Schéma : STUDY DRUGS: Nadofaragene firadenovec (Recombinant adenovirus vector containing the human interferon alpha-2b gene: rAd-IFN), celecoxib, and gemcitabine

INDICATION: Malignant pleural mesothelioma (MPM)

SITES: Approximately 80 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 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.

Screening assessments must be completed within 28 days of Study Day 1, and eligible patients will be randomized to either:

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 repeated every 3 weeks until disease progression/early termination [ET]); or
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 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 other intrapleural access device 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.

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.

Survival Follow-Up Phase Following disease progression, patients will be followed every 3 months for survival. All previously recorded TEAEs and SAEs will be followed until resolution or stabilization.


DOSAGE FORMS AND ROUTE OF ADMINISTRATION:

Patients randomized to the treatment group will receive rAd-IFN (3 × E11 viral particles) on Day 1 of the study, diluted to a total volume of 25 mL using sterile normal saline and administered into the pleural space via an IPC or similar intrapleural device.

All study patients (treatment and control) will receive:
- Celecoxib administered at a dose of 400 mg twice daily orally on Days 1 to 14 of the study; 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 and continued every 3 weeks until disease progression/ET.