Phase II Study of Dasatinib in Previously Treated Patients With Advanced NSCLC (TOP0801)

• Determine progression free and overall survival in previously treated patients with advanced NSCLC treated with dasatinib with and without active Src pathway. [ Time Frame: Progression and survival every 6 months ] [ Designated as safety issue: No ]
• Assess toxicity associated with dasatinib treatment. [ Time Frame: Duration of dasatinib treatment plus 30 days ] [ Designated as safety issue: Yes ]
• Describe change in serum levels of C-terminal cross-linked collagen I between pre-treatment and 6 weeks after starting dasatinib. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
• Determine relationship between K-ras gene mutation and response to dasatinib. [ Time Frame: 2 years ] [ Designated as safety issue: No ]

On this study patients will receive dasatinib, a targeted therapy, for advanced NSCLC that has progressed after previous therapy. Safety and response to dasatinib will be assessed.

Fresh frozen tumor tissue must be available for genomics analysis prior to initiating dasatinib therapy. A biopsy must be obtained after any prior chemotherapy. If fresh frozen tumor tissue is not available, a biopsy will be required to participate in this trial.

Lung cancer is the leading cause of cancer death in the United States. Twenty to seventy-five percent of patients initially treated with surgery or radiotherapy recur and become candidates for systemic therapy. Src expression has been identified in a majority of NSCLC cell lines and may be important in hypoxic growth and angiogenesis of NSCLC.

This phase II trial will investigate the activity of the oral Src inhibitor dasatinib in advanced stage NSCLC. We hypothesize that the inhibition of Src pathway with dasatinib will show anti-tumor activity in advanced NSCLC, with a tolerable safety profile.

Fresh frozen tissue is needed for the genomics analysis, thus a biopsy will be required to participate in this trial. The genomic analysis will determine if the tumor is Src-active or Src-inactive and responses to dasatinib compared. In stage I, 40 patients will be treated without prior knowledge of their tumoral Src-activity. If all stage I responses are observed in the Src-active patients, the second stage will only accrue that cohort. If all responses are observed in the Src-inactive cohort, the activity of dasatinib and genomic determination of dasatinib response will be re-evaluated. Otherwise, if during Stage I, responses are observed in both cohorts, they will be accrued separately and evaluated in a two-stage manner.

Dasatinib will be give orally twice daily and continue until progression of disease, intolerable toxicity or patient withdrawal. Imaging studies will be done pre-treatment then every 6 weeks to assess radiologic response to therapy.

Patients will be followed for 30 days after the last dose of dasatinib to assess toxicity.

Inclusion Criteria:

1. Histological/cytological documented non-small cell lung cancer (NSCLC). Documentation of recurrence required if treated with surgical resection and/or external beam radiation therapy (XRT) with curative intent and now have recurrent disease.
2. Fresh tissue biopsy material for genomics analysis prior to initiating dasatinib. If prior XRT, tissue biopsy must be outside XRT field. Biopsy must be after any prior chemotherapy.

3. Prior treatment (tx) to include one of the following:

   • At least 1 prior systemic regimen (IV or oral agent) for Stage IV NSCLC or for recurrent disease.
   • Recurrence within 12 months after completion of systemic neoadjuvant/adjuvant chemotherapy for early stage NSCLC.
   • Combined modality platinum-based tx for Stage III NSCLC.
4. Prior XRT permitted if ≥1 week since completion, XRT must be <25% of bone marrow reserve.
5. At least one, non-radiated, measurable lesion (per RECIST).
6. Age ≥18 years.
7. Eastern Cooperative Oncology Group (ECOG) 0-2.

8. Adequate Organ Function:

   1. Total bilirubin < Upper limit normal (ULN)
   2. Hepatic enzymes (AST, ALT) ≤2.5x ULN
   3. Serum creatinine <1.5x ULN
   4. Hemoglobin ≥9 gm/dL
   5. Neutrophil count (ANC/AGC) ≥1500 per μL
   6. Platelets ≥100,000 per μL
   7. Prothrombin time (PT)/a Partial thromboplastin time (PTT) ≤1.5x control
9. No other serious medical or psychiatric illness.
10. Ability to take oral medication (dasatinib must be swallowed whole).
11. Women of childbearing potential must have negative serum pregnancy test ≤72 hours and not >7 days prior to starting study drug.
12. Sexually active males and females of reproductive potential must agree to use adequate method of contraception during tx and for at least 4 weeks after study drug stopped.
13. Signed, written informed consent including Health Insurance Portability and Accountability Act (HIPAA) according to institutional guidelines.

Exclusion Criteria:

1. Previous or concomitant malignancy in past 2 years other than curatively treated carcinoma in situ of cervix, or basal cell/squamous cell carcinoma of the skin.
2. Prior tx with dasatinib or other agents that inhibit Src.
3. Evidence of symptomatic pleural effusions (grade 2) unless undergo therapeutic thoracentesis as part of non-study care. Successful pleurodesis allowed. Patients who require supplemental oxygen or with oxygen saturation on room air <89% are not eligible. Pericardial effusions of any grade are not eligible.
4. Untreated documented symptomatic central nervous system (CNS) metastases.

5. Cardiac Symptoms:

   1. Uncontrolled angina, congestive heart failure(CHF)or myocardial infarction within 6 months
   2. Diagnosed congenital long QT syndrome
   3. Any h/o clinically significant ventricular arrhythmias
   4. Prolonged QT corrected (QTc) interval on pre-entry EKG (>450 msec)
   5. Uncontrolled B/P as defined as >160/90 on B/P therapy
6. Hypokalemia or hypomagnesaemia if it cannot be corrected.
7. H/o diagnosed congenital acquired bleeding disorders.
8. Ongoing or recent (≤3 months) significant (≥grade 3) GI bleeding.

9. Con Meds:

   1. Drugs having risk of causing Torsades de Pointes (must stop drug 7 days before dasatinib);
   2. Current therapeutic dose unfractionated heparin, low-molecular weight heparin, or coumadin therapy;
   3. St. John's Wort must be stopped while on dasatinib;
   4. IV bisphosphonates stopped 2 weeks pre/6 weeks post dasatinib.
10. Prisoners/subjects compulsorily detained for tx of psychiatric and/or physical illness.
11. Pregnant or breastfeeding.
12. Active or uncontrolled infection requiring IV antibiotics.
13. Impairment of GI function/disease that may alter absorption of dasatinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
14. Received investigational drugs ≤4 weeks prior to starting study drug and/or not recovered from side effects of such therapy. Any other anti-neoplastic and/or molecular therapy must be discontinued 7 days prior to starting dasatinib.