Sublingual Anvirzel in Advance Non-Small Cell Lung Cancer (NSCLC)

Study Drug Administration:

If you are eligible and agree to take part in the study, you will be assigned to a dose
level of nerium oleander based on when you join this study. Up to 5 dose levels of nerium
oleander will be tested. At least 3 participants will be enrolled at each dose level. The
first group of participants will receive the lowest dose level. Each new group will receive
a higher dose than the group before it, if no intolerable side effects were seen. This will
continue until the highest tolerable dose of nerium oleander is found.

You will take nerium oleander by mouth by placing it under your tongue. You should hold the
nerium oleander under your tongue for 3 minutes before swallowing. It is very important
for you to hold the nerium oleander under your tongue for 3 full minutes. Holding it under
your tongue for 3 minutes before swallowing helps your body to take in the highest amount of
the drug that you can receive. If you hold the nerium oleander under your tongue for less
than 3 minutes, your body will not receive as much of the study drug and may not possibly
benefit as much. You will take nerium oleander 3 times a day while participating in this
study. Nerium oleander should be taken on an empty stomach or at least 15 minutes before
any large meal, to help your body take in as much of the drug as possible.

Study Visits:

Each of your chemotherapy cycles are 21 days.

Each week while on study, you will complete the questionnaire about any symptoms you may be
having. It should take about 5 minutes to complete it each time.

Cycle 1:

On Day -7 (7 days before you start chemotherapy):

- You will complete the questionnaire about your physical and mental health. It should
take about 5 minutes to complete it.

- Blood (about 2 teaspoons each time) will be drawn 6 times over 8 hours for
pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the body
at different time points.

- Blood (about 6 teaspoons) will be drawn to learn if the study drug is reducing
inflammation.

- Blood (about 2 teaspoons) will be drawn to test the effect of the study drug on your
immune system.

On Day -6, blood (about 2 teaspoons each time) will be drawn 1 time for PK testing.

On Day 1 (the day you start chemotherapy):

- You will be asked about any symptoms you may be having or drugs you may be taking.

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

- Your performance status will be recorded.

- You will complete the questionnaire about your physical and mental health.

- Blood (about 1 teaspoon) will be drawn for routine tests.

- Blood (about 2 teaspoons each time) will be drawn 6 times over 8 hours for PK testing.

- Blood (about 6 teaspoons) will be drawn to learn if the study drug is reducing
inflammation.

- Blood (about 2 teaspoons) will be drawn to test the effect of the study drug on your
immune system.

- You will have an EKG.

On Day 2:

- Blood (about 2 teaspoons) will be drawn for PK testing.

- Blood (about 6 teaspoons) will be drawn to learn if the study drug is reducing
inflammation.

- Blood (about 2 teaspoons) will be drawn to test the effect of the study drug on your
immune system.

On Day 8 (+/- 2 days):

- Blood (about 6 teaspoons) will be drawn to learn if the study drug is reducing
inflammation.

- Blood (about 2 teaspoons) will be drawn to test the effect of the study drug on your
immune system.

On Day 1 of Cycles 2-3:

- You will be asked about any symptoms you may be having or drugs you may be taking.

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

- Blood (about 1 teaspoon) will be drawn for routine tests.

- Your performance status will be recorded.

- You will have an EKG.

- You will complete the questionnaire about your physical and mental health.

- On Day 1 of Cycle 3 only, you will have a CT scan to check the status of the disease.

On Day 1 of Cycle 4:

- You will be asked about any symptoms you may be having or drugs you may be taking.

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

- You will complete the questionnaire about your physical and mental health.

- Blood (about 1 teaspoon) will be drawn for routine tests.

- Your performance status will be recorded.

- You will have an EKG.

- Blood (about 2 teaspoons each time) will be drawn 6 times over 8 hours for PK testing.

- Blood (about 6 teaspoons) will be drawn to learn if the study drug is reducing
inflammation.

- Blood (about 2 teaspoons) will be drawn to test the effect of the study drug on your
immune system.

On Day 2 of Cycle 4:

- Blood (about 2 teaspoons) will be drawn for PK testing.

On Day 8 and Day 21 of Cycle 4 (+/- 2 days):

- Blood (about 6 teaspoons) will be drawn to learn if the study drug is reducing
inflammation.

- Blood (about 2 teaspoons) will be drawn to test the effect of the study drug on your
immune system.

Length of Study:

You may continue taking the study drug for as long as the doctor thinks it is in your best
interest or up to 4 cycles. 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 after the follow-up visit.

End-of-Dosing Visit:

After your last dose of study drug, you will return to the clinic. The following tests and
procedures will be performed:

- You will be asked about any symptoms you may be having or drugs you may be taking.

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

- Blood (about 1 teaspoon) will be drawn for routine tests.

- You will have an EKG.

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

- You will complete both questionnaires.

Follow-Up Visit:

About 30 days after your last dose of study drug, the following tests and procedures will be
performed:

- You will be asked about any symptoms you may be having or drugs you may be taking.

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

- Blood (about 1 teaspoon) will be drawn for routine tests.

- You will have an EKG.

- You will complete both questionnaires.

This is an investigational study. Nerium oleander is not FDA approved or commercially
available. Its use in this study is considered investigational.

Up to 36 participants will be enrolled in this study. All will take part at MD Anderson.

Inclusion Criteria:

1. Patients must have histologically or cytologically confirmed diagnosed advanced
non-small cell lung cancer (Stage IIIB and IV) and be scheduled to receive four
cycles of carboplatin and docetaxel chemotherapy.

2. Newly diagnosed or previously treated patient with NSCLC. Previously treated patients
are allowed to have any previous chemotherapy for the treatment of NSCLC.

3. Age >18 years

4. ECOG performance status < or =2 (Karnofsky > or = 60%)

5. Life expectancy of greater than 6 months

6. Patients must have normal organ and marrow function as defined below: - leukocytes >
or = 3,000/mcL - absolute neutrophil count > or = 1,500/mcL - platelets > or =
100,000/mcL - total bilirubin within normal institutional limits -
AST(SGOT)/ALT(SGPT) < or = 2.5 X institutional upper limit of normal - creatinine
within normal institutional limits OR - creatinine clearance > or = 60 mL/min/1.73 m2
for patients with creatinine levels above institutional normal

7. Negative serum or urine pregnancy test in women of child-bearing potential

8. Scheduled to begin carboplatin and docetaxel chemotherapy in the next 30 days

9. The effects of Anvirzel on the developing human fetus are unknown. For this reason,
women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation. Should a woman become pregnant or suspect
she is pregnant while participating in this study, she should inform her treating
physician immediately.

10. Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

1. Patients receiving any other investigational agents

2. History of allergic reactions attributed to compounds of similar chemical or biologic
composition to cardiac glycosides

3. Patients receiving any medications or substances that are inhibitors or inducers of
CYP 3A4 are ineligible

4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

5. Pregnant or breastfeeding women

6. HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with Anvirzel. In addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy.

7. Uncontrolled or significant cardiovascular disease, including: • Myocardial
infarction within 6 months • Uncontrolled angina within 6 months • Newly diagnosed
congestive heart failure within 6 months, defined as NYHC-II or currently
uncontrolled congestive heart failure • Diagnosed or suspected congenital long QT
syndrome • Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, Wolff-Parkinson-White (WPW)
syndrome, or torsade de pointes). Prolonged QTc interval on pre-entry
electrocardiogram (> 450 msec). If the automated reading is prolonged (i.e., > 450
msec), the EKG should be manually over-read • Any history of second or third degree
heart block • Heart rate < 50 beats/minute or sustained heart rate > 110 on pre-entry
electrocardiogram • Newly diagnosed atrial fibrillation within 6 months or currently
uncontrolled atrial fibrillation • Uncontrolled hypertension defined as sustained
blood pressure of >/= 140/90mm Hg

8. Current use of a pacemaker

9. Patients using or scheduled to use bevacizumab during study period

10. Current use of cardiac glycoside