Phase II Study Evaluating The Safety And Response To Neoadjuvant Dasatinib In Early Stage Non-Small Cell Lung Cancer
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
Intervention: Dasatinib
Intervention description: Fresh frozen tumor tissue must be available prior to initiating dasatinib. Eligible patients will receive neoadjuvant dasatinib 70 mg PO twice daily for 3 weeks followed by surgery. The surgical specimen will be evaluated for pathologic response. The second tumor sample will be obtained after 3 weeks of dasatinib therapy at the time of definitive surgical resection which will be evaluated for changes in genomic expression profiles. Patients with at least a 15% decrease or better objective response, without evidence of progression (per tumor evaluation pre-surgery) or pathologic response (as defined as ≥30% tumor necrosis or cell death) to neoadjuvant dasatinib therapy will be eligible to receive dasatinib 70 mg twice daily for 90 days after the completion of standard adjuvant therapy.
Intervention MeSH terms: Dasatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 2.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Non Small Cell Lung Cancer (NSCLC); carcinoma; dasatinib; neoadjuvant; adjuvant; resection; genomic signature; predictor; microarray

Summary:

      Src expression has been identified in a majority of Non-Small Cell Lung Cancer (NSCLC) cell
      lines and there is preclinical evidence that Src family kinases may be important in hypoxic
      growth and angiogenesis in NSCLC. We hypothesize that the inhibition of Src pathway with
      dasatinib will demonstrate anti-tumor activity in early stage NSCLC, with a tolerable safety
      profile.

      Patients will receive dasatinib, a Src inhibitor, for 3 weeks prior to surgical resection for
      early stage NSCLC. Fresh frozen tumor tissue is needed for genomic analysis. If fresh frozen
      tumor tissue is not available from the initial diagnosis, a biopsy will be required to
      participate in this trial. A second tumor sample will be obtained at time of surgical
      resection to evaluate for changes in genomic expression profiles.

      Patients will be eligible to receive 3 months of adjuvant dasatinib therapy after completion
      of standard adjuvant therapy or after recovery from surgery if no standard adjuvant therapy
      is given, if there is evidence of neoadjuvant tumor response (radiologic and/or pathologic)
      to dasatinib.

      Many patients who present with NSCLC are active smokers. Patients who are smoking up until
      the time of their surgery experience increased peri-operative complications compared to
      patients who have not smoked cigarettes immediately prior to surgery. While this trial will
      not be limited to active smokers, the period of smoking cessation prior to surgery is an
      attractive window of opportunity during which the potentially active novel anticancer therapy
      dasatinib can be offered to the patient.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Suspected or histological/cytological diagnosis of Non-Small Cell Lung Cancer (NSCLC),
             Stage IB (≥4 cm per CT) or Stage IIA or IIB, amenable to surgical resection

          -  Must be deemed a surgical candidate

          -  Tumors ≥2 cm in maximum diameter without radiographic, bronchoscopic or pathologic
             evidence of nodal metastases are eligible for biopsy

          -  Fresh tissue biopsy material must be available for genomics analysis prior to
             initiating dasatinib therapy

          -  Age ≥18 years

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2

          -  No prior chemotherapy, immunotherapy, radiation therapy or biologic/targeted therapy
             for any malignancy

          -  Adequate Organ Function:

               -  Total bilirubin <institutional upper limit normal (ULN)

               -  Hepatic enzymes (AST, ALT) ≤2.5x institutional ULN

               -  Serum creatinine <1.5x institutional ULN

               -  Hemoglobin ≥9 gm/dL

               -  Neutrophil count (ANC or AGC) ≥1500 per μL

               -  Platelets ≥100,000 per μL

               -  Prothrombin time (PT)/a partial thromboplastin time (PTT) ≤1.5x control

          -  No other serious medical or psychiatric illness

          -  Ability to take oral medication (dasatinib must be swallowed whole)

          -  Women of childbearing potential (WOCBP) must have a negative serum pregnancy test
             preferably within 72 hours and no later than 7 days, prior to the start of study drug
             administration

          -  Both sexually active males and females of reproductive potential must agree to use an
             adequate method of contraception throughout treatment and for at least 4 weeks after
             study drug is stopped

          -  Signed written informed consent including Health Insurance Portability and
             Accountability Act (HIPAA) according to institutional guidelines

        Exclusion Criteria:

          -  Previous or concomitant malignancy in the past 2 years other than curatively treated
             carcinoma in situ of the cervix, basal cell or squamous cell carcinoma of the skin

          -  Prior dasatinib therapy

          -  Evidence of pleural or pericardial effusion of any grade

          -  Cardiac Symptoms:

               -  Uncontrolled angina, congestive heart failure (CHF), or myocardial infarction
                  (MI) within 6 months

               -  Diagnosed congenital long QT syndrome

               -  Any history of clinically significant ventricular arrhythmias (such as
                  ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes)

               -  Prolonged QT corrected (QTc) interval on pre-entry EKG (>450 msec)

               -  Uncontrolled hypertension defined as >160/90 on a regimen of antihypertensive
                  therapy

          -  Subjects with hypokalemia or hypomagnesaemia if it cannot be corrected

          -  History of diagnosed congenital acquired bleeding disorders (e.g., von Willebrand's
             disease)

          -  Ongoing or recent (≤3 months) significant (≥grade 3) gastrointestinal bleeding

          -  Concomitant Medications:

               -  Drugs that are generally accepted to have a risk of causing Torsades de Pointes
                  including: (Patients must discontinue drug 7 days prior to starting dasatinib)

                  **quinidine, procainamide, disopyramide, amiodarone, sotalol, ibutilide,
                  dofetilide, erythromycin, clarithromycin, chlorpromazine, haloperidol,
                  mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone,
                  arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine,
                  sparfloxacin, lidoflazine

               -  Current therapeutic dose heparin or coumadin therapy

               -  St. John's Wort and all herbal supplements must be stopped while on dasatinib

               -  IV bisphosphonates will be withheld for 2 weeks prior and 6 weeks after dasatinib
                  administration due to risk of hypocalcaemia

          -  Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (e.g., infectious) illness

          -  Pregnant or breastfeeding

          -  Active or uncontrolled infection requiring intravenous antibiotics

          -  Impairment of gastrointestinal (GI) function or GI disease that may significantly
             alter the absorption of dasatinib (e.g., ulcerative diseases, uncontrolled nausea,
             vomiting, diarrhea, malabsorption syndrome, or small bowel resection)

          -  Patients who have received investigational drugs ≤4 weeks prior to starting study drug
             and/or who have not recovered from side effects of such therapy