Primary Outcome Measures:
Est MTD, study pharmacokinetics, observe anti-tumor response
Secondary Outcome Measures:
Monitor antibody formation to drug and impact of these on PK’s
Detailed Description:
- Background:
- SS1(dsFV)PE38, is a recombinant immunotoxin targeting the tumor antigen mesothelin that is highly expressed in malignant mesothelioma. The maximum tolerated dose (MTD) of SS1(dsFV)PE38 has been established in a phase I study.
- Combination therapy with pemetrexed plus cisplatin is the standard first line therapy for malignant mesothelioma, but results in a median overall survival of only 12.1 months.
- Combination of SS1(dsFV)PE38 with pemetrexed plus cisplatin could result in improved outcomes for patients with mesothelioma.
- Objectives:
- To determine the MTD of SS1(dsFV)PE38 that can be safely administered in combination with pemetrexed plus cisplatin in patients with mesothelioma.
- To characterize the toxicity profile of SS1(dsFV)PE38.
- To study the pharmacokinetics of SS1(dsFV)PE388.
- To observe anti-tumor activity, if any of SS1(dsFV)PE38 in combination with pemetrexed plus cisplatin.
- Eligibility:
- Subjects with histologically confirmed epithelial pleural mesothelioma.
- No prior radiotherapy (except palliative extra-thoracic localized radiotherapy),systemic chemotherapy or biologic therapy for pleural mesothelioma.
- Design:
- This is a phase I dose-escalation study of SS1(dsFV)PE38 in combination with pemetrexed plus cisplatin.
- The dose of pemetrexed plus cisplatin will be the standard dose approved for malignant mesothelioma. The dose of SS1(dsFV)PE38 will be escalated to find the safe dose in combination with pemetrexed plus cisplatin.
- SS1(dsFV)PE38 will be administered concurrently with pemetrexed plus cisplatin in cycles one and two, and subjects will receive additional cycles of pemetrexed and cisplatin as per standard practice.
- Patients will be assessed for response every 6 weeks.
Eligibility Criteria
- Inclusion Criteria:
- Subjects must meet all of the following criteria to be eligible to participate in the study:
- Subjects must have histologically confirmed epithelial or biphasic pleural mesothelioma not amenable to potentially curative surgical resection. However, patients with biphasic tumors that have a predominantly sarcomatoid component will be excluded.
- Measurable disease
- Subjects must be greater than or equal to 18 years old
- Karnofsky Performance Status (KPS) of greater than or equal to 70
- Life expectancy of greater than 3 months, as assessed by the principal investigator.
- Adequate organ function with:Hepatic function: serum transaminases (either ALT or AST) or bilirubin, less than or equal to Grade 1, unless due to cancer or Gilbert’s disease; less than or equal to Grade 2, if due to cancer
- Renal function: serum creatinine clearance greater than or equal to 60mL/min as estimated by Cockroft-Gault formula.
- Bone marrow function: ANC of at least 1,500/mm (3), Platelet count at least 100,000/mm (3)
- Pulmonary Function: FEV (1) greater than or equal to 50 percent of predicted value (post-pleural drainage and bronchodilation if these are indicated)
- Must be able to understand and sign informed consent
- Female and male subjects agree to use an approved method of contraception during the study
- Exclusion Criteria:
-
- Subjects must not be pregnant or breast feeding
- Prior radiotherapy (except palliative extra-thoracic localized radiotherapy) or biologic therapy for malignant pleural mesothelioma within 4 weeks
- Prior systemic chemotherapy for malignant pleural mesothelioma
- Documented and ongoing central nervous system involvement with their malignant disease (history of CNS involvement is not an exclusion criterion but the CNS metastases should have been adequately treated (radiation or surgical resection) and subjects are free from symptoms for 3 months off steroids).
- Clinically significant heart disease (New York Heart Association Class III or IV)
- Active bacterial or fungal infection.
- Baseline coagulopathy greater than or equal to Grade 3 unless due to anticoagulant therapy
- Surgery or pleurodesis within 2 weeks
- HIV positive serology (due to increased risk of severe infection and unknown interaction of SS1(dsFv)PE38 with antiretroviral drugs)
- Hepatitis B surface antigen positivity
- Subjects with other (non-mesothelioma) cancers who meet eligibility criteria and have had less than 5 years of disease-free survival will be considered on a case-by-case basis
- Uncontrolled, symptomatic, intercurrent illness including but not limited to: infections requiring systemic antibiotics, unstable angina pectoris, cardiac arrhythmia, psychiatric illness, or social situations that would limit compliance with study requirements.
