Clinical Trials /

MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

NCT02592551

Description:

The objective of this study is to determine whether MEDI4736 or combination therapy with MEDI4736 + tremelimumab are associated with favorable alterations of the intratumoral immunologic environment in subjects undergoing resectional surgery for Malignant Pleural Mesothelioma MPM.

Related Conditions:
  • Malignant Pleural Mesothelioma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma
  • Official Title: Window Of Opportunity Phase II Study Of MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

Clinical Trial IDs

  • ORG STUDY ID: H-36952
  • NCT ID: NCT02592551

Conditions

  • Mesothelioma

Interventions

DrugSynonymsArms
MEDI4736MEDI4736
TremelimumabMEDI4736 + Tremelimumab

Purpose

The objective of this study is to determine whether MEDI4736 or combination therapy with MEDI4736 + tremelimumab are associated with favorable alterations of the intratumoral immunologic environment in subjects undergoing resectional surgery for Malignant Pleural Mesothelioma MPM.

Detailed Description

      Subjects with MPM will undergo surgical mediastinal lymph node biopsy (cervical
      mediastinoscopy) and simultaneous surgical biopsy of the pleural tumor by thoracoscopy, at
      which time tumor tissue (at least 2 g) and peripheral blood will be collected for the study.
      These procedures are performed as standard of care in the treatment of these subjects. The
      subject will be randomized. Three days to three weeks after the biopsy, subjects will be
      randomly treated with either MEDI-4736 (15 mg/kg once intravenously) or MEDI-4736 (1500 mg
      once intravenously) plus tremelimumab (75 mg once intravenously) or a control group in a
      randomized controlled study design. There will be two treatment arms (MEDI4736 only and
      combination MEDI4736+tremelimumab) and one untreated arm (control). Randomization, stratified
      by receiving previous chemotherapy or not, will be performed and will help to minimize
      patient selection biases between three arms. Subjects under 30 kg will be treated with
      weight-based dosing for both MEDI4736 and Tremelimumab combination therapy. These patients
      are excluded from fixed based dosing to limit endotoxin exposure from the drug preparations.
      One to six weeks after the infusion, subjects will undergo resectional surgery, including
      extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D), at which time the tumor
      will be removed (typically 200-1000 g) and obtained for study. Four patients that do not
      undergo treatment with MEDI-4736 or tremelimumab will be included as controls. Blood will be
      obtained after the induction of general anesthesia for both the thoracoscopy procedure and
      the EPP or P/D resectional procedure, as is routinely done in these procedures. The sixth rib
      will be obtained at the time of the resection. After the removal of the tumor, standard
      protocol includes intraoperative heated chemotherapy using a lavage of intracavitary
      cisplatin in the presence of conserved renal function (Sugarbaker et al., 2013, 2014;
      Richards et al., 2006).
    

Trial Arms

NameTypeDescriptionInterventions
MEDI4736Experimental8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection.
  • MEDI4736
MEDI4736 + TremelimumabActive Comparator8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection.
  • MEDI4736
  • Tremelimumab
Untreated arm (control)Placebo ComparatorUntreated arm (control)

    Eligibility Criteria

            Inclusion Criteria:
    
              1. Written informed consent obtained from the subject prior to performing any
                 protocol-related procedures, including screening evaluations
    
              2. Age >/= 18 years at time of study entry
    
              3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
    
              4. Adequate normal organ and marrow function as defined below:
    
                 Hemoglobin ≥ 9.0 g/dL Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (> 1500 per mm3)
                 Platelet count ≥ 100 × 109/L (>100,000 per mm3) Serum bilirubin ≤ 1.5× institutional
                 upper limit of normal (ULN)AST<3.0 Creatinine clearance >50mL/miN Aspartate
                 transaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN if documented
                 liver metastasis are present); Serum creatinine ≤ 2.0 mg/dL or calculated creatinine
                 clearance ≥ 50 mL/min as determined by the Cockcroft-Gault equation;
    
                 Males:
    
                 Creatinine CL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)
    
                 Females:
    
                 Creatinine CL (mL/min) = Weight (kg) × (140 - Age) × 0.85 72 × serum creatinine
                 (mg/dL)
    
              5. Female subjects must either be of non-reproductive potential (i.e., post-menopausal by
                 history: ≥60 years old and no menses for >/=1 year without an alternative medical
                 cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history
                 of bilateral oophorectomy) or must have a negative serum pregnancy test upon study
                 entry.
    
              6. Subject is willing and able to comply with the protocol for the duration of the study
                 including undergoing treatment and scheduled visits and examinations including follow
                 up.
    
              7. Surgically resectable MPM with no disease extension beyond the ipsilateral hemithorax
    
              8. Planned resectional surgery for MPM [extrapleural pneumonectomy (EPP) or pleurectomy
                 and decortication (P/D)]
    
              9. Any MPM histology (epithelial, mixed, sarcomatoid)
    
             10. N0 or N1 nodal disease as present on perioperative chest CT and/or PET CT.
    
             11. N2 nodal disease if no progression after 2 cycles of standard chemotherapy.
                 Progression will be considered if additional N1 or N2 disease develop during
                 chemotherapy
    
            Exclusion Criteria:
    
              1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
                 staff and/or staff at the study site) or previous enrollment or randomization in the
                 present study
    
              2. Participation in another clinical study with an investigational product during the
                 last 3 months
    
              3. Any previous treatment with a PD1 or PD-L1 inhibitor, including MEDI4736
    
              4. Receipt of the last dose of anti-cancer therapy (chemotherapy, immunotherapy,
                 endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
                 antibodies, other investigational agent) 30 days prior to the first dose of study
                 drug, and 30 days prior to the first dose of study drug for subjects who have received
                 prior TKIs [e.g., erlotinib, gefitinib and crizotinib] and within 6 weeks for
                 nitrosourea or mitomycin C).
    
              5. Current or prior use of immunosuppressive medication within 28 days before the
                 infusion with MEDI4736 or MEDI4736 + tremelimumab and through 90 days post infusion,
                 with the exceptions of intranasal and inhaled corticosteroids or systemic
                 corticosteroids at physiological doses, which are not to exceed 10 mg/day of
                 prednisone, or an equivalent corticosteroid.
    
              6. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.
    
              7. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous
                 immunotherapy agent, or any unresolved irAE >Grade 1
    
              8. Active or prior documented autoimmune disease within the past 2 years NOTE: Subjects
                 with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within
                 the past 2 years) are not excluded.
    
              9. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
                 ulcerative colitis)
    
             10. History of primary immunodeficiency
    
             11. History of allogeneic organ transplant
    
             12. History of hypersensitivity to MEDI4736 or any excipient
    
             13. History of hypersensitivity to tremelimumab or the combination of MEDI4736 +
                 tremelimumab
    
             14. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
                 infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
                 angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active
                 bleeding diatheses including any subject known to have evidence of acute or chronic
                 hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric
                 illness/social situations that would limit compliance with study requirements or
                 compromise the ability of the subject to give written informed consent
    
             15. Known history of previous clinical diagnosis of tuberculosis
    
             16. History of leptomeningeal carcinomatosis
    
             17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 6
                 months of receiving MEDI4736 or MEDI + tremelimumab
    
             18. Receipt of drugs with laxative properties and herbal or natural remedies for
                 constipation within 90 days of receiving MEDI4736 or MEDI + tremelimumab
    
             19. Receipt of sunitinib within 3 months of receiving tremelimumab
    
             20. Female subjects who are pregnant, breastfeeding, or male or female subjects of
                 reproductive potential who are not employing an effective method of birth control
    
             21. Any condition that, in the opinion of the investigator, would interfere with the
                 evaluation of the study treatment or interpretation of subject safety or study results
    
             22. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive
                 of but not limited to surgery, radiation, and/or corticosteroids.
    
             23. Subjects with uncontrolled seizures
    
             24. N3 nodal disease
    
             25. History of interstitial lung disease/pneumonitis
    
             26. No tissue is obtainable at the time of thoracoscopy.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:Accepts Healthy Volunteers

    Primary Outcome Measures

    Measure:Intratumoral ratio of CD8 T cells to regulatory T cells (CD8/Treg). [Ratio]
    Time Frame:2-4 weeks
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Baylor College of Medicine

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