Effects of Mirtazapine on Appetite in Advanced Cancer Patients

Mirtazapine is a drug that is used to treat clinical depression. It is designed to cause
hormones ("chemical messengers" such as norepinephrine and serotonin) to be released in the
brain, while blocking certain molecules that cause nausea, nervousness, headache, insomnia,
diarrhea, and lowered sex drive. The release of these hormones may provide proper hormonal
balance in the brain, which may increase appetite and weight.

Before you can start treatment on this study, you will have "screening tests." These tests
will help the study doctor decide if you are eligible to take part in this study. You will
have a physical exam, including measurement of your vital signs (blood pressure, heart rate,
temperature, and breathing rate). You will be asked to complete 5 questionnaires that will
ask about your diagnosis, the medication you are taking, how you have been feeling (such as
tense or "wound up"), and any symptoms you may be having (such as pain, poor appetite, weight
loss, fatigue, nausea, sleep problems, and depression), and times you have usually gone to
bed during the past month. In total, these questionnaires will take about 40 minutes to
complete. Women who are able to have children must have a negative urine pregnancy test.

If you are not found to be eligible to take part in this study, you will be provided with a
referral to a palliative care doctor who will check your symptoms and plan the appropriate
treatment.

If you are found to be eligible to take part in this study, you will be randomly assigned (as
in the toss of a coin) to 1 of 2 groups. You will have an equal chance of being in 1 of the 2
groups. Neither you nor your doctor will know which treatment group you are assigned to.
However, in the event of an emergency, for your safety your doctor will be informed about
what treatment you are receiving.

Participants in one group will take a specified dose of mirtazapine (with or without food) at
bedtime on Days 1-15. On Day 15, you will return to the clinic to repeat the same tests that
you had during the screening visit and to be checked for any side effects you may have
experienced. You will get 2 more prescriptions (2 different doses--a lesser dose and a
greater dose) for mirtazapine. You will then take a lesser dose of mirtazapine (with or
without food) for 7 days. During Week 3, you will take the greater dose of mirtazapine for
another 7 days until Day 29.

Participants in the other group will take a placebo (a substance that looks like the study
drug but has no active ingredients) for 2 weeks. On Day 15, you will return to the clinic to
repeat the same tests that you had during the screening visit and to be checked for any side
effects you may have experienced. You will be given 2 prescriptions (2 different doses--a
lesser dose and a greater dose) for mirtazapine. You will then take a lesser dose of
mirtazapine (with or without food) for a 7 days. During Week 3, you will take the greater
dose of mirtazapine for another 7 days until Day 29.

You will continue taking part in this study until Day 29, unless the disease gets worse or
you experience any intolerable side effects. Otherwise, your participation will end on Day
29, and you will have an end-of-study visit at that time.

Your right arm muscle diameter, your skin fold thickness below your shoulder blade, on the
front and back of your right arm, above your right hip bone, and on the front of your right
thigh will be measured using a skinfold caliper. The caliper is a device used on the outside
of your body to measure skin thickness. You will also be asked to stand on a special scale
that will send an extremely low energy, high frequency electrical signal from one foot to
your other foot. You will not be able to feel this at all. The device uses the speed at which
the signal travels through your body's tissues to calculate body fat weight and body fat
percentage. These numbers are used together to determine your body fat, lean body weight, and
water content of your body. This will be done on Days 1, 15, and 29.

Participants in both groups will be asked to keep 3 weekly diaries: a food diary, a pill
diary recording when mirtazapine is taken, and a daily log of any symptoms that may have been
experienced from the cancer before and after treatment began on this study. You will be asked
to return to the outpatient clinic at the end of 2 weeks (Day 15) when all tests that were
performed during the screening visit will be repeated. All 3 diaries will be reviewed by the
research nurse during this clinic visit.

The study nurse will call you on the phone on Days 2 and 16 to find out if you have had
increased drowsiness or sleepiness (since the beginning of this study). You will also be
called on Days 8 and 22 by the study nurse to check your symptoms, difficulty sleeping, and
other side effects you may be experiencing. The phone calls should last about 5-10 minutes
each time.

For your end-of-study visit (Day 29), you will return to the outpatient Palliative Care and
Rehabilitation Medicine Clinic at M. D. Anderson to be checked on. You will have all of the
same tests that you had during the screening visit as well as a review of any side effects
you may be experiencing. You will repeat the questionnaires, which should take about 40
minutes to complete. You will need to bring your food diary, pill diary, and symptom log
diary to this visit.

All of the study visits will occur on the day listed in this form, or within 3 days earlier
or later.

This is an investigational study. Mirtazapine is approved by the FDA (only at the dose levels
that will be provided in this study) for depression and commercially available. Its use in
this study is experimental. Up to 98 patients will take part in this study. All will be
enrolled at M. D. Anderson.

Inclusion Criteria:

1. Advanced cancer patients seen in outpatient clinics or inpatient units at MD Anderson
Cancer Center, with presence of anorexia for at least one month, and accompanied by
weight loss of > 5 % of pre-illness body weight in the last 6 months. Anorexia on the
day of enrollment (day 0 +/-3) must be > 4/10 on ESAS.

2. Patients > 18 years of age

3. Karnofsky Performance score of > 40 at time of inclusion into study

4. Ability to provide informed consent and comply with study procedures

5. Ability and willingness to return to engage in telephone follow-up by research nurse
on days 2 (+/- 3 days), 8 (+/- 3 days), 16 ( +/- 3 days), and 22 (+/- 3 days) and
return to outpatient clinic for evaluation on days 15 (+/- 3 days), and 29 (+/- 3
days).

6. Negative urine pregnancy test at time of inclusion into study for female patients of
childbearing potential, within 24 hours of study enrollment.

7. For patients receiving chemotherapy eligibility to be determined after discussion with
primary oncologist

8. Drowsiness of Mirtazapine

9. Patient can continue all medications including complementary therapies or
antineoplastic therapy while on-study (with the permission of their Attending MD) if
they have been on stable dose for at least 2 weeks.

10. Patients who are on stable doses of antidepressants for at least 2 months.

Exclusion Criteria:

1. Patients who have known dementia or delirium at time of enrollment as determined by a
physician.

2. Known hypersensitivity to any ingredient of Mirtazapine

3. Inability to maintain oral intake over the course of the study, such as with
mechanical obstruction of the alimentary tract or intractable vomiting

4. Ongoing use of tube feeding or parenteral nutrition

5. Current use of corticosteroids (with the exception of scheduled doses during time of
chemotherapy), dronabinol, testosterone and progesterone derivatives such as megestrol
acetate, or in the preceding 1 week prior to study enrollment.

6. Pregnancy or lactation or unwillingness to use contraceptives

7. A score of 11 or more, in each subscale of the Hospital Anxiety and Depression scale
(HADS) indicating clinical depression or anxiety. Those with HADS scores of > 11 at
baseline indicating moderate or severe depression will be excluded from the study and
will be referred for appropriate follow up by counselor and psychiatry evaluation.

8. Patients on chronic use of benzodiazepines are excluded