Clinical Trials /

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

NCT03710876

Description:

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

Related Conditions:
  • Pleural Biphasic Mesothelioma
  • Pleural Epithelioid Mesothelioma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Efficacy & Safety of rAd-IFN Administered With Celecoxib & Gemcitabine in Patients With Malignant Pleural Mesothelioma
  • Official 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

Clinical Trial IDs

  • ORG STUDY ID: rAd-IFN-MM-301
  • SECONDARY ID: 2017-003169-82
  • NCT ID: NCT03710876

Conditions

  • Malignant Pleural Mesothelioma

Interventions

DrugSynonymsArms
rAd-IFNNadofaragene firadenovecTreatment Group
Celecoxib Oral ProductCOX II InhibitorTreatment Group
GemcitabineChemotherapyTreatment Group

Purpose

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

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment GroupActive ComparatorrAd-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]
  • rAd-IFN
  • Celecoxib Oral Product
  • Gemcitabine
Control GroupPlacebo ComparatorCelecoxib 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.
  • Celecoxib Oral Product
  • Gemcitabine

Eligibility Criteria

        Inclusion Criteria:

          1. Aged 18 years or older at the time of consent;

          2. Able to give informed consent;

          3. 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;

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

          5. 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;

          6. 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;

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

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

          9. 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; and

         10. 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:

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

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

          3. Has previously received treatment with gemcitabine;

          4. Has stage IV extrathoracic metastatic disease;

          5. Inadequate pulmonary function of clinical significance as per Investigator review;

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

          7. 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;

          8. Patient previously treated with IFNs (e.g., for chronic active hepatitis);

          9. Suspected/known hypersensitivity to IFN-α2b;

         10. Known hypersensitivity to celecoxib or sulfonamides;

         11. Impaired cardiac function or clinically significant cardiac disease including the
             following:

               -  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;

         12. Women who are pregnant or breastfeeding;

         13. 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;

         14. 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;

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

         16. History of ulcer disease or gastrointestinal bleeding;

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

         18. Patients receiving lithium;

         19. 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;

         20. 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

         21. Has a congenital or acquired immunodeficiency, including patients with known history
             of infection with human immunodeficiency virus.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Survival
Time Frame:60 months
Safety Issue:
Description:Time to death (from any cause) from randomization

Secondary Outcome Measures

Measure:Survival rate
Time Frame:60 months
Safety Issue:
Description:Number of deaths (from any cause) from randomization
Measure:Progression Free Survival
Time Frame:60 months
Safety Issue:
Description: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
Measure:Best response
Time Frame:60 months
Safety Issue:
Description:Best response after randomization (complete response, partial response, or stable disease)

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Trizell Ltd

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