Anti-TGF Monoclonal Antibody (GC1008) in Relapsed Malignant Pleural Mesothelioma

Primary: - To assess progression-free survival rate at three months.

Secondary: - To determine the toxicity and safety of systemic infusion of anti-TGF beta antibody at three-week dosing intervals. - To assess time to progression and overall survival - to assess response rate using Modified RECIST Criteria for Mesothelioma Additional Objectives: - To assess efficacy using serial measurements of serum [and intrapleural, if indwelling catheter in place] biomarkers, including serum-mesothelin related peptide (SMRP/Mesomark®) and osteopontin. - To assess systemic [and intrapleural if indwelling catheter in place] humoral anti-tumor immune responses after repeated anti-TGF beta antibody instillation. - To assess systemic [and intrapleural, if indwelling catheter in place] TGF beta, and other cytokine levels after repeated anti-TGF beta antibody instillation. - To assess biologic response measurements of TGF beta blockade from serum tests and from pleural fluid or biopsy tissue if this is available.

Inclusion criteria

• Pathologically [histologically or cytologically] documented pleural malignant mesothelioma.

Patients must have had at least one, but no more than two prior systemic therapies, at least one of which contained pemetrexed.

• Documented progressive disease evaluable by Modified RECIST criteria. [Progressive symptoms after 1st line therapy in the absence of objective progression are acceptable as a criterion for enrollment]. Patients who have had previous extrapleural pneumonectomy and disease recurrence will be eligible if they have no other exclusion criteria.
• ECOG Performance status of 0 or 1.
• Greater or equal to 18 years of age.
• Male and female patients of child-producing potential must agree to use effective contraception while enrolled on study and receiving the experimental drug, and for at least 3 months after the last treatment.
• Women of childbearing potential must have a negative serum or urine pregnancy test within 1 week prior to beginning treatment on this trial.
• Must be able and willing to give written informed consent. Patients may not be consented by a durable power of attorney.
• Serum albumin greater or equal to 2.5
• Adequate organ function
• Patients must have negative tests for human immunodeficiency virus (HIV) and for hepatitis viruses B and C (antibody and/or antigen) unless the result is consistent with prior vaccination or prior infection with full recovery.
• At the time of enrollment, patients must be greater than 3 weeks since major surgery, radiotherapy, chemotherapy (greater or equal to 6 weeks if they were treated with a nitrosourea, mitomycin or monoclonal antibody), immunotherapy, or biotherapy/targeted therapies and recovered from the toxicity of prior treatment to less than or equal to Grade 1, exclusive of alopecia. Concurrent non-protocol cancer therapy is not permitted. (In patients who received long acting agents, a treatment free interval of 2 half lives should be considered.) Note: Although a patient can be entered by these criteria, if a patient is less than 3-6 months from radiotherapy or talc pleurodesis, FDG-PET scanning will not be useful. 12).

Exclusion criteria

• Known central nervous system (CNS) metastases, meningeal carcinomatosis, malignant seizures, or a disease that either causes or threatens neurologic compromise (e.g., unstable vertebral metastases).
• Presence of pericardial effusion
• Rapidly re-accumulating, symptomatic malignant pleural effusions status-post thoracentesis or pleural catheter insertion that requires immediate mechanical or chemical pleurodesis for adequate palliation.
• Active thrombophlebitis, thromboembolism, hypercoagulability states, bleeding, or use of anti-coagulation therapy (including lovenox, warfarin, or anti platelet agents such as aspirin [with the exception of low dose ASA ~ 81 mg/d] , clopidogrel, ticlopidine, dipyridamole, and other agents used to induce long-acting platelet dysfunction). Patients with a history of deep venous thrombosis may participate if successfully treated, completely resolved, and no treatment has been given for greater than 4 months.
• Pregnant or nursing women, due to the unknown effects of GC1008 on the developing fetus or newborn infant.
• Other active invasive malignancy requiring ongoing therapy.
• Patients with an organ transplant, including those that have received an allogeneic bone marrow transplant.
• Use of investigational agents within 4 weeks prior to study enrollment (within 6 weeks if the treatment was with a long-acting agent such as a monoclonal antibody).
• Patients on immunosuppressive therapy
• Significant or uncontrolled medical illness, such as congestive heart failure (CHF), myocardial infarction, symptomatic coronary artery disease, significant ventricular arrhythmias within the last 6 months, or significant pulmonary dysfunction.

Patients with a remote history of asthma or active mild asthma may participate.

• Active infection, including active herpes zoster, as well as unexplained fever (temperature 38.1C), or antibiotic therapy within 1 week prior to enrollment.
• Systemic autoimmune disease (e.g., systemic lupus erythematosus, active rheumatoid arthritis, etc.).
• Positive stool fecal occult blood test (patients who are positive will need a standard GI work-up consisting of an Esophagogastroduodenoscopy (EGD) and Colonoscopy) prior to enrollment to rule out possible reasons for bleeding. A patient will be eligible with negative results for both exams.
• Active GI bleeding within past 5 years other than due to benign anorectal causes such as hemorrhoids, fissures and stricture.
• A known allergy to any component of GC1008.
• Patients who, in the opinion of the Investigator, have significant medical or psychosocial problems that warrant exclusion.