Primary Outcome Measures:
- To determine the safety of administering intrapleural SCH 721015, Ad.hIFN-alpha2b (Adenoviral-mediated Interferon-alpha) in combination with chemotherapy for the management of MPM. [ Designated as safety issue: Yes ]
No dose escalation is planned; however, dose de-escalation is possible should two or more DLTs be encountered in the first six patients treated. With 0 DLTs in 6 patients at a given dose, the upper exact 90% confidence limit on the DLT rate is 32%. With 1 DLT in 6 patients, the Bayesian upper 90% probability limit on the DLT rate is 58%. With 10 subjects per treatment group, we can identify with 90% power any unanticipated toxicity that has prevalence at least 20.6%; with n=15 per group, this figure decreases to 14.2%.
Secondary Outcome Measures:
- To estimate objective response rates and distribution [ Designated as safety issue: Yes ]
Will estimate response rates by 95% confidence intervals, whose half-width will range from as low as 26% (if n=15 subjects are enrolled) to 32% (if n=10).
- Time to Progression [ Designated as safety issue: Yes ]
Will summarize the distributions of time to progression (TTP) and time to death from any cause by Kaplan-Meier curves. In analyses of TTP, subjects who die without progression will be considered censored at the time of death. Further secondary goals include the evaluation of immunologic indicators of response, including systemic and intrapleural cytokines and cellular and humoral immune responses.
Malignant pleural mesothelioma (MPM) is a cancer for which there is no cure. The most effective combination chemotherapy, Pemetrexed (Alimta)/Cisplatin, has yielded overall response rates of up to 40%, but with improvements in overall median survival of only 3.5 months. Prior Phase I trials of intrapleural infusion (IP) of Ad.hIFN-beta (BG00001) were safe. The most recent trial of IP Ad.IFNalpha (SCH 721015) at a dose of 3e11 viral particles (vp) given three days apart was safe and well tolerated, and showed high levels of IFN in pleural fluid and serum. Our preclinical data modeling this proposed study suggest that two IP doses of Ad.IFN-alpha in combination with chemotherapy are well tolerated and markedly enhances efficacy. The purpose of the new study is to determine the safety of administrating intrapleural SCH 721015 (Ad.hIFN-alpha 2b) in combination with chemotherapy for the management of malignant pleural mesothelioma. This study will enroll subjects with pleural mesothelioma. Subjects will receive two fixed dosed of SCH 721015 followed by 4-6 cycles of chemotherapy. Subjects will require placement of a pleural catheter for administration of SCH 721015.
Some patients require a pleural catheter for control of pleural fluid while some will have it placed for research purpose only. Protocol participation will last about 6 months the subjects will be followed up by telephone every 6 months for 15 years.