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

• Disease control rate (DCR) [ Time Frame: 1 year ] [ Designated as safety issue: No ]
  DCR is the proportion of treated subjects that achieved confirmed CR or PR or stable disease (SD) The DCR is assessed using the modified RECIST Criteria for pleural mesothelioma umor assessment and the the immune-related response criteria
• Safety [ Time Frame: 3 years ] [ Designated as safety issue: Yes ]
  The assessment of safety includes serious and non-serious adverse events according to NCI-CTC criteria version 3.0. In addition, laboratory evaluation, abnormal vital signs and physycal examination findings are also included.
• Progression free survival [ Time Frame: 1 years ] [ Designated as safety issue: No ]
  Progression free survival is computed from the first day of study treatment to the day of documented progression according to the modified RECIST Criteria for pleural mesothelioma or death, whichever occurs first

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