Efficacy & Safety of rAd-IFN Administered With Celecoxib & Gemcitabine in Patients With Malignant Pleural Mesothelioma

This study will evaluate intrapleural administration of Adenovirus-Delivered Interferon Alpha-2b (rAd-IFN) in combination with Celecoxib and Gemcitabine in patients with histologically confirmed Malignant Pleural Mesothelioma (MPM) who have failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen. Eligible patients will be randomized 1:1 to either: 1. Treatment group: rAd-IFN + Celecoxib followed by Gemcitabine 2. Control group: Celecoxib followed by Gemcitabine Patients randomized to the treatment group will receive rAd-IFN administered into the pleural space via an Intrapleural catheter (IPC) or similar intrapleural device on study Day 1. The primary objective of this study is to compare the overall survival (OS) associated with rAd IFN, when administered with celecoxib and gemcitabine, versus that associated with celecoxib and gemcitabine alone for the treatment of patients with MPM

TITLE: A Phase 3, Open-Label, Randomized, Parallel Group Study to Evaluate the Efficacy and Safety of Intrapleural Administration of Adenovirus-Delivered Interferon Alpha-2b (rAd-IFN) in Combination with Celecoxib and Gemcitabine in Patients with Malignant Pleural Mesothelioma PROTOCOL NUMBER: rAd-IFN-MM-301 STUDY DRUGS: Nadofaragene firadenovec (Recombinant adenovirus vector containing the human interferon alpha-2b gene: rAd-IFN), celecoxib, and gemcitabine PHASE: 3 INDICATION: Malignant pleural mesothelioma (MPM) SPONSOR: Ferring Ventures Ltd. SITES: Up to 45 sites globally OBJECTIVES: The primary objective of this study is to compare the overall survival (OS) associated with rAd IFN, when administered with celecoxib and gemcitabine, versus that associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who have failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen. The secondary objectives of this study are: * To compare between rAd-IFN, when administered with celecoxib and gemcitabine, versus that associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who have failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen, with respect to: * Survival rate at 12 months and every 6 months thereafter; * Progression-free survival (PFS); * Best response (complete response, partial response, or stable disease); and * Safety of rAd-IFN; and * To evaluate rAd-IFN, when administered with celecoxib and gemcitabine, in a sub-set of patients with MPM who have failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen, with respect to viral shedding and biodistribution. The exploratory objectives of this study are: • To compare between rAd-IFN, when administered with celecoxib and gemcitabine, versus that associated with celecoxib and gemcitabine alone for the treatment of patients with MPM who have failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen, with respect to: * Health-related Quality-of-Life, * The relationship between immunological status and response to treatment, and * Biocorrelates of response to treatment. POPULATION: The population for this study is patients with histologically confirmed MPM of epithelioid or biphasic (predominantly \[\>50%\] epithelioid) histology who have failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen. STUDY DESIGN AND DURATION: The study is an open-label, randomized, parallel group study conducted in patients with MPM and confirmed epithelioid or biphasic histology (if biphasic, histology must be predominantly \[\>50%\] epithelioid) who have received a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, 1 of which must have been an anti-folate and platinum combination regimen. Screening assessments must be completed within 28 days prior to Study Day 1, and eligible patients will be randomized to either: 1. Treatment group: rAd-IFN (Study Day 1) + celecoxib (Study Days 1 to 14) + gemcitabine (Study Days 14 and 21 \[i.e., Days 1 and 8 of the first gemcitabine treatment cycle\], gemcitabine will be administered on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and repeated every 3 weeks until disease progression/early termination \[ET\]); or 2. Control group: celecoxib (Study Days 1 to 14) + gemcitabine (Study Days 14 and 21\[i.e., Days 1 and 8 of the first gemcitabine treatment cycle\], gemcitabine will be administered on a 21-day cycle, unless the cycle is modified due to toxicity/delay, and repeated every 3 weeks until disease progression/ET). Treatment Phase Patients randomized to receive rAd-IFN (treatment group) will have an intrapleural catheter (IPC) or similar device either previously in place or inserted for the study, permitting drug administration to an accessible pleural space. The rAd-IFN will be diluted to a volume of 25 mL using sterile normal saline and will be administered directly to the pleural space via the IPC or similar device. The IPC or similar device will then be flushed with up to 20 mL of sterile normal saline. Patients will receive gemcitabine until disease progression/ET. All adverse events will be captured from the time of the main study's informed consent through 30 days after the last dose of study treatment (rAd-IFN, celecoxib, and/or gemcitabine). All treatment emergent adverse events (TEAEs) and serious adverse events (SAEs) will be followed until resolution or stabilization. Clinical Follow-Up Phase Following disease progression/ET, patients in the rAd-IFN treatment group will be followed every 6 months (±14 days) for survival and safety for up to 5 years after receiving the first dose of rAd-IFN, assuming consent has not been withdrawn. All previously recorded TEAEs and SAEs will be followed until resolution or stabilization. Patients in the control group will not continue in the clinical Follow-up phase and study participation will conclude after end of study treatment. DOSAGE FORMS AND ROUTE OF ADMINISTRATION: Patients randomized to the treatment group will receive rAd-IFN (3 × 1011 viral particles) on Study Day 1, diluted to a total volume of 25 mL using sterile normal saline and administered into the pleural space via an IPC or similar device. The IPC or similar device will then be flushed with up to 20 mL of sterile normal saline. All study patients (treatment and control) will receive: * Celecoxib administered at a dose of 400 mg twice daily orally on Study Days 1 to 14; and * Gemcitabine starting on Study Day 14, using the following treatment regimen: 1250 mg/m2 administered intravenously on Days 1 and 8 of a 21-day gemcitabine cycle, unless the cycle is modified due to toxicity/delay, and continued every 3 weeks until disease progression/ET. STATISTICAL ANALYSES: The primary analysis of the primary endpoint is a comparison of the OS curves between the 2 treatment groups using a log-rank test. A Cox proportional hazards model with treatment as an explanatory variable will be used to assess the magnitude of the treatment difference in OS. The hazard ratio and the associated 95% confidence interval obtained from the Cox proportional hazards model will be presented. The median OS and the 95% confidence interval for each treatment group will be estimated using the Kaplan-Meier method and summarized by treatment group. Plots of the Kaplan-Meier curve of OS will be presented by treatment group. Secondary analyses of the primary endpoint will include a comparison of the survival rates at various time points since randomization. Secondary time-to-event endpoints will be analysed in the same manner as the primary efficacy endpoint. Categorical efficacy endpoints will be summarized and compared between groups using Fisher's exact test. The nature, incidence, severity, relatedness, expectedness, seriousness, and outcome of TEAEs will be summarized by treatment group for safety analyses. SAMPLE SIZE DETERMINATION: The planned sample size is approximately 50 patients. The sample size is not based on statistical considerations. Patient recruitment into the study has been significantly slower than expected due to several technical study challenges. Therefore, Trizell has decided to discontinue screening and enrolment into the study after a total of approximately 50 patients have been randomized to treatment. It is anticipated that approximately 44 events (equivalent to 89% of the planned 50 enrolled patients) will be observed 24 months after the last patient is randomized. The final analysis of the study will be conducted after the forty-fourth event (death) or 30 months after the last patient is randomized, whichever occurs first. DATA AND SAFETY MONITORING BOARD: An independent Data and Safety Monitoring Board (DSMB) will be convened for this study to monitor safety, efficacy, and study integrity. All aspects of the DSMB's scope of review and procedures will be detailed in a DSMB charter.