Pazopanib in Molecularly Selected Patients With Advanced NSCLC
Condition: Carcinoma, Non-Small Cell Lung; Non-Small Cell Lung Cancer; Nonsmall Cell Lung Cancer
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Pazopanib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 16.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Advanced Non-Small Cell Lung Cancer; NSCLC; Pazopanib

Summary:

      The purpose of this study is to evaluate how participants with advanced non-small cell lung
      cancer (NSCLC) that have certain abnormalities in the pazopanib target genes respond to
      pazopanib treatment.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed diagnosis of advanced (metastatic or unresectable) non-small
             cell lung cancer (NSCLC) with mutations, rearrangement and fusion involving RET
             oncogene, or abnormalities in the pazopanib target genes defined as VEGFR1-3, PDGFRA,
             PDGFRB, or TP53 with abnormalities including deletion, insertion, early stop codon,
             and/or nonsynonymous mutations with functional consequences. CLIA certified lab
             testing for pazopanib target genes using cell free DNA from peripheral blood and/or
             assays performed on tumor tissues are acceptable.

          -  Evaluable disease by imaging or physical exam OR measurable disease defined as at
             least one lesion that can be accurately measured in at least one dimension (longest
             diameter to be recorded) as ≥ 10 mm with CT scan, as ≥ 20 mm by chest x-ray, or ≥ 10
             mm with calipers by clinical exam.

          -  Failed at least one standard chemotherapeutic treatment for NSCLC.

          -  At least 18 years of age.

          -  ECOG performance status ≤ 2

          -  Normal bone marrow and organ function as defined below:

               -  Absolute neutrophil count ≥ 1,500/mcl

               -  Platelets ≥ 100,000/mcl

               -  Hemoglobin ≥ 9.0 g/dL

               -  PT or INR ≤ 1.2 x IULN

               -  aPTT ≤ 1.2 x IULN

               -  Total bilirubin ≤ 1.5 x IULN

               -  AST(SGOT)/ALT(SGPT) ≤ 2.5 x IULN

               -  Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 30 mL/min/1.73 m2 for patients
                  with creatinine levels above 1.5 mg/dL

               -  UPC < 1 or, if UPC ≥ 1, 24-hour urine protein < 1 g; use of urine dipstick for
                  renal function assessment is not acceptable.

          -  Patients receiving anticoagulation therapy are eligible if their INR is stable and
             within the recommended range for the desired level of anticoagulation.

          -  Ability to swallow and retain oral tablets.

          -  Women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control, abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while participating in this study, she must inform her treating physician
             immediately.

          -  Ability to understand and willingness to sign an IRB approved written informed consent
             document.

        Exclusion Criteria:

          -  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, investigational therapy or hormonal therapy within
                  14 days prior to the first dose of pazopanib

          -  Prior treatment with any VEGFR tyrosine kinase inhibitor.

          -  Administration of any non-oncologic investigational drug within 30 days or 5
             half-lives (whichever is longer) prior to the first dose of pazopanib.

          -  Use of a strong CYP3A4 inhibitor less than 14 days prior to initiation of study
             treatment

          -  A history of other malignancy ≤ 5 years previous with the exception of basal cell or
             squamous cell carcinoma of the skin which were treated with local resection only or
             carcinoma in situ of the cervix.

          -  Symptomatic brain metastases. Patients with known brain metastases are allowed if they
             are asymptomatic.

          -  A history of allergic reactions attributed to compounds of similar chemical or
             biologic composition to pazopanib or other agents used in the study.

          -  Any ongoing toxicity from prior anti-cancer therapy that is > grade 1 and/or that is
             progressing in severity (except alopecia). Any IO related adverse events must be ≤
             grade 1 to be eligible.

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, uncontrolled seizure disorder, chronic underlying liver disease unrelated
             to cancer, or psychiatric illness/social situations that would limit compliance with
             study requirements.

          -  Corrected QT interval (QTc) > 480 msecs.

          -  History of any one or more of the following cardiovascular conditions within the past
             6 months: cardiac angioplasty or stenting, myocardial infarction, unstable angina
             pectoris, coronary artery bypass graft surgery, symptomatic peripheral vascular
             disease, class III or IV congestive heart failure as defined by the New York Heart
             Association (see Appendix B).

          -  Poorly controlled hypertension (defined as systolic blood pressure of ≥ 140 mmHg or
             diastolic blood pressure of ≥ 90 mmHg). Note: initiation or adjustment of
             antihypertensive medication(s) is permitted prior to study entry. Following
             antihypertensive medication initiation or adjustment, blood pressure must be
             reassessed three times at approximately 2-minute intervals. At least 24 hours must
             have elapsed between antihypertensive medication initiation or adjustment and blood
             pressure measurement. These three values should be averaged to obtain the mean
             diastolic and systolic blood pressures, which must be < 140/90 mmHg in order for a
             patient to be eligible for the study.

          -  Clinically significant gastrointestinal abnormalities that may increase the risk for
             gastrointestinal bleeding, including (but not limited to) active peptic ulcer disease,
             known intraluminal metastatic lesions with risk of bleeding, inflammatory bowel
             disease (e.g., ulcerative colitis, Crohn's disease) or other GI conditions with
             increased risk of perforation, history of abdominal fistula or intra-abdominal abscess
             within 28 days prior to beginning study treatment.

          -  Clinically significant gastrointestinal abnormalities that may affect absorption of
             pazopanib, including (but not limited to) malabsorption syndrome or major resection of
             the stomach or small bowel.

          -  History of cerebrovascular accident including transient ischemic attack, pulmonary
             embolism (including asymptomatic or previously treated PE), or untreated deep venous
             thrombosis within the past 6 months. Patients with recent DVT who have been treated
             with therapeutic anti-coagulating agents for at least 6 weeks are eligible.

          -  Major surgery or trauma within 28 days prior to first dose of pazopanib and/or
             presence of any non-healing wound, fracture, or ulcer (procedures such as catheter
             placement not considered to be major surgery).

          -  Evidence of active bleeding or bleeding diathesis.

          -  Known endobronchial lesions and/or lesions infiltrating major pulmonary vessels that
             increase the risk of pulmonary hemorrhage. Note: lesions infiltrating major pulmonary
             vessels (contiguous tumor and vessels) are excluded; however, the presence of a tumor
             that is touching but not infiltrating (abutting) the vessels is acceptable (CT with
             contrast is strongly recommended to evaluate such lesions). Large protruding
             endobronchial lesions in the mail or lobar bronchi are excluded; however,
             endobronchial lesions in the segmented bronchi are allowed. Lesions extensively
             infiltrating the main or lobar bronchi are excluded; however, minor infiltrations in
             the wall of thee bronchi are allowed.

          -  Recent hemoptysis (≥ ½ teaspoon of red blood within 8 weeks before first dose of
             pazopanib).

          -  Pregnant and/or breastfeeding. Patient must have a negative serum pregnancy test
             within 14 days of study entry.

          -  Known HIV-positivity. Appropriate studies will be undertaken in patients receiving
             combination antiretroviral therapy when indicated.