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

Primary Outcome Measures

• Overall Survival [ Time Frame: 60 months ]
  Time to death (from any cause) from randomization

Secondary Outcome Measures

• Survival rate [ Time Frame: 60 months ]
  Number of deaths (from any cause) from randomization
• Progression Free Survival [ Time Frame: 60 months ]
  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 [ Time Frame: 60 months ]
  Best response after randomization (complete response, partial response, or stable disease)

Inclusion Criteria

Aged 18 years or older at the time of consent;

Able to give informed consent;

Has a confirmed histological diagnosis of MPM with histological type epithelioid or biphasic (predominantly [>50%] epithelioid). Histological diagnosis of MPM will be confirmed centrally using specimens or slides from tumor specimens obtained at the time of initial presentation or a subsequent procedure. Central confirmation of diagnosis with immunohistochemistry will be performed, and independent central confirmation will be required for study entry;

Measurable disease, per modified Response Evaluation Criteria in Solid Tumor [RECIST] for pleural mesothelioma;

Has failed a minimum of 1 treatment regimen and a maximum of 2 treatment regimens, which may have been chemotherapeutic and/or immunotherapeutic treatment regimens for MPM which included at least 1 anti-folate and platinum combination regimen. Patients who have undergone primary surgical resection and/or radiation therapy to the pulmonary site are eligible to participate. For clarity, surgical resection and/or radiation therapy to the pulmonary site are not exclusionary and are not considered a line of therapy;

Has a pleural space accessible for pleural catheter insertion. Patients with a previously inserted pleural catheter may be enrolled, and the pre-existing catheter can be used for vector administration as long as it is functional and has no evidence of local infection;

Life expectancy >12 weeks in the judgement of the Investigator;

Eastern Cooperative Oncology Group (ECOG) status of 1 or 0;

Female and male patients:

• Female patients must be either postmenopausal (no menstrual period for a minimum of 12
  months) or surgically sterile upon entry into the study. Female patients of childbearing potential
  must have a negative pregnancy test upon entry into this study and agree to use a highly effective
  method of contraception from Screening until 1 month following administration of gemcitabine;
• Highly effective methods of contraception that result in a low failure rate (i.e., <1% per
  year) when used consistently and correctly include combined (estrogen and progestogen containing)
  hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or
  transdermal), progestogen-only hormonal contraception associated with inhibition of ovulation
  (oral, injectable, or implantable), intrauterine device, intrauterine hormone-releasing system,
  bilateral tubal occlusion, vasectomized partner, or sexual abstinence;
• True abstinence, when in line with the preferred and usual lifestyle of the patient, is
  considered a highly effective method only if defined as refraining from heterosexual intercourse
  during the entire period of study participation and for 1 month post-gemcitabine administration.
  The reliability of sexual abstinence needs to be evaluated in relation to the duration of the
  clinical study and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g.,
  calendar, ovulation, symptothermal, and post-ovulation method) and withdrawal are not acceptable
  methods of contraception;and
• Male patients must be either surgically sterile or agree to use a double-barrier contraception
  method from Screening until 1 month post-gemcitabine administration;

Adequate laboratory values at Screening:

• Hemoglobin 9 g/dL;
• White blood cell count 3500/µL;
• Absolute neutrophil count 1500/µL;
• Platelet count 100,000/µL;
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) below the upper limit of normal (ULN). It is expected that patients receiving anticoagulation therapy will not have INR and aPTT results that fall within normal limits. It is not intended to exclude these patients and, therefore, medical discretion is permitted for patients who have clinically acceptable results in regards to their current concomitant anticoagulant therapy;
• Aspartate aminotransferase (AST) 3 × ULN;
• Alanine aminotransferase (ALT) 3 × ULN;
• Total bilirubin 2 × ULN;
• Estimated glomerular filtration rate 50 mL/min/1.73 m2; and
• Serum albumin 2.5 g/dL

Exclusion Criteria

Is “treatment-naïve” (i.e., has not received at least 1 anti-folate and platinum combination regimen);

Has previously received 3 or more lines of systemic chemotherapeutic or immunotherapeutic treatment;

Has previously received treatment with gemcitabine;

Has stage IV extrathoracic metastatic disease;

Inadequate pulmonary function of clinical significance as per Investigator review;

Clinically significant pericardial effusion (i.e., as judged by the Investigator and/or requiring drainage) detected by computed tomography (CT) scan at Screening;

Prior therapy(ies), if applicable, must be completed according to the criteria below prior to vector administration:

• Cytotoxic chemotherapy, at least 21 days from last dose;
• Non-cytotoxic chemotherapy (e.g., small molecule inhibitor), at least 14 days from last
  dose;
• Monoclonal antibody, at least 3 half-lives from last dose;
• Non-antibody immunotherapy (e.g., tumor vaccine), at least 42 days from last dose;
• Radiotherapy, at least 14 days from last local site radiotherapy;
• Hematopoietic growth factor, at least 14 days from last dose; or Study drug, 30 days or
  5 half-lives, whichever is longer, from last dose;

• New York Heart Association class III or IV congestive heart failure;
• Myocardial infarction within the last 12 months; and
• Patients known to have impaired left ventricular ejection fraction per institutional standards and of clinical significance as per Investigator review;

Women who are pregnant or breastfeeding;

Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, depression, or psychiatric illness/social situations within the last 12 months;

Patients with active, known, or suspected auto-immune disease or a syndrome that requires systemic or immunosuppressive agents (oral prednisolone or equivalent at a dose of <10 mg per day is permitted); NOTE: patients with vitiligo, residual hypothyroidism due to auto immune disease only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll;

History of asthma, urticaria, or other allergic-type reactions after taking aspirin or
other NSAIDs;

History of ulcer disease or gastrointestinal bleeding;

Uncontrolled or poorly controlled hypertension requiring 3 or more anti-hypertensive drugs;

Patients receiving lithium;

Any significant disease which, in the opinion of the Investigator, would place the patient at increased risk of harm if he/she participated in the study;

History of malignancy of other organ system within the past 5 years, except treated basal cell or squamous cell carcinoma of the skin, or early stage prostate cancer (stage T2a or smaller, prostate specific antigen <10 ng/mL, Gleason score <6); or

Has a congenital or acquired immunodeficiency, including patients with known history of infection with human immunodeficiency virus.