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.
|First Received Date||October 19, 2015|
|Last Changed Date||December 6, 2016|
|Start Date||May 2016|
|Anticipated Primary Completion Date||May 2018|
|Primary Outcome Measures||
Intratumoral ratio of CD8 T cells to regulatory T cells (CD8/Treg). [Ratio] [Time Frame: 2-4 weeks]
The percentage of inducible T-cell co-stimulator (ICOS) + CD4 T cells. [Time Frame: 2-4 weeks]
The tumor expression programmed death-ligand 1 (PD-L1). [Semi-quantitative assessment: 0, 1+, 2+, 3+, 4+] [Time Frame: 2-4 weeks]
|Study Arms / Comparison Groups||3 / 0|
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. One 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. Two 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).
|Ages||18 Years - N/A|
|Accepts Healthy Volunteers||Accepts Healthy Volunteers|
Michelle G Almarez, BBA
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) ≤ 3 × 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;
Creatinine CL (mL/min) = Weight (kg) × (140 - Age) 72 × serum creatinine (mg/dL)
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
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. Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 electrocardiograms (ECGs) using Bazett's Correction
6. 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.
7. Any unresolved toxicity (>CTCAE grade 2) from previous anti-cancer therapy.
8. Any prior Grade ≥3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1
9. 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.
10. Active or prior documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis)
11. History of primary immunodeficiency
12. History of allogeneic organ transplant
13. History of hypersensitivity to MEDI4736 or any excipient
14. History of hypersensitivity to tremelimumab or the combination of MEDI4736 + tremelimumab
15. 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
16. Known history of previous clinical diagnosis of tuberculosis
17. History of leptomeningeal carcinomatosis
18. Receipt of live attenuated vaccination within 30 days prior to study entry or within 6 months of receiving MEDI4736 or MEDI + tremelimumab
19. Receipt of drugs with laxative properties and herbal or natural remedies for constipation within 90 days of receiving MEDI4736 or MEDI + tremelimumab
20. Receipt of sunitinib within 3 months of receiving tremelimumab
21. Female subjects who are pregnant, breastfeeding, or male or female subjects of reproductive potential who are not employing an effective method of birth control
22. 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
23. Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids.
24. Subjects with uncontrolled seizures
25. N3 nodal disease
26. History of interstitial lung disease/pneumonitis
|Sponsor||Baylor College of Medicine|
|Verification Date||December 2016|