Bevacizumab in Multiple Phase I Combinations

The Study Drugs:

Bevacizumab (Avastin™) is designed to prevent or slow down the growth of cancer cells by
blocking the growth of blood vessels

Sunitinib malate (SutentTM) is designed to block pathways that control important events such
as the growth of blood vessels that are vital for the growth of cancer.

Sorafenib (NexavarTM) is designed to block the function of important proteins in cancer
cells. These proteins, when active, are in part responsible for the abnormal growth and
behavior of cancer cells.

Erlotinib hydrochloride (TarcevaTM) is designed to block the activity of a protein found on
the surface of many tumor cells that may control tumor growth and survival. This may stop
tumors from growing.

Cetuximab (ErbituxTM) is designed to prevent or slow down the growth of cancer cells by
blocking proteins inside the cancer cell, called the epidermal growth factor receptor (EGFR).

Trastuzumab (HerceptinTM) is designed to prevent or slow down the growth of cancer cells by
blocking proteins inside the cancer cell, called the Her2/neu receptor.

Lapatinib (TykerbTM) is designed to prevent or slow down the growth of cancer cells by
blocking proteins inside the cancer cell, called the Her2/neu receptor and EGFR.

Study Drug Dose Level:

If you are found to be eligible to take part in this study, your doctor will decide which
study drugs you will receive based on the disease type and on the drugs you have taken in the
past.

Once it is decided which drugs you will receive, 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.

Once the highest tolerated dose is found for each group, up to 10 more participants will be
added to each group at that dose level.

The dose levels testing the study drug combination of bevacizumab with either sunitinib or
sorafenib are now closed.

Study Drug Administration:

Avastin™ is given through a needle in your vein. The first infusion is over 90 minutes. The
next infusion may be over 60 minutes if the first infusion was well tolerated. If you
tolerate the second infusion well, the third infusion may be over 30 minutes. If you take
trastuzumab and lapatinib with Avastin™, you will receive Avastin™ every 21 days. If you take
cetuximab and erlotinib with Avastin™, you will receive Avastin™ every 14 days.

If you are assigned to take cetuximab and erlotinib, cetuximab will be given by vein once
every week. The first time you receive cetuximab, it will be given over 2 hours. All other
infusions will be given over 60 minutes. Erlotinib is taken by mouth every day during the
28-day study cycle. You should take erlotinib on an empty stomach either 1 hour before eating
or 2 hours after eating.

If you are assigned to take trastuzumab and lapatinib, trastuzumab will be given by vein once
every 21-day study cycle. The first infusion will be over 90 minutes. If you handle the
infusion well, each additional infusion will be over 30 minutes Lapatinib will be taken by
mouth every day for 21 days. You should take lapatinib on an empty stomach either 1 hour
before eating or 2 hours after eating.

Study Visits:

Avastin, cetuximab, and erlotinib:

During Cycle 1, you will have a study visit during Weeks 1 and 2. During Cycles 2 and beyond,
you will have a study visit during Week 1. At these visits, you will have a physical exam,
and blood (about 1 tablespoon) will be drawn for routine tests. If the routine urine test
done at screening had abnormal results, urine may be collected for additional routine tests
during the study. After 2 cycles, you will have the physical exam every 1-2 months.

Every week, you will have blood drawn (about 2 teaspoons) for routine tests.

During Week 1 of all cycles, you will have urine collected for routine tests.

After every 2 cycles, you will have a CT or MRI scan to check the status of the disease.
After 6 months (6 cycles) of study drug treatment, you will have the CT or MRI scan every 2-4
cycles.

Avastin, trastuzumab, and lapatinib:

During Cycle 1, you will have a study visit during Weeks 1 and 2. During Cycles 2 and beyond,
you will have a study visit during Week 1. At these visits, you will have a physical exam,
and blood (about 1 tablespoon) will be drawn for routine tests. If the routine urine test
done at screening had abnormal results, urine may be collected for additional routine tests
during the study. After 2 cycles, you will have the physical exam every 1-2 months.

During Week 1 of all cycles, you will have urine collected for routine tests.

After every 2 cycles, you will have a CT or MRI scan to check the status of the disease.
After 6 months (8 cycles) of study drug treatment, you will have the CT or MRI scan every 2-4
cycles.

Length of Study:

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

This is an investigational study. Avastin™, erlotinib, cetuximab, trastuzumab, and lapatinib
are all FDA approved and commercially available. Avastin™ is FDA approved for the treatment
of colorectal cancer and lung cancer. Erlotinib is FDA approved for the treatment of lung
cancer and pancreatic cancer. Cetuximab is FDA approved for the treatment of colorectal
cancer and cancer of the head and neck. Trastuzumab is FDA approved for the treatment of
breast cancer. Lapatinib is FDA approved for the treatment of breast cancer. The use of these
drugs together is investigational and authorized for use in research only.

Up to 354 patients will take part in this study. All will be enrolled at M. D. Anderson.

Inclusion Criteria:

1. Patients with advanced or metastatic cancer that is refractory to standard therapy,
relapsed after standard therapy, or have no standard therapy that induces a CR rate of
at least 10% or improves survival by at least three months.

2. Patients must be three weeks from prior cytotoxic therapy; if they have recovered
their blood counts to eligibility levels sooner and have no mucositis or other acute
toxicities, they may be treated earlier but no sooner than two weeks after their last
chemotherapy. Patients must be two weeks or five half lives from biologic therapy,
whichever is shorter.

3. ECOG performance status /= 60%).

4. Patients must have normal organ and marrow function defined as: absolute neutrophil
count >/= 1,000/mL; platelets >/=75,000/mL; creatinine bilirubin erlotinib + cetuximab arm and the bevacizumab + trastuzumab + lapatinib arm: no
minimum absolute neutrophil count or platelet count.

5. The effects of bevacizumab on the developing human fetus are unknown. Angiogenesis is
of critical importance to fetal development, and bevacizumab is likely to have adverse
consequences in terms of fetal development. 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, for the duration of study
participation, and for 30 days after the last dose.

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

7. Life expectancy of at least 3 months.

8. Patients with a prior DVT/PE are eligible for treatment if they are receiving or have
finished receiving appropriate anticoagulation therapy.

Exclusion Criteria:

1. Patients with hemoptysis within 28 days prior to entering the study.

2. Patients with clinically significant unexplained bleeding within 28 days prior to
entering the study.

3. Uncontrolled systemic vascular hypertension (Systolic blood pressure > 140 mmHg,
diastolic blood pressure > 90 mmHg on medication).

4. Patients with clinically significant cardiovascular disease: history of CVA within 6
months, myocardial infarction or unstable angina within 6 months, or unstable angina
pectoris.

5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring parenteral antibiotics on Day 1.

6. Pregnant or lactating women.

7. History of hypersensitivity to bevacizumab, murine products, or any component of the
formulation.

8. (For patients on the sunitinib treatment arm and the trastuzumab/lapatinib treatment
arm only) Left ventricular ejection fraction of less than 50% unless the patient is
receiving an angiotensin-converting enzyme (ACE) inhibitor / angiotensin receptor
blocker (ARB) and a beta-blocker.

9. (For sorafenib treatment arm only) Hypersensitivity to sorafenib or any component of
the formulation.

10. (For erlotinib and cetuximab treatment arm only) History of hypersensitivity to
erlotinib or any component of the formulation.

11. (For erlotinib and cetuximab treatment arm only) History of hypersensitivity to
cetuximab, murine products, or any component of the formulation.

12. (For trastuzumab and lapatinib treatment arm only) History of hypersensitivity to
trastuzumab, Chinese hamster ovary cell proteins, or any component of the formulation.

13. (For trastuzumab and lapatinib treatment arm only) History of hypersensitivity to
lapatinib or any component of the formulation.

14. Patients with clinically significant gastrointestinal bleeding within 28 days prior to
entering the study.

15. Patients with hemorrhagic brain metastases.

16. Patients with prior abdominal surgery within 30 days prior to entering the study.

17. (For patients on the sunitinib treatment arm and the trastuzumab/lapatinib treatment
arm only) Left ventricular ejection fraction of less than 50%, unless the patient is
receiving an angiotensin-converting enzyme (ACE) inhibitor / angiotensin receptor
blocker (ARB) and a beta-blocker.

18. (For patients on the sunitinib treatment arm and the trastuzumab/lapatinib treatment
arm only) QTc prolongation, defined as greater than 440 milliseconds for males, and
greater than 460 milliseconds for females.