Bevacizumab and Temsirolimus Alone or in Combination With Valproic Acid or Cetuximab in Treating Patients With Advanced or Metastatic Malignancy or Other Benign Disease

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of
treatment with bevacizumab and temsirolimus in combination and plus valproic acid or
cetuximab.

SECONDARY OBJECTIVES:

I. Preliminary descriptive assessment of anti-tumor efficacy of each combination.

II. Preliminary assessment of the pharmacokinetic, pharmacodynamic markers of target
inhibition and correlates of response (optional).

OUTLINE: This is a dose-escalation study of bevacizumab and temsirolimus. Patients are
assigned to 1 of 3 treatment groups.

GROUP I: Patients receive temsirolimus intravenously (IV) over 30-60 minutes on days 1, 8,
15, and 22; bevacizumab IV over 30-90 minutes on days 1 and 15; and cetuximab IV over 1-2
hours on days 1, 8, 15, and 22.

GROUP II: Patients receive temsirolimus and bevacizumab as in Group I and valproic acid
orally (PO) daily on days 1-7 and 15-21.

GROUP III: Patients receive temsirolimus and bevacizumab as in Group I.

In all groups, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

Inclusion Criteria:

- Patients with advanced or metastatic cancer that is refractory to standard therapy,
relapsed after standard therapy, or have no standard therapy that induces a complete
response of at least 10% or improves survival by at least three months; in addition,
patients with disease that are "benign" by pathology, but relentlessly progressive,
leading to disability, pain, and premature death in the majority of cases (including,
but not limited to lymphangioleiomyomatosis [LAM], type 2 neurofibromatosis [NF],
Erdheim Chester disease, and Castleman's disease) may also be considered for
enrollment

- Patients should be at least four weeks from the last day of therapeutic radiation or
cytotoxic chemotherapy or from antibody therapy, or at least five half-lives from
non-cytotoxic targeted or biologic therapy; patients may have received palliative
radiation immediately before (or during) treatment provided radiation is not to the
only target lesion available

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Karnofsky >= 60%

- Lansky performance status of >= 60% for participants 16 years old or younger

- Absolute neutrophil count >= 1,000/mL

- Platelets >= 50,000/mL

- Creatinine =< 3 X upper limit of normal (ULN)

- Total bilirubin =< 3.0

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 5 X ULN

- Fasting level of total cholesterol of no more than 350 mg/dL

- Triglyceride level of no more than 400 mg/dL

- 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 90 days after the last dose

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

- Patients may not be receiving any other investigational agents and/or any other
concurrent anticancer agents or therapies

Exclusion Criteria:

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

- Uncontrolled systemic vascular hypertension (systolic blood pressure > 140 mmHg,
diastolic blood pressure > 90 mmHg on medication)

- Patients with clinically significant cardiovascular disease: History of CVA
(cerebrovascular accident) within 6 months, myocardial infarction or unstable angina
within 6 months, unstable angina pectoris

- Pregnant or breast-feeding women

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

- History of hypersensitivity to temsirolimus or its metabolites (including sirolimus),
polysorbate 80, or to any component of the formulation

- History of hypersensitivity to cetuximab, murine products, or any component of the
formulation

- Patients that are taking cytochrome P450 family 3, subfamily A, polypeptide 4 (CYP3A4)
inducers and/or inhibitors; if a patient has a history of taking CYP3A4 inducers
and/or inhibitors prior to enrollment on the protocol, it is strongly recommended that
the patient stops the drug and waits at least 5 half-lives of said drug before
initiating therapy on protocol

- Colorectal cancer patients with known v-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog (KRAS) mutation (for the arm combining bevacizumab, temsirolimus and
cetuximab)

- Patients who have had major surgery within 6 weeks of enrollment in the study