TUSC2-nanoparticles and Erlotinib in Stage IV Lung Cancer

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of DOTAP:Chol-TUSC2 and erlotinib hydrochloride based on when you join this study. Up
to 4 dose levels of the study drug combination will be tested. Three (3) participants will be
enrolled at each dose level. The first group of participants will receive the first dose
combination level. After this dose is given, the participants will be watched for 3 weeks to
check for any serious side effects at that dose level. If any participants in this first
group have intolerable side effects, 1-2 lower dose combinations of the study drugs may be
tested.

If no intolerable side effects are seen in the first group, the second study group will
receive the next planned dose combination. If no intolerable side effects are seen in this
group, the last dose combination will be tested.

If you are enrolled in the Phase II portion, you will receive the highest study combination
dose that was tolerated in the Phase I portion.

During the Phase II portion of the study, half of the participants will not start receiving
erlotinib hydrochloride until Day 8 of Cycle 1 (+/- 1 day). Every odd-numbered participant
(1, 3, 5, and so on) enrolled in Phase II will receive this delayed schedule for erlotinib
hydrochloride. NOTE: For all participants dosing of erlotinib has been changed to begin on
Day 8 of Cycle 1 and then daily.

Study Drug Administration:

You will receive the drugs dexamethasone and diphenhydramine before each infusion of
DOTAP:Chol-TUSC2, to try to lower the risk of possible allergic reactions to the study drug.
Dexamethasone will be given by mouth about 24 hours before your dose of DOTAP:Chol-TUSC2, and
by vein about 30 minutes before the dose. Diphenhydramine will also be given (either by mouth
or as an injection) about 30 minutes before the dose.

DOTAP:Chol-TUSC2 is given by vein as an infusion over 25-35 minutes, on Day 1 of every 3-week
study cycle.

You will take erlotinib hydrochloride by mouth in tablet form every day you are on study
(except for first week of Cycle 1, if you were enrolled in the Phase II delayed-schedule
group).

Erlotinib hydrochloride tablets should be taken at about the same time each day. Each
erlotinib dose should be taken with about 8 ounces of water, and should be taken 1 hour
before or 2 hours after meals. The whole dose must be taken at one time. If you vomit after
taking the tablet(s), you should only re-take the dose if the tablet(s) can still be seen and
counted.

Study Tests:

Each study cycle is 3 weeks.

On Day 1 of each cycle:

- Your vital signs (blood pressure, heart rate, temperature, and breathing rate) will be
measured.

- Urine will be collected for routine tests.

- You will have a test to measure the level of oxygen in your blood.

On Day 1 of Cycle 1 only, blood (about 4 tablespoons total) will be drawn before your first
dose of DOTAP:Chol-TUSC2 and then about 24 hours later (+/- 4 hours), for research tests to
check your immune system.

On Day 2 of each cycle:

- Blood (about 2 teaspoons) will be drawn for routine tests and tests to check your immune
system.

- Your vital signs will be recorded, and you will be asked about any side effects you may
have.

On Day 7 of Cycle 1, you will have a liquid tumor biopsy for genetic research tests.

On Day 21 of each cycle:

- You will have a physical exam, including measurement of your vital signs.

- Your medical history will be recorded, and you will be asked about any side effects you
may be having.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

On Day 21 of every other cycle (Cycles 2, 4, 6, and so on), you will have either a chest CT
or PET/CT scan to check the status of the disease. Other scans may be performed, if your
doctor thinks they are needed.

PK Testing:

If you are in Phase 1 and are one of the first 6 participants to be enrolled on this study,
blood (about 2 teaspoons each time) will be drawn for pharmacokinetic (PK) testing. PK
testing measures the amount of study drug in the body at different time points. PK samples
will be drawn during Cycle 1, at the following times:

- Day 1--before the dose of DOTAP:Chol-TUSC2, at 15 and 30 minutes after the dose, and
then 1, 3, and 6 hours after the dose

- Day 2

- Day 4

- Day 8

- Day 15

Length of Treatment:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse,
intolerable side effects occur, or you are unable to follow study directions.

Long-Term Follow-up:

You will be called by the study staff every 3 months after you stop taking the study drugs.
The study staff will ask you questions to find out how you are doing and to collect
information on any other therapies you have received for cancer. The call should take about
15 minutes.

This is an investigational study. Erlotinib hydrochloride is commercially available and FDA
approved for the treatment of non-small-cell lung cancer. At this time, DOTAP:Chol-TUSC2 is
only being used in research.

Up to 57 patients will take part in this study. All will be enrolled at MD Anderson as well
as additional clinical sites.

Inclusion Criteria:

1. Histologically or cytologically documented non-small cell lung cancer (NSCLC)

2. Stage IV NSCLC or recurrent NSCLC that is not potentially curable by radiotherapy or
surgery. There is no limit to the number or form of prior therapy regimens received,
but patients must have received at least one.

3. All subjects must have tumor specimens adequate for analysis of EGFR mutations or have
tumor accessible for pretreatment biopsy, and must consent to post-treatment Guardant
ctDNA liquid biopsy. Subjects must have specimens adequate for analysis of EGFR
mutations (and other clinically relevant biomarkers)

4. All subjects with an activating EGFR mutation (exon 19 deletion or exon 21 L858R
mutation) are eligible IF they have progressed following treatment with a first,
second, or third generation EGFR inhibitor. All subjects who are EGFR negative or have
wild-type EGFR or another non-activating mutation are eligible.

5. ECOG or Zubrod Performance Status ≤1

6. Age ≥18 years

7. Subjects must have voluntarily signed an informed consent in accordance with
institutional policies.

8. Female subjects of childbearing potential (non-childbearing is defined as greater than
one year post-menopausal or surgically sterilized) must have a Negative serum
pregnancy test (serum beta-HCG) ≤7 days of study treatment. Since beta-HCG may be
falsely elevated as a result of malignancy, women of child-bearing potential who have
an elevated serum beta-HCG level are eligible for enrollment if they have two (2)
Transvaginal Ultrasound (TVUS) scans one (1) week apart along with serial beta-HCG
levels two (2) weeks apart that are inconsistent with pregnancy and a Gynecology
consult to ensure that the beta- HCG level was at a value high enough to see pregnancy
with TVUS.

9. Subjects are required to agree to practice effective birth control (i.e., abstinence,
intrauterine device for female subjects) during the study period.

10. Subjects must be ≥4 weeks beyond major surgical procedures such as thoracotomy,
laparotomy or joint replacement, and must be ≥1.5 weeks beyond minor surgical
procedures such as biopsy of subcutaneous tumors, pleuroscopy, etc., and must not have
evidence of wound dehiscence, active wound infection, or comparable major residual
complications of the surgery. Note: placement of pleurex catheter is not considered
minor surgery for this study.

11. ANC >1500/mm3, platelet count >100,000/mm3 ≤14 days of study treatment

12. PT and PTT <1.25 times the institutional upper limit of normal ≤14 days of study
treatment

13. Adequate renal function documented by serum creatinine of ≤1.5 mg/dl or calculated
creatinine clearance >50 ml/min ≤14 days of study treatment

14. Adequate hepatic function as documented by serum bilirubin <1.5 mg/dl and SGOT and
SGPT ≤2.5 X upper limit of normal ≤14 days of study treatment

15. Subjects with asymptomatic brain metastases that have been treated are eligible if the
following criteria are met: No history of seizures in the preceding 6 months.
Definitive treatment must have been completed ≥4 weeks prior to start of study
treatment. Subjects must be off steroids that were being administered because of brain
metastases or related symptoms for ≥2 weeks prior to start of study treatment.
Post-treatment imaging ≤2 weeks of informed consent must demonstrate stability or
regression of the brain metastases.

16. Stable cardiac condition with a left ventricular ejection fraction ≥40% ≤28 days of
study treatment

Exclusion Criteria:

1. Subject is female who is pregnant or breast-feeding.

2. Subject received investigational therapy (i.e., agents that are not FDA-approved),
including monoclonal antibodies such as bevacizumab or cetuximab, or has received
radiotherapy to the skull, spine, thorax or pelvis within ≤30 days of start of study
treatment. Subjects are permitted to have received palliative radiotherapy to an
extremity provided ≥14 days have elapsed since completion of radiotherapy, provided
the subject received ≤10 radiotherapy fractions and a dose ≤30 Gy to that site, and
provided skull, spine, thorax or pelvis were not in the radiotherapy field.

3. Subject received standard chemotherapy with FDA-approved agents within ≤21 days of
start of study treatment.

4. Subject received a targeted therapy within ≤14 days prior to start of study treatment.

5. Subject has active systemic viral, bacterial or fungal infection(s) requiring
treatment.

6. Subject has brain metastases (except as allowed in Section 3.2.1). Neurological
assessment will be used to determine brain metastases.

7. Subject has serious concurrent illness or psychological, familial, sociological,
geographical, or other concomitant conditions that, in the opinion of the
investigator, would not permit adequate follow-up and compliance with the study
protocol.

8. Subject received prior gene therapy or cell therapy.

9. Subject has history of myocardial infarction or unstable angina ≤6 months of start of
study treatment.

10. Subject is known to be HIV positive.