Trial Information

A Phase I Study of Temsirolimus, Topotecan, and Bortezomib in Patients With Advanced Malignancy

The Study Drugs:

Temsirolimus is designed to block pathways that control important events such as the growth
of blood vessels that are vital for the growth of cancer. This may cause cancer cells to
die.

Topotecan hydrochloride is designed to block the function of important proteins in cancer
cells. These proteins, when active, allow a cell's genes to duplicate and for the cancer
cells to divide.

Bortezomib is designed to block the function of important proteins in cancer cells. These
proteins control the destruction of proteins in tumor cells, which is important for their
growth. This may cause cancer cells to die.

Study Drug Dose Level:

If you are found to be eligible to take part in this study, you will be enrolled into a
group of about 3-6 participants that are receiving the same drug combination. The first
group of participants will receive the lowest dose of the drug combination. The next group
of participants will receive the next highest dose of the drug combination. The third group
will receive an even higher dose than that. This process will continue until the study
doctor finds the highest safe dose of the drug combination. The dose that you receive will
depend on when you are enrolled in this study and the safety data that is available at that
time. The dose that you receive may be lowered if you do not tolerate the study drug
combination well. You will not receive any doses of the study drug higher than the dose you
are first assigned to.

Once the highest tolerated dose is found, up to 10 more participants will be added at that
dose level. This is called an Expansion Group.

Study Drug Administration:

Temsirolimus, topotecan, and bortezomib will be given in "cycles." Cycles will be about 21
days long or longer, depending on any side effects you may experience.

On Days 1, 8, and 15 of each cycle, you will receive temsirolimus through a needle in your
vein over about 30-60 minutes.

On Days 1 and 8 of each cycle, you will receive topotecan hydrochloride by vein over about
30-60 minutes.

On Days 1, 4, 8, and 11 of each cycle, you will receive bortezomib by vein over less than 1
minute.

While on study you will not be able to take any drugs that may interfere with the study
drugs. You should talk with your doctor before taking any non-study drugs.

Study Visits:

Once a week during Cycle 1, the following tests and procedures will be performed:

- You will have a physical exam.

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

- If the doctor thinks it is needed, urine will be collected for routine tests.

If you are in the Expansion Group, then during Week 3 of Cycle 1, you will have a tumor
biopsy to compare the activity of the tumor before treatment and after treatment has begun.
This is done for research purposes only.

If you are in the Expansion Group, then 24-48 hours after starting Week 1 of Cycle 1, you
will have a bone marrow aspiration performed. The tissue will be used to see how the study
drug combination acts in the body and to learn the effect it may have on cancer cells. This
is done for research purposes only.

During Week 1 of Cycle 2, you will have an ECG. After this, you will have extra ECGs if the
doctor thinks it is needed.

During Week 1 of Cycles 2 and beyond, the following tests and procedures will be performed:

- You will have a physical exam.

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

- If the doctor thinks it is needed, urine may be collected for routine tests.

Once every 2 cycles (Cycles 2, 4, 6, and so on), you will have a CT or MRI scan to check the
status of the disease.

FDG-PET Scans:

Every 2-3 months while you are on study and before Cycle 1 if you have not had a FDG-PET
within the last 1 month, you may have a FDG-PET scan. You must fast for at least 6 hours
before the FDG-PET scan. If you are a diabetic, you must fast for at least 4 hours before
the FDG-PET scan. If it is needed, you may take drugs or drink water. The FDG-PET will be
used to see if the activity of the cancers decreased with the drugs.

You will receive a small amount of FDG solution by vein. You will then rest in a quiet
darkened room for 45-60 minutes before the PET scan. Pictures of your body will be taken
using a PET scanner, which will about take 1 1/2 hours. The entire procedure should take
about 3 hours.

Each time you have a FDG-PET scan, blood (either a finger stick or about 1 teaspoon) will be
drawn to measure your blood sugar levels.

Length of Study Participation:

You will be on study for as long as you are benefiting. You will be taken off study if the
disease gets worse or intolerable side effects occur.

End-of-Treatment Visit:

After you are off study, you will have an end-of-treatment visit. At this visit, the
following tests and procedures will be performed:

- You will have a physical exam.

- Blood (about 2 teaspoons) will be drawn for routine tests.

This is an investigational study. Temsirolimus, topotecan, and bortezomib are all FDA
approved and commercially available. Temsirolimus is FDA approved for the treatment of
renal cell cancer. Topotecan hydrochloride is FDA approved for the treatment of ovarian,
small cell lung, and cervical cancers. Bortezomib is FDA approved for the treatment of
multiple myeloma and mantle cell lymphoma. The use of these drugs together is
investigational and authorized for use in research only.

Up to 80 patients will take part in this study. All will be enrolled at M. D. Anderson.