Primary Outcome Measures:
- Number of subjects reporting adverse events [ Time Frame: From first study dose through duration of study (up to 30 weeks or longer) ] [ Designated as safety issue: Yes ]
- Induction of immune response to mesothelin by enzyme-linked immunosorbent spot (ELISPOT) assay [ Time Frame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer) ] [ Designated as safety issue: No ]
Secondary Outcome Measures:
- Objective tumor response [ Time Frame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer) ] [ Designated as safety issue: No ]
- Time to progression [ Time Frame: From date of randomization until date of documented progression (by modified RECIST or immune-related response criteria) or death, assessed up to 12 months or longer ] [ Designated as safety issue: No ]
- Serum mesothelin as correlate of therapeutic response [ Time Frame: Change over time assessed at multiple time points until disease progression or death (up to 12 months or longer) ] [ Designated as safety issue: No ]
Detailed Description:
Up to 16 subjects will be enrolled in this study. Eligible subjects will receive 2 prime vaccinations of CRS-207 (1×10^9 colony-forming units [CFU] given intravenously [i.v.] over 2 hours) 2 weeks apart followed 2 weeks later by up to 6 cycles of pemetrexed and cisplatin 21 days apart. Three weeks after completion of chemotherapy, subjects will receive an additional 2 infusions (boost vaccinations) of CRS-207 3 weeks apart. Subjects will be followed every 8 weeks until disease progression by immune-related response criteria. Subjects who continue to meet dosing eligibility may receive additional CRS-207 infusions (maintenance vaccinations) every 16 weeks.
Study assessments include blood draws for safety and immune response monitoring and CT scans [with optional fluorodeoxyglucose positron emission tomography (FDG-PET)] or magnetic resonance imaging (MRI) to monitor disease status. In addition, optional tumor biopsies may be performed before, during and after treatment.
Eligibility Criteria
- Inclusion Criteria:
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- Have histologically confirmed epithelial or biphasic MPM not amenable to potentially curative surgical resection (subjects with biphasic tumors that have a predominantly (≥50%) sarcomatoid component will be excluded)
- Be at least 18 years of age
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Have an anticipated life expectancy of greater than 6 months
- For women and men of childbearing potential, a medically acceptable method of highly effective contraception (oral hormonal contraceptive, condom plus spermicide, or hormone implants) must be used throughout the study period and for 28 days after their final vaccine administration. (A barrier method of contraception must be employed by all subjects [male and female], regardless of other methods.)
- Be willing and able to give written informed consent, and be able to comply with all study procedures
- Have adequate organ function as defined by specified laboratory values
- Exclusion Criteria:
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- A candidate for curative surgery
- Surgery within 2 weeks prior to dosing
- Prior radiotherapy or biologic therapy
- Treatment with an investigational agent within 4 weeks before dosing
- Prior systemic chemotherapy
- Currently have or have history of certain study-specified heart, liver, kidney, lung, neurological, immune or other medical conditions
- Documented and ongoing brain metastases
- Have any evidence of hepatic cirrhosis or clinical or radiographic ascites
- Have clinically significant and/or malignant pleural effusion
- Known or suspected allergy or hypersensitivity to yeast or any other component of CRS-207 (e.g., glycerol), Platinol or platinum-containing compounds, or pemetrexed
- Used any systemic steroids within 28 days of study treatment
- Use more than 3 g/d of acetaminophen
- An artificial (prosthetic) joint or other artificial implant or device that cannot be easily removed (with some exceptions for dental and breast implants and biliary stents and mediports)
- Infection with HIV or hepatitis B or C at screening
- Any immunodeficiency disease or immunocompromised state or active autoimmune disease or history of autoimmune disease requiring systemic steroids or other immunosuppressive treatment
- Be a woman who is pregnant or breastfeeding
- Unable to avoid close contact with another individual known to be at high risk of listeriosis (e.g., newborn infant, pregnant woman, HIV-positive individual) during the course of CRS-207 treatment until completion of antibiotic regimen
- Conditions, including alcohol or drug dependence, intercurrent illness, or lack of sufficient peripheral venous access, that would affect the patient’s ability to comply with study visits and procedures
