Biomarker-Integrated Approach of Targeted Therapy for Lung Cancer Elimination Plus External Beam Radiation Therapy (BATTLE-XRT)

Study Groups:

If you are found to be eligible to take part in this study and you have an EGFR mutation,
you will be enrolled in Arm A. If you have the wild-type EGFR, you will be randomly assigned
(as in the flip of a coin) to either Arm B or C. You will have an equal chance of being
enrolled in either arm.

- If you are in Arm A, you will receive standard chemoradiation, erlotinib, and
onartuzumab.

- If you are in Arm B, you will receive standard chemoradiation, erlotinib, and
onartuzumab.

- If you are in Arm C, you will receive standard chemoradiation and onartuzumab only.

If you are assigned to Arm A or B, you will receive standard chemoradiation, erlotinib, and
onartuzumab. You will be assigned to a dose level of onartuzumab based on when you join this
study. After the first dose level of onartuzumab is given, you will be watched for 2 weeks
after the end of radiation treatment to check for any serious side effects at that dose
level. If any participants in this first group have intolerable side effects, a lower dose
combination of the study drugs may be tested. Once the highest tolerable dose is found,
extra participants will receive onartuzumab at that dose level.

All participants in Arms A and B will receive the same dose level of erlotinib.

Study Drug Administration:

All participants will receive onartuzumab by vein on Day 1 of each 3-week cycle. The first
infusion should be given over about 60 minutes. If the infusion is tolerated, other doses
will be given over about 30 minutes.

You will receive paclitaxel and carboplatin by vein over about 6 hours 1 time a week for 7
weeks. You will receive a separate consent form for chemoradiation, which will describe the
procedure and risks in more detail.

If you are taking erlotinib, it should be taken by mouth with about 1 cup of water. You
should take erlotinib at about the same time every day, at least 1 hour before a meal and at
least 2 hours after a meal.

Study Visits:

One (1) time each week:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests. If you are taking Coumadin
or a similar drug, this blood will also be used to check how well your blood clots.

Length of Study:

You may continue taking onartuzumab until you complete radiation therapy. You will no longer
be able to take the study drug if the disease gets worse, if intolerable side effects occur,
or if you are unable to follow study directions.

Your participation on the study will be over 4 years after your last dose of study drug.

Follow-Up:

You will have follow-up visits around 30 days after your last dose of study drug, every 3
months for 2 years, and then every 4 months for the next 2 years. During these visits:

- You will have a physical exam.

- You will have a CT or PET scan to check the status of the disease.

- If you are taking Coumadin or a similar drug, blood (about 2 teaspoons) will be drawn
to check how well your blood clots.

You will be called about every 4 weeks and asked how you are doing for as long as your
doctor thinks it is needed.

This is an investigational study. Onartuzumab is not FDA approved or commercially
available. It is currently being used for research purposes only. Erlotinib, carboplatin,
and paclitaxel are all FDA approved and commercially available for the treatment of NSCLC,
but their use in this study is investigational. Radiation therapy is delivered using
FDA-approved and commercially available methods. The study doctor can explain how the study
drugs are designed to work.

Up to 90 participants will take part in this study. All will be enrolled at MD Anderson.

Inclusion Criteria:

1. Histologically or cytologically documented NSCLC, including squamous cell carcinoma,
adenocarcinoma (including bronchoalveolar cell), and large cell anaplastic carcinoma
(including giant and clear cell carcinomas) and poorly differentiated (not otherwise
specified, NOS) non-small cell lung cancer; totally resected tumors are excluded.
Patients should have tumor tissue for biomarker testing if available. Archival
samples may be used. Patients without tissue for biomarker testing may be enrolled at
the discretion of the investigator. The determination of MET status should be done by
a pathologist who is trained in using the SP44 antibody with the Ventana platform and
using the Ventana/Genentech algorithm.

2. Patients with T1or T2 disease with N2 or T3N1-2 disease (Stage IIIA) are eligible if
they are deemed inoperable. Patients with T4 with any N or any T with N2 or N3
disease are eligible if unresectable. Patients may have limited stage M1 disease,
with a maximum of 3 metastatic sites (including the single brain mets) only if the
other sites are to be treated with definitive intent, unless they are no longer
clinically present secondary to induction chemotherapy. Treatment to the other sites
can be delivered prior to or after this trial. Measurable disease is required. See
Response Evaluation Criteria in Solid Tumors (RECIST) definitions of measurable
disease.

3. Patients must be >/=18 years of age.

4. Patients with Zubrod performance status 0-2.

5. Adequate hematologic function defined as: ANC >/= 1,500/mm3, platelets >/=
100,000/mm3, and hemoglobin >/= 9 g/dL (prior to transfusions); adequate hepatic
function defined as: total bilirubin adequate renal function defined as a serum creatinine level phosphatase
6. FEV1 with >/= 1000 cc.

7. Patients with a pleural effusion that is a transudate, cytologically negative and
nonbloody are eligible if the radiation oncologists feel the tumor can still be
encompassed within a reasonable field of radiotherapy. If a pleural effusion can be
seen on the chest computed tomography (CT) but not on chest x-ray (CXR) and is too
small to tap, the patient is eligible.

8. If patients had exploratory thoracotomy, they must have recovered from the procedure
( be within one month.

9. Women of childbearing potential (A woman of child-bearing potential is a sexually
mature woman who has not undergone a hysterectomy or who has not been naturally
postmenopausal for at least 24 consecutive months [i.e., who has had menses at any
time in the preceding 24 consecutive months]) and male participants must practice
effective contraception (oral, injectable, or implantable hormonal contraceptive;
tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or
vasectomized partner) throughout the study and for four weeks after completion of
treatment.

10. For women of childbearing potential, a urine or blood pregnancy test must be
performed within 48 hours prior to the start of protocol treatment.

11. Prior induction chemotherapy will be allowed, as is prior target therapy. Patients
with progression on an EGFR targeting agent will also be allowed, but stratified
between the two arms.

12. Patients must sign a study-specific consent form prior to study entry.

Exclusion Criteria:

1. Active pulmonary infection not responsive to conventional antibiotics

2. History of interstitial lung disease.

3. History of severe chronic obstructive pulmonary disease (COPD) requiring >/= 3
hospitalizations over the past year.

4. Significant history of cardiac disease, i.e., uncontrolled hypertension (i.e. can't
reduce blood pressure (BP) below a systolic of 160 or diastolic of 100), unstable
angina, uncompensated congestive heart failure, myocardial infarction within the past
2 months, or cardiac ventricular arrhythmias requiring medication.

5. Patients with > grade 3 neuropathy.

6. Evidence of life threatening disease resulting in a life expectancy of less than 3
months.

7. Women who are pregnant or breast feeding, as treatment involves unforeseeable risks
to the participant, embryo, fetus, or nursing infant; women with a positive pregnancy
test on enrollment or prior to study drug administration.

8. Women of childbearing potential and male participants who are unwilling or unable to
use an acceptable method of contraception (oral, injectable, or implantable hormonal
contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with
spermicide; or vasectomized partner) throughout the study and for four weeks after
completion of treatment or those who are using a prohibited contraceptive method
(methods with unknown efficacy).

9. Patients who currently are participating in other clinical trials and/or who have
participated in other clinical trials (These patient may be enrolled but radiation
must not start within 15 days of any previous experiment therapy).