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

To determine the objective response [ Time Frame: Weeks 24 ] [ Designated as safety issue: No ]
The objective response is defined as a confirmed complete response (CR), or partial response (PR) according to the modified RECIST Criteria for pleural mesothelioma and the immune-related (ir) Response Criteria

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

Detailed Description:

Primary endpoint:

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

Secondary endpoints:

To define toxicity profile according to NCI CT-CAE V. 3
To assess the overall survival (OS)
To estimate disease control rate (DCR) (proportion of patients with best response of CR+PR+SD) according to the modified Recist criteria
To assess the progression-free survival in treated patients according to modified Recist criteria
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