Purpose: This clinical trial will evaluate the safety and immune response of the sequential administration cancer vaccine CRS-207 followed by standard of care chemotherapy (pemetrexed and cisplatin). CRS-207 is a weakened (attenuated) form of Listeria monocytogenes that has been genetically-modified to reduce its capacity to cause disease, while maintaining its ability to stimulate potent immune responses. CRS-207 has been engineered to elicit an immune response against the tumor-associated antigen mesothelin, which has been shown to be present at higher levels on certain tumor cells (such asmesothelioma) than on normal cells. Pemetrexed and cisplatin are the standard chemotherapy regimen to treat malignant pleural mesothelioma. This trial will evaluate whether giving CRS-207 cancer vaccine with chemotherapy will induce anti-tumor immune responses and/or objective tumor response.

Experimental Arm: Vaccine plus chemotherapy

Weeks 1 and 3: CRS-207 (1 × 10^9 CFU)

Weeks 5, 8, 11, 14, 17 and 20 (up to 6 cycles every 21 days): Pemetrexed (500 mg/m2) and cisplatin (75 mg/m2)

Weeks 23 and 26: CRS-207

Maintenance Vaccinations: CRS-207 every 16 weeks (starting at Week 30) until disease progression

Assigned Interventions: Biological: Vaccine plus chemotherapy

• CRS-207
• Listeria
• Pemetrexed
• Cisplatin
• ALIMTA
• Platinol

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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.

Experimental Arm: single arm with Tremelimumab

Tremelimumab: 10mg/Kg ev day 1 every 4 weeks for 6 doses in induction phase, then every 12 weeks in maintenance phase until disease progression of severe toxicity

Assigned Intervention:

• Drug: Tremelimumab
  Tremelimumab is administered as endovenous infusion
• Other Name: CP-675,206

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Purpose: This study is for patients with malignant mesothelioma of the lung lining (called pleura) who are planning to have pemetrexed-cisplatin chemotherapy.

We are investigating whether giving a vaccine called TroVax® with pemetrexed-cisplatin chemotherapy is both safe and potentially beneficial in patients with mesothelioma. This vaccine has been used in combination with chemotherapy in other types of cancer and has been shown to be safe. Cancer vaccines work by stimulating the person’s immune system to fight the disease, in a similar way to the immune system fighting infection. In laboratory experiments, the vaccine has been shown to stimulate an immune response to a particular protein widely found on mesothelioma cells called 5T4. In patients with mesothelioma it is hoped that the vaccine will stimulate the immune system to attack mesothelioma cells carrying the 5T4 protein.

Pemetrexed-cisplatin chemotherapy is currently seen as the best treatment for patients with mesothelioma, and this is why we plan to combine it with the vaccine. It is hoped that the combination of the TroVax® vaccine and chemotherapy is more beneficial than chemotherapy alone.

Pemetrexed-cisplatin will be given into a vein in the arm (intravenously) every 3 weeks. The TroVax® vaccine will be given as an injection into the shoulder muscle (intramuscularly) 3 weeks before chemotherapy starts, one week before chemotherapy starts, then every 3 weeks. Each participant will receive 4 chemotherapy and 9 vaccine treatments if they complete the planned trial schedule. We aim to recruit 26 patients into the trial over a two year period. If this study shows that pemetrexed-cisplatin chemotherapy plus the TroVax® vaccine is safe and beneficial in terms of stimulating the immune system, the combination will be tested further in larger clinical trials.

Arms: Experimental: TroVax®

In this single-arm study, all participants will receive 9 injections of the TroVax® vaccine, plus standard cisplatin and pemetrexed chemotherapy.

Interventions

Biological: TroVax®: Dose of 1 x 10^9 TCID 50/ml, in 1ml, given on day 1 of weeks 1, 3, 6, 9, 12, 15, 18, 21, 24.

Drug: Pemetrexed
500 mg/m^2 over 10 mins, given on day 3 of weeks 4, 7, 10, 13.

Drug: Cisplatin
75mg/m^2 over 1 hour, given on day 3 of weeks 4, 7, 10, 13

Dietary Supplement: Vitamin B12
1000μg intramuscular, Day 2 of weeks 3 and 12

Dietary Supplement: Folic Acid
400μg oral daily from Day 2 of week 3 to Day 2 of week 16

Drug: Dexamethasone
4mg BD, Days 2-6 of weeks 4, 7, 10, 13

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