Phase I-II Study of Dasatinib and Erlotinib in Non-Small Cell Lung Cancer

Inclusion Criteria:

1. Advanced malignancy that is appropriate for systemic therapy without curative intent.

2. Patients must provide verbal and written informed consent indicating they are aware
of the investigational nature of the study. Parental consent and patient assent is
required for those aged 16-17.

3. Patients must be at least 16 years of age.

4. ECOG performance status 0-1.

5. Adequate hematologic, hepatic, and renal function as follows: creatinine < 1.5 x the
institutional upper limit of normal (ULN), total bilirubin < 2.0 x ULN, AST and ALT <
2.5 x ULN, absolute granulocytes >/= 1500/mm^3; platelets >/= 75,000 mm^3; hemoglobin
>/= 10 g/dL.

6. Serum potassium, magnesium, and phosphate within the institutional limits of normal.
Patients with low potassium, phosphate, or magnesium levels may be repleted to allow
for protocol entry.

7. Serum calcium >/= the institutional limits of normal. Patients with low calcium
levels may be repleted to allow for protocol entry.

8. Ability to take oral medication (dasatinib and erlotinib must be swallowed whole)

9. Patients-both males & females-w/reproductive potential must agree to use an adequate
method of contraception to include hormonal contraceptives (birth control pills,
injections, implants), IUD, barrier contraceptive with spermicide, and/or abstinence
throughout the study & for at least 4 wks after the study drugs are stopped. Females
w/ reproductive or childbearing potential include any female who has experienced
menarche & who has not undergone successful surgical sterilization (hysterectomy,
bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal

10. -Continued from Inclusion #9 - [defined as amenorrhea >/=12 consecutive mths;or women
on hormone replacement therapy (HRT) w/ documented serum follicle stimulating hormone
(FSH) level > 35 mIU/mL]. Prior to study enrollment, women of childbearing potential
must be advised of the importance of avoiding pregnancy during trial participation
and the potential risk factors for an unintentional pregnancy.

11. Women of childbearing potential must provide a negative pregnancy test (serum or
urine) within 72 hours prior to the start of study drug administration.

12. Asymptomatic brain metastases with prior cranial irradiation or resection are
acceptable if there is no bleeding, no midline shift, and no need for steroids or
anti-convulsants. Asymptomatic brain metastasis without prior treatment are
acceptable if the largest lesion is less than 7 mm in diameter, there is no bleeding,
midline shift, nor need for steroids or anti-convulsants.

13. Patient agrees to discontinue St. Johns Wort at least 5 days before starting
dasatinib or erlotinib.

14. Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of
dasatinib therapy due to risk of hypocalcemia.

15. The patient's O^2 saturation must be >92% on room air.

16. (Phase II only) - Patient has never received prior therapy with dasatinib, or
erlotinib, or another EGFR or SFK inhibitor.

17. (Phase I only) - Histological or unequivocal cytological proof of solid tumor
malignancy.

18. (Phase I only) - At least one prior systemic chemotherapy or biological therapy for
recurrent or metastatic solid tumor (i.e., this protocol therapy must be administered
as second line or greater), ), except if there is no standard or experimental
systemic therapy available. If no effective systemic agent is available for first
line therapy, then patients may be enrolled on the phase I as first line therapy.

19. (Phase I only) - Prior radiotherapy is permitted (see exclusion criterion 4 for
details on unallowable radiotherapy).

20. (Phase II only) - Histological or unequivocal cytological proof of NSCLC.

21. (Phase II only) - NSCLC that is appropriate for systemic therapy without curative
intent: Stage IV, Stage IIIB with pleural effusion, or incurable recurrent disease
after surgery or radiotherapy.

22. (Phase II only) - Zero to one line of prior systemic therapy for recurrent or
metastatic NSCLC. Prior adjuvant chemotherapy or adjuvant biologic therapy for NSCLC
is not included as a line of prior therapy if it was completed greater than 3 months
prior to recurrence, provided that the patient has never received any EGFR or SFK
inhibitors.

23. (Phase II only) - Measurable disease as defined by RECIST criteria.

24. (Phase II only) - Availability of tumor tissue that is at least adequate for EGFR
mutational analysis. This can come from pre-existing paraffin blocks (from diagnostic
biopsy or surgical resection) or patient may undergo a biopsy for research purposes.

25. (Phase II only) - Prior radiotherapy is permitted as long as there is measurable
disease outside of the radiotherapy port OR clearly recurrent and growing within the
radiotherapy port (see exclusion criterion 2 for details on unallowable
radiotherapy).

Exclusion Criteria:

1. Women who are pregnant, breastfeeding, or have child-bearing potential and are
unwilling/unable to use an acceptable method of contraception for the entire study
period and for at least 4 weeks after cessation of the study drugs. All women of
child-bearing potential must have a negative pregnancy test prior to first receiving
protocol therapy. If the pregnancy test is positive, the patient must not receive
dasatinib or erlotinib, and must not be enrolled on the study

2. Radiotherapy to ribs, sternum, pelvis, vertebrae or skull within 4 weeks prior to
entering the study. (If none of these axial skeletal areas are included in the
radiotherapy field, patients may have received palliative radiotherapy to long bones
provided that it has ended at least 2 weeks prior to initiation of
dasatinib-erlotinib therapy.)

3. Patients with any of the following cardiac problems should be excluded: (a)
Uncontrolled angina, congestive heart failure, or myocardial infarction within the
previous 6 months; (b) Diagnosed congenital long QT syndrome; (c) Any history of
clinically significant ventricular arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or Torsades de pointes); (d) Prolonged QTc interval on
pre-entry electrocardiogram (> 450 msec in women or >440 msec in men). If the
automated reading is prolonged, the ECG should be manually over read.

4. Continued from Exclusion #4: (e) Any history of second or third degree heart block
unless they currently have a pacemaker; (f) Heart rate < 50 / minute on pre-entry
electrocardiogram;(g) Uncontrolled hypertension defined as systolic blood pressure >
150 or diastolic >100;(h) Subjects with hypokalemia or hypomagnesemia if it cannot be
corrected prior to dasatinib administration.

5. Patients with pericardial effusion > grade 1 (by CTCAE v3.0).

6. Patients with pleural effusion > grade 2 (by CTCAE v3.0). A grade 3 pleural effusion
that is managed by a thoracentesis or an indwelling catheter is allowable as long as
supplemental oxygen is not required.

7. Patients with any condition that impairs their ability to swallow, retain, or absorb
dasatinib or erlotinib tablets are excluded. This includes any condition resulting in
an inability to take oral medication, a requirement for IV alimentation, prior
surgical procedures that have resulted in chronic malabsorption, or active peptic
ulcer disease.

8. Patients with > grade 2 neuropathy

9. Patients with a history of pulmonary fibrosis (other than in a radiated field).

10. Patients with inflammatory bowel disease or uncontrolled chronic diarrhea.

11. Patients with a history of significant bleeding disorder unrelated to cancer,
including: (a) Diagnosed congenital bleeding disorders (e.g., von Willebrand's
disease); (b) Diagnosed acquired bleeding disorder within one year (e.g., acquired
anti-factor VIII antibodies); (c) Ongoing or recent ( gastrointestinal bleeding, defined as clinically evident hematemesis or hematochezia
requiring therapeutic intervention.

12. Known HIV-positive patients are ineligible because of the potential for
pharmacokinetic interactions between dasatinib and antiretroviral therapy. In
addition, these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy.

13. Pts currently receiving any of the following medications will be excluded: (a) Any
concurrent systemic anticancer therapy; (b) Any concurrent investigational agents (c)
Category I drugs that are generally accepted to have a risk of causing Torsades de
Pointes including: (Pts must discontinue such drugs 7 days or more prior to starting
dasatinib):i. quinidine, procainamide, disopyramide;ii. amiodarone, sotalol,
ibutilide, dofetilide;iii. erythromycin, clarithromycin;iv. chlorpromazine,
haloperidol, mesoridazine, thioridazine, pimozide

14. Continued from Exclusion#14:v.cisapride,bepridil,droperidol,methadone,arsenic,
chloroquine,domperidone,halofantrine,levomethadyl,pentamidine,sparfloxacin,
lidoflazine;(d)The concomitant use of H2 blockers or proton pump inhibitors w/
dasatinib is not recommended.The use of antacids should be considered in place of H2
blockers or proton pump inhibitors in pts receiving dasatinib therapy.If antacid
therapy is needed,the antacid dose should be administered at least 2 hours prior to
or 2 hours after the dose of dasatinib.

15. Continued from Exclusion #15: (e)Pt may not be receiving any prohibited CYP3A4
inhibitors Potent inhibitors of CYP3A4 are prohibited during study; for such
medications, a wash-out period of 7 days is required prior to starting dasatinib.
Potent CYP3A4 inhibitors include: · itraconazole, ketoconazole, miconazole,
voriconazole; amprenavir, atazanavir, fosamprenavir, indinavir, nelfinavir,
ritonavir; ciprofloxacin, clarithromycin, diclofenac, doxycycline, enoxacin,
imatinib, isoniazid, ketamine nefazodone, nicardipine, propofol, quinidine,
telithromycin. (f) St.Johns Wort

16. The patient has received prior investigational therapy, chemotherapy, radiotherapy,
or major surgery within 3 weeks of initiating study drug.