The Anti-CTLA-4 Monoclonal Antibody Tremelimumab in Malignant Mesothelioma

A SECOND-LINE, SINGLE ARM, PHASE II CLINICAL STUDY WITH TREMELIMUMAB, A FULLY HUMAN ANTI-CTLA-4 MONOCLONAL ANTIBODY, AS MONOTHERAPY IN PATIENTS WITH UNRESECTABLE MALIGNANT MESOTHELIOMA. The MESOT-TREM-2012

RATIONAL: Preliminary results fron the Study MESOT-TREM-2012 indicate a promising activity of tremelimumab in malignant mesothelioma (MM) patients.

PURPOSE: The proposed study MESOT-TREM-2012 aims to explore the efficacy of a more intensive schedule of treatment with tremelimumab in 29 MM patients. Subjects will receive investigational product every 4 weeks (wks) for 6 doses, followed by doses every 12 wks until confirmed disease progression.

Primary endpoint:

1) To assess the rate of objective clinical complete response (CR) or partial response (PR)

Secondary endpoints:

1. To define toxicity profile according to NCI CT-CAE V. 3
2. To assess the overall survival (OS)
3. To estimate disease control rate (DCR) (proportion of patients with best response of CR+PR+SD) according to the modified Recist criteria
4. To assess the progression-free survival in treated patients according to modified Recist criteria
5. To evaluate qualitative and quantitative changes in cellular and humoral immune responses

Inclusion Criteria:

• Histologically or cytologically confirmed MM
• Have received only one prior systemic chemotherapy platinum-based regimen for advanced MM
• Measurable disease, defined at least 1 unidimensionally measurable lesion > 20 mm by conventional techniques or > 10 mm by spiral CT scan (modified RECIST criteria)
• Disease not amenable to curative surgery
• No known brain metastasis
• Age 18 and over
• Performance status 0-2
• Life expectancy > 12 weeks
• Adequate hematologic, hepatic and renal function
• Platelet count > 75000/mm3
• Absolute granulocyte count > 1000/mm3
• Hemoglobin > 9 g/dL
• Bilirubin total < 1.5 x ULN (Upper limited normal), except patients with documented Gilbert's syndrome, who must have a total bilirubin < 3.0 mg/dl
• AST and ALT < 2.5 x ULN ( < 5 x ULN if documented liver metastasis are present)
• Creatinine level < 2mg/dl or calculated creatinine clearance > 60 mL/min as determined by the Cockcroft Gault equation.
• Not pregnant or nursing
• Fertile patients must use effective contraception
• Patient must be willing and able to provide written informed consent, and the trial have to be approved by the institutional review board at each institution

Exclusion Criteria:

• Symptomatic chronic inflammatory or autoimmune disease
• Active hepatitis B or C
• Prior treatment with tremelimumab or other anti-CTLA-4 antibody or anti-PD1, anti-PDL-1 agents
• Clinically relevant cardiovascular disease
• History of psychiatric disabilities, potentially interfering with the capability of giving adequate informed consent
• Uncontrolled active infections
• Other concurrent chemotherapy, immunotherapy, radiotherapy or investigational agents
• History of other malignancies except for adequately treated basal cell carcinoma or squamous cell skin cancer or carcinoma of cervix, unless the patient has been disease-free for at least 5 years