The purpose of this research study is to evaluate how effective the combination of Carboplatin, Bevacizumab (Avastin™) and, Pemetrexed (Alimta™) is in the treatment of patients with Malignant Pleural Mesothelioma (MPM). A combination of cisplatin and pemetrexed is considered standard for this disease and typically off protocol patients would receive cisplatin or carboplatin and pemetrexed as standard of care.

Primary:

Determine the Overall Survival (OS), (median survival(MS) and 1-yr survival (1-yr S)), in newly diagnosed patients with MPM who are treated with a regimen consisting of cisplatin, bevacizumab, and pemetrexed. Patients will be followed until death and survival curves will be generated. Response rates will be assessed.

Secondary:

• Estimate the progression free survival (PFS)
• Determine the response rates
• Safety of the regimen will also be assessed.

The planned length of the study (first subject screened to last subject enrolled) is 24 months. The planned length of the entire study (enrollment period + the treatment period + a follow-up period of at least 12 months) is 36 months.

A blood sample will be taken to check the patient's blood and platelet counts before each Pemetrexed dose. Before each cycle, we will review the patient's medical history, give them a physical exam (including vital signs: blood pressure, heart rate, breathing rate, temperature), and check their weight, performance status and blood. The patient's tumor will be measured after every other cycle. The patient's urine will be tested before every other cycle with Bevacizumab.

Treatment Regimen: To ensure the safety, before initiating the phase II dose, we will have a brief phase I portion, where tiered dose escalation to the anticipated phase II dose will occur.

Tier I Carboplatin at AUC of 5 Bevacizumab 15 mg/Kg I.V. on day 1 Pemetrexed 500 mg/m2 on day 1 Every 21 days

Tier II (Target dose) Carboplatin at AUC of 6 Bevacizumab 15 mg/Kg I.V. on day 1 Pemetrexed 500 mg/m2 on day 1 Every 21 days

Tier (-1) Carboplatin at AUC of 4 Bevacizumab 15 mg/Kg I.V. on day 1 Pemetrexed 500 mg/m2 on day 1 Every 21 days

With each cycle, we will give the following:

Folic Acid 300 µg to 1 mg orally once daily starting day 1. B12 injections given subcutaneously any time between days -7 to 1 of the first cycle and then every 9 weeks.

Dexamethasone 4mb BID on day-1,0, and day +1

Patients will be enrolled in cohorts of three. If one of the three patients has a dose limiting toxicity (DLT) then three additional patients will be enrolled. If no DLTs occur then patients will be accrued in the next dose level. If two DLTs occur in a cohort of three patients or in an expanded cohort of 6 patients then that dose level will be called the Maximum Administered Dose (MAD). A dose level below will be called the MTD and will be the recommended dose for further phase II testing. Al three patients in a cohort must complete one full cycle, before proceeding to the next cohort.

DLT will be defined as grade 4 neutropenia, febrile neutropenia, and any grade 3 or 4 non-hematologic toxicity except for alopecia and nausea/vomiting/diarrhea without adequate prophylaxis. (CTC version 3.0).

No further dose escalation will be attempted beyond dose Tier 2. If there are no dose-limiting toxicities in dose Tier 2 then this will be considered the phase II dose. If there is a DLT in dose Tier 1 then we will enroll 3 patients in Tier -1 and if no further DLTs occur then Tier -1 will be the phase II dose.

When the patient goes off-study, they will have a physical exam, tumor measurements, and blood test evaluations.

Each study patient will be contacted every 3 months for the rest of their life. Information about any extra treatments they have received will be collected and recorded if they are taken off-study because their disease got worse. If they are taken off-study for any other reason, we will collect information on any extra anti-cancer treatments they have received for Malignant Pleural Mesothelioma (MPM).

A: Tiered Dose Escalation/Phase II Dose,

B: Maintenance Therapy

Inclusion Criteria:

• Patient must have histologically proven diagnosis of Malignant Pleural Mesothelioma (MPM)
• Patient must have MPM with measurable disease.
• Patients must have Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
• Patient must have adequate renal function with a serum creatinine level of less than 1.5 mg/dl and patient should have a calculated creatinine clearance of more than 40ml/min.
• Patient must have adequate hepatic function with a serum bilirubin level of less that 3mg/dl, and an alkaline phosphatase, ALT and AST of less than five times the upper limit of normal
• Patient must also have evidence of adequate bone marrow function with an absolute neutrophil count of more than 1500 cells per deciliter and a platelet count of more than 100,000 per deciliter.
• Patients must be more than 28 days since prior open biopsy; more than 7 days since prior fine-needle aspiration; more than 7 days since prior core biopsy; more than 28 days since prior surgery.
• Patients must be able to take dexamethasone, folic acid, and vitamin B-12 supplementation.
• All patients must sign informed consent that will detail the investigational nature of the study in accordance with the institutional and federal guidelines.
• Patients with clinically significant pleural effusions or ascites (symptomatic or detectable by clinical exam) should have their effusions drained prior to enrollment on the clinical trial.

Exclusion Criteria:

• Patients with hypercalcemia (corrected calcium of more than 11 mg/dl) will be excluded.
• Patients with history of hemoptysis, haematemesis, coagulopathy or thrombosis will be excluded.
• Patients requiring anticoagulation for any reason will be excluded.
• History of palliative radiation therapy within 2 weeks
• Blood pressure of >160/100 mmHg, despite adequate anti-hypertensive use.
• Currently ongoing unstable angina
• New York Heart Association (NYHA) Grade II or greater congestive heart failure.
• History of stroke within 6 months
• Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to the day of initiation of treatment, anticipation of need for major surgical procedure during the course of the study
• Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to the day of initiation of treatment.
• Pregnant (positive pregnancy test) or lactating
• Urine calculated creatinine clearance of less than 40ml/minute. - History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to Day 0
• Serious, non-healing wound, ulcer, or bone fracture
• Inability to comply with study and/or follow-up procedures

Laboratory Values:

• Patient must have adequate renal function with a serum creatinine level of less than 1.5 mg/dl and patient should have a calculated creatinine clearance of more than 40ml/min.
• Patient must have adequate hepatic function with a serum bilirubin level of less than 3 mg/dl, and an alkaline phosphatase, ALT and AST of less than five times the upper limit of normal
• Patient must also have evidence of adequate bone marrow function with an absolute neutrophil count of more than 1, 500 cells per deciliter and a platelet count of more than 100,000 per deciliter.