Trial Information

A Phase 1 Trial of Lapatinib in Combination With 1) Sirolimus or 2) Metformin in Advanced Cancer

The Study Drugs:

Lapatinib is designed to prevent or slow down the growth of cancer cells by blocking 2
proteins on the surface of the cancer cell, which are HER 1 and HER 2 receptors.

Sirolimus is designed to block a protein called mTOR (a protein that is thought to cause
cancer cells to grow) inside the cancer cell. This may interfere with the growth or spread
of cancer cells or possibly kill the cancer cells.

Metformin was designed to treat patients with diabetes. It may be able to block mTOR and
slow the growth of tumors.

Study Drug Groups:

If you are found to be eligible to take part in this study, your doctor will decide if you
will receive lapatinib with metformin or lapatinib with sirolimus. Once it is decided which
combination you will receive, you will be assigned to a dose level based on when you join
the study.

Up to 7 dose levels of lapatinib with sirolimus will be tested. Up to 6 dose levels of
lapatinib with metformin will be tested. Three (3) to 6 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 the combination
of lapatinib with either sirolimus or metformin is found.

Once the highest tolerated dose of the combination of lapatinib with either sirolimus or
metformin is found, 14 participants with the tumor type that has responded to the study drug
combination will receive the study drugs at that dose level.

Study Drug Administration:

Each study "cycle" is 28 days.

You will take lapatinib by mouth 1 time each day. You should take it at about the same time
each day on an empty stomach with a cup (about 8 ounces) of water, 1 hour before and 2 hours
after a meal.

If you are also taking metformin, you will take it by mouth 1 time every day. You should
take it at about the same time each day with a meal and cup of water (about 8 ounces).

If you are also taking sirolimus, you will take it by mouth 1 time every day. You should
take it at about the same time each day on an empty stomach with a cup of water, 1 hour
before and 2 hours after a meal.

Study Visits:

At every study visit, you will be asked about any current health conditions you have, any
other drugs you are taking, and if you have experienced any side effects.

On about Days 1, 8, and 15 of Cycle 1, blood (about 2 teaspoons) will be drawn for routine
tests.

On about Day 1 Cycle 1, urine will be collected for routine tests.

On about Day 1 of Cycles 2 and beyond:

- You will have a physical exam.

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

Every 6 weeks, you will have a blood (about 1 teaspoon) drawn or urine collected for
pregnancy test if you are able to become pregnant.

Every 8 weeks for the first 4 cycles, you will have an x-ray, CT scan, MRI scan, and/or
PET/CT scan to check the status of the disease. If the study doctor thinks it is needed,
they will be performed more often. After 4 cycles you will have an x-ray, CT scan, MRI scan,
and/or PET/CT scan every 8 - 12 weeks as your study if the study doctor feels it is
appropriate.

Length of Study:

You may stay on study for as long as you are benefitting. You will be taken off study if you
experience intolerable side effects, the study doctor thinks it is in your best interest, or
the disease gets worse.

This is an investigational study. Sirolimus is FDA approved and commercially available as
an anti-rejection drug for kidney transplant recipients. Lapatinib is FDA approved and
commercially available for the treatment of advanced breast cancer. Metformin is FDA
approved and commercially available for the treatment of diabetes mellitus. The combination
of these drugs to treat advanced cancer is investigational.

Up to 106 patients will take part in this study. All will be enrolled at M. D. Anderson.