This is a non-randomized Phase II study. Patients determined at initial diagnosis to have a carcinoma of unknown primary site (CUP) will have their treatment selected with the use of a molecular profiling assay. The assay will be performed on paraffin-embedded tumor tissue from a biopsy specimen. Patients given specific diagnoses (e.g., lung, pancreas, colon, breast, renal cell, prostate and ovarian cancer) will receive treatment regimens of proven activity. If no specific diagnosis is made with the molecular profiling assay, empiric chemotherapy with paclitaxel, carboplatin, bevacizumab and erlotinib will be administered.

The primary objective of the study is evaluate the impact of the molecular assay prediction on the efficacy of therapy for patients with carcinoma of unknown primary site (CUP). Investigators will use tumor profiling results to direct standard, site-specific first-line therapy for patients with CUP.

Inclusion Criteria:

1. Patients must have carcinoma of unknown primary site after the following diagnostic procedures have been performed and are unrevealing of a primary site:

   • Complete medical history and physical examination,
   • Complete blood counts, chemistry profile,
   • CT scans of the chest and abdomen,
   • Directed evaluation of any symptomatic areas,
   • PET scan (recommended).

2. Patients must have biopsy-proven metastatic carcinoma, with any of the following light microscopic histologies:

   • Adenocarcinoma,
   • Poorly differentiated adenocarcinoma,
   • Poorly differentiated carcinoma (all patients with poorly differentiated carcinoma must have immunoperoxidase stains to rule out other treatable malignancies [e.g., lymphoma, neuroendocrine carcinoma]),
   • Poorly differentiated squamous carcinoma.

3. Patients must have biopsy material available from a surgical biopsy, a core needle biopsy, or a fine needle aspiration biopsy to provide an adequate specimen (must be 40% tumor) for the molecular profiling assay.

4. An ECOG performance status 0, 1, or 2.

5. No previous treatment with any systemic therapy.

6. Measurable or evaluable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST).

7. Laboratory values as follows:

   • WBC 4000/micro L,
   • Platelets 100,000/micro L,
   • Serum bilirubin <1.5 times the institutional upper limits of normal (ULN),
   • Serum creatinine < 2.0 mg/dL.

8. Patients with brain metastases are eligible only if all lesions have been controlled by surgical resection or radiation therapy, the patient is not steroid-dependent, and the patient meets all other eligibility criteria.

9. Patients must be > 4 weeks from any major operative procedure.

10. To be eligible for the TREATMENT portion of the study, patients must have one of the five following diagnoses: colorectal, pancreas, NSCLC, ovary, renal cancer.

11. Patients must be able to understand the nature of this study and give written informed consent.

Exclusion Criteria:

1. Patients with the following specific syndromes are not eligible:

   • Patients with neuroendocrine carcinoma,
   • Women with adenocarcinoma isolated to axillary lymph nodes,
   • Women with adenocarcinoma isolated to peritoneal involvement,
   • Patients with carcinoma involving only 1 site, with resectable tumor at that site, or
   • Patients with squamous carcinoma limited to cervical, supraclavicular, or inguinal lymph nodes.

2. Patients with uncontrolled brain metastases and all patients with meningeal metastases.

3. Patients with insufficient biopsy material available for molecular profiling assay.

4. Women who are pregnant or lactating. All females of child-bearing potential must have a negative serum or urine pregnancy tests within 7 days prior to study treatment.

5. Men and women of childbearing potential are required to use effective methods of contraception during this study and for 6 months after ending therapy.

6. Patients who have received any other experimental drug within 28 days of starting treatment.

Exclusion Criteria for All Patients Receiving Bevacizumab-Containing Regimens

1. Patients with history of acute myocardial infarction within 6 months, other clinically significant cardiovascular disease (e.g., unstable angina, New York Heart Association [NYHA] grade 2 congestive heart failure [CHF], serious cardiac arrhythmias requiring medication) or > grade 2 vascular disease.

2. Patients with uncontrolled hypertension (systolic blood pressure [BP] 150 or diastolic BP >100mm Hg) or uncontrolled cardiac arrhythmias.

3. Prior hypertensive crisis or hypertensive encephalopathy.

4. Patients with clinical history of hemoptysis (defined as bright red blood of

   ½ teaspoon per episode) or hematemesis within 1 month prior to Day 1.

5. Patients with PEG tubes or G tubes.

6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 or anticipation of need for major surgical procedure during the course of the study.

7. Core biopsy or other minor surgical procedure excluding placement of a vascular access device, within 7 days prior to Day 1.

8. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to Day 1.

9. Patients with proteinuria (1000 mg/24 hours) at screening will be excluded. A 24-hour urine collection is not required in all patients (e.g., patients whose treatment plans exclude bevacizumab); however, all patients receiving bevacizumab with 1+ proteinuria on dipstick urinalysis at study entry must have a subsequent 24-hour urine collection.

10. Patients with any non-healing wound, ulcer, or long bone fracture.

11. Patients with any history of a bleeding diathesis or coagulopathy (in the absence of therapeutic anticoagulation).

12. Patients with a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning bevacizumab.

13. Patients with a history of stroke or transient ischemic attach within 6 months prior to first bevacizumab dose.

14. Known hypersensitivity to any component of bevacizumab.

15. Patients with history of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of a novel regimen, or that might affect the results of this study or render the subject at high risk for treatment complications.

The sponsor can review/embargo results communications prior to public release for a period that is >60 but =180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites