A Phase I Trial of the IGF-1R Antibody AMG 479 in Combination With Everolimus (RAD001) and Panitumumab in Patients With Advanced Cancer (The RAP Trial)

Inclusion Criteria:

1. Histologically and/or cytologically confirmed malignant solid tumor that is
refractory to standard therapies, or for which no standard therapies exist. Disease
must be measurable by RECIST criteria.

2. Age >18 years.

3. ECOG performance status 0-2.

4. Life expectancy of at least 3 months.

5. Subjects must have adequate organ and marrow function as defined below:

- Absolute neutrophil count >/=1,500/μl

- Platelets >/=100,000/μl

- Magnesium > 1.8 mg/dL

- Phosphorus > 2.3 mg/dL

- Total bilirubin
- AST(SGOT)/ALT(SGPT) PTT
- Creatinine clearance >/=40 mL/min/m2 by Cockroft-Gault or MDRD equation

- Hemoglobin >9 g/dL

- Continuation of erythropoietin products is permitted. Hemoglobin must be stable
above 9 g/dL for at least 2 weeks without blood transfusion to maintain
hemoglobin level.

- Fasting blood sugar
- Patient may be on diabetic medication to achieve glucose control:

- Documented fasting blood sugars
- Diabetic subjects who have recently had their glycemic control regimens
adjusted and have documented fasting blood glucose concentrations ≤ 160
mg/dL may be considered regardless of HgbA1c value, if per investigator
discretion the subject is considered to have adequate glycemic function

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

Exclusion Criteria:

1. Radiation therapy, hormonal therapy, biologic therapy or chemotherapy for cancer
within the 28 days prior to day 1 of study drug.

2. Active CNS metastases. MRI (or CT) required within 3 months of starting treatment for
all tumor types known to commonly metastasize to the brain (i.e. all tumors except
pancreas, colorectal, ovarian) and for all patients with CNS symptoms that may
represent CNS metastases. Metastases which have been treated with radiotherapy > 2
months prior to start of protocol therapy and are asymptomatic (off steroid therapy
for at least 1 month) may be included. Patients must have had normal or stable (if
treated, no new lesions) brain imaging (CT or MRI) within the two months prior to day
1 of study drug.

3. Inadequately controlled hypertension (defined as systolic blood pressure 140 and/or
diastolic blood pressure > 90 mmHg). Initiation of antihypertensive is permitted
provided adequate control is documented over at least 1 week prior to day 1 of study
drug.

4. Evidence of active bleeding diathesis or coagulopathy.

5. No warfarin therapy. Low molecular weight heparin anticoagulation is permitted
provided that patients have been clinically stable on anti-coagulation for at least 2
weeks prior to day 1 of study drug and meet platelet inclusion criteria. No history
of active GI bleeding or other major bleeding within previous 6 months prior to day 1
of study drug.

6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
prior to day 1 of study drug (56 days for hepatectomy, open thoracotomy, major
neurosurgery) or anticipation of need for major surgical procedure during the course
of the study.

7. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to day 1 of study drug.

8. Serious, non-healing wound, ulcer, or bone fracture.

9. Any prior history of hypertensive crisis or hypertensive encephalopathy.

10. New York Heart Association (NYHA) Grade II or greater congestive heart failure.

11. History of clinically significant vascular disease, including any of the following
within 6 months prior to day 1 of study drug: myocardial infarction or unstable
angina, percutaneous coronary intervention, bypass grafting, ventricular arrhythmia
requiring medication, stroke or transient ischemic attack, symptomatic peripheral
arterial disease and/or involvement of great vessels by tumor with or without
vascular grafting.

12. Chronic treatment with systemic steroids or another immunosuppressive agent with the
following exceptions:

Intermittent steroids may be used on an as-needed basis (e.g. treatment for
chemotherapy-related nausea.) Patients on physiologic replacement doses of steroids
due to adrenal insufficiency for any reason may remain on these medications.

13. A known history of HIV seropositivity, hepatitis C virus, acute or chronic active
hepatitis B infection, or other serious chronic infection requiring ongoing
treatment.

14. Impairment of gastrointestinal function or gastrointestinal disease that may
significantly alter drug absorption (e.g. inflammatory bowel disease, uncontrolled
nausea, vomiting, diarrhea, malabsorption syndrome or significant small bowel
resection).

15. Patient unwilling to or unable to comply with the protocol.

16. Medical need for the continuous administration of any drugs which affect CYP3A4
though the use of low dose glucocorticoids (e.g. Dexamethasone equivalent) for anorexia and /or nausea is permitted.

17. History of interstitial lung disease e.g. pneumonitis or pulmonary fibrosis, or any
evidence of interstitial lung disease on baseline chest CT scan.

18. Patients who are pregnant and/or lactating are excluded from this study. (The effect
of the investigational drugs on the developing human fetus is not known, but these
drugs are likely to be embryo- and feto-toxic. Women of child-bearing potential and
men must agree to use two forms of adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to day 1 of study drug, the duration of study
participation and 6 months after the last dose of study drug. Should a woman become
pregnant or suspect she is pregnant while she or her partner are participating in
this study, she should inform her treating physician and study PI immediately. Oral,
implantable, or injectable contraceptives may be affected by cytochrome P450
interactions, and are therefore not considered effective for this study. )

19. Other concurrent severe and/or uncontrolled medical, psychiatric or social conditions
that could compromise the safety or compliance of treatment as so judged by treating
physician. Examples include but are not limited to:

History of severely impaired lung function defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is room air.

Uncontrolled diabetes mellitus consistent fasting blood glucose readings > 160 mg/dL
or < 50 mg/dL). Use of diabetic medications is permitted.

Hyperlipidemia (>CTC Grade 2: Total Cholesterol > 300-400; Triglycerides > 2.5 ULN).
Use of lipid lowering agents is permitted.

Other: e.g. severe infection, severe malnutrition, ventricular arrhythmias, known
active vasculitis of any cause, tumor invasion of any major blood vessel, severe
chronic liver or renal disease, active upper GI tract ulceration.

20. No immunizations with attenuated live vaccines within one week of study entry or
during study period.