumin (≥ 2.5 g/dL), Serum bilirubin(≤1.5 X upper limit of normal (ULN)
             unless due to Gilbert's syndrome), aspartate aminotransferase (AST) and alanine
             aminotransferase (ALT) (≤2.0 X ULN) Renal:Serum creatinine(≤1.5 mg/dL) OR Calculated
             creatinine clearance (≥30 mL/min), Urine Protein (Trace or +1 by dipstick urinalysis
             or <1.0 gram determined by 24-hour urine protein analysis.)

          -  Ability to swallow and retain oral medication

          -  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 >40mIU/mL and an
             estradiol value <40pg/mL (<140pmol/L).

          -  Subjects must discontinue HRT prior to study enrollment due to the potential for
             inhibition of cytochrome P450 enzymes that metabolize estrogens and progestins. For
             most forms of HRT, at least 2-4 weeks must elapse between the cessation of HRT and
             determination of menopausal status; length of this interval depends on the type and
             dosage of HRT. If a female subject is determined not to be post-menopausal, they must
             use adequate contraception, as defined immediately below.

          -  Childbearing potential, including any female who has had a negative serum pregnancy
             test within 2 weeks prior to the first dose of study treatment, preferably as close to
             the first dose as possible, and agrees to use adequate contraception. GlaxoSmithKline
             (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) Note:
             Oral contraceptives are not reliable due to potential drug-drug interactions.

          -  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
             15 days following the last dose of study drug.

          -  A male with a female partner of childbearing potential is eligible to enter and
             participate in the study if he uses a barrier method of contraception or abstinence
             during the study.

          -  Subjects must complete all screening assessments as outlined in the protocol

        Exclusion criteria:

          -  Active malignancy or any malignancy in the 6 months prior to first dose of study drug.

          -  Concurrent disease or condition that would make the subject inappropriate for study
             participation including (1) any unresolved or unstable, serious toxicity from prior
             administration of another investigational drug, (2) any serious medical disorder that
             would interfere with the subject's safety, obtaining informed consent, or compliance
             with all study related procedures.

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks
             prior to beginning therapy, or anticipation of the need for a major surgical procedure
             during the course of the study; minor surgical procedures such as fine needle
             aspiration or core biopsy within 1 week prior to beginning therapy are also excluded.

          -  History or clinical evidence of central nervous system (CNS) metastases or
             leptomeningeal carcinomatosis. Routine screening with CNS imaging studies (computed
             tomography [CT] or magnetic resonance imaging [MRI]) is required only if clinically
             indicated.

          -  History of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.

          -  History of hemoptysis

          -  Malabsorption Syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel. Subjects with ulcerative colitis are also
             excluded

          -  Active peptic ulcer disease, inflammatory bowel disease, or other gastrointestinal
             condition increasing the risk of perforation; history of abdominal fistula,
             gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to
             beginning therapy

          -  Active or uncontrolled infection

          -  Concurrent treatment with an investigational agent or participation in another
             clinical trial.

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to pazopanib

          -  Has taken/received prohibited medications within specified timeframes.

          -  Corrected QT interval (QTc) prolongation defined as QTc interval >480 msecs

          -  History of any one of the following cardiac conditions within the past 6 months:
             cardia angioplasty or stenting, myocardial infarction,or unstable angina

          -  History of cerebrovascular accident within the past 6 months

          -  Has Class II, III or IV heart failure as defined by the New York Heart Association
             (NYHA) functional classification system.

          -  Poorly controlled hypertension (mean systolic blood pressure (SBP) of ≥140mmHg, or
             mean diastolic blood pressure (DBP) of ≥ 90mmHg. Note: Initiation or adjustment of
             anti-hypertensive medication(s) is permitted prior to study entry. The blood pressure
             (BP) must be re-assessed on two occasions that are separated by a minimum of 5
             minutes. The mean SBP/DBP values from both BP assessments must be < 140/90mmHg in
             order for a subject to be eligible for the study.

          -  History of untreated deep venous thrombosis (DVT) within the past 6 months (e.g. calf
             vein thrombosis).

          -  Presence of any non-healing wound, fracture, or ulcer, or the presence of symptomatic
             peripheral vascular disease.

          -  Receiving therapeutic warfarin or heparin as a concurrent medication. Note:
             prophylactic low-dose warfarin (less than or equal to 2 mg daily) is permitted.

          -  Evidence of bleeding diathesis or coagulopathy

          -  Pregnant or lactating female