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rAd-IFN (Study Day 1) + celecoxib oral product (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 \[ET\]

Celecoxib oral product (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.

rAd-IFN

Celecoxib Oral Product

1250 mg/m2 administered intravenously on Days 1 and 8 of a 21-day cycle and continued every 3 weeks until disease progression/ early termination

Daniel Sterman, MD

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: Trizell, Ltd.

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:

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 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 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.

STATISTICAL ANALYSES:

The primary analysis of the primary endpoint is a comparison of the OS curves between the 2 groups using a log-rank test. The log-rank test will be stratified using the same variables used for stratifying the randomization.

Secondary analyses of the primary endpoint will include a comparison of the survival rates at various time points since randomization and a comparison of the median survival times. The effect of baseline covariates will be assessed by constructing a proportional hazard model. Exploratory analyses will include comparison of the survival curves by methods that do not rely on proportional hazards.

Secondary time-to-event endpoints will be analyzed in the same manner as the primary efficacy endpoint.

Categorical efficacy endpoints will be summarized and compared between groups using a Pearson's test, with the effect of baseline covariates assessed using logistic regression.

The nature, incidence, severity, relatedness, expectedness, seriousness, and outcome of TEAEs will be summarized by treatment group for safety analyses.

There are 2 interim analyses planned:

* Analysis for futility will be assessed upon reaching 123 deaths (estimated to occur 27 months after first patient first visit \[FPFV\]). Approximately half of the available Beta will be spent at this interim; and
* Analysis for efficacy will be assessed upon reaching 234 deaths (estimated to occur 45 months after FPFV). Approximately one-fifth of the available Alpha will be spent at this interim.

The final analysis will be assessed upon reaching 267 deaths (estimated to occur 60 months after FPFV).

SAMPLE SIZE DETERMINATION:

The planned sample size is approximately 300 patients. Based on a 1:1 randomization between treatment groups, a 2.5% one-sided significance level, and a predicted survival at 18 months of 35% in the rAd-IFN treatment group versus 20% in the control group, the study will have at least 90% power (after adjusting for the interim analyses) to detect a statistically significant difference between the treatment groups in the primary endpoint using the log-rank test.

The calculation was based on the assumptions that recruitment is uniform over 3 years and that all alive patients are followed-up for 2 years after the end of recruitment.

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.

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

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

To evaluate the number of patients with Common Terminology Criteria for Adverse Events Grade 3 or 4

To evaluate post-treatment levels of rAd-IFN-related viral DNA in biological

Change in total score and individual components of the EQ-5D-5L;

Assessment of health status including:

1. Mobility
2. Self-Care
3. Usual Activities
4. Pain/ Discomfort
5. Anxiety/ Depression
6. Health Status (scale 0-100)

Change in total score and individual components of the Lung Cancer Symptom Scale-mesothelioma

Assessment of symptoms including:

1. Appetite
2. Fatigue
3. Coughing
4. Shortness of Breath
5. Pain
6. Symptom Severity
7. Normal Activities
8. Quality of Life

Correlation between the presence of adenovirus type 5 neutralizing antibodies prior to treatment and survival (death from any cause)

Correlation between pre- and post-treatment levels and treatment outcomes

Time to death (from any cause) from randomization

Number of deaths (from any cause) from randomization

Time from randomization to the time when the modified Response Evaluation Criteria in Solid Tumor criteria for disease progression are first met, or when death from any cause occurs

Best response after randomization (complete response, partial response, or stable disease)

Spots Global Cancer Trial Database for celecoxib oral product