MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

Window Of Opportunity Phase II Study Of MEDI4736 Or MEDI4736 + Tremelimumab In Surgically Resectable Malignant Pleural Mesothelioma

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.

Study Overview

• Status: Completed
• Conditions: Mesothelioma
• Intervention / Treatment: Drug: MEDI4736; Drug: Tremelimumab; Other: no other name

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).

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor St Lukes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MEDI4736; 8 patients will receive an infusion of MEDI4736 (15 mg/kg intravenously, once), one to six weeks prior to surgical resection.	Drug: MEDI4736; MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.; Other Names: durvalumab
Active Comparator: MEDI4736 + Tremelimumab; 8 patients will receive an infusion of MEDI4736 (1500 mg intravenously, once) + tremelimumab (75mg intravenously, once), one to six weeks prior to surgical resection.	Drug: MEDI4736; MEDI4736 is formulated at 50 mg/mL in 26 mM histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% (w/v) polysorbate 80, pH 6.0.; Other Names: durvalumab; Drug: Tremelimumab; Tremelimumab Drug Product is formulated at a nominal concentration of 20 mg/mL in 20 mM histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 0.02% (weight/volume [w/v]) polysorbate 80, 0.27 mM disodium edetate dihydrate (EDTA), pH 5.5.; Other Names: no other name
Placebo Comparator: Untreated arm (control); 4 patients will not receive MEDI4736 or Tremelimumab.	Other: no other name; Neither MEDI4736 nor Tremelimumab will be used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg)	Tissue biomarker immune response of CD8 and Treg to before and after MEDI-4736 and Tremelimumab will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.	at day 1 after screening and at a surgery within one to six weeks after treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells.	Tissue biomarker for the immune response of ICOS+ CD4 T cells to before and after MEDI-4736 and Tremelimumab will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.	at day 1 after screening and at a surgery within one to six weeks after treatment
Change in Tumor Expression Programmed Death-ligand 1 (PD-L1).	Tumor expression programmed death-ligand 1 (PD-L1) before and after treatment with combination MEDI-4736 and Tremelimumab will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.	at day 1 after screening and at a surgery within one to six weeks after treatment
Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone.	Tissue biomarker immune response of CD8 and Treg after MEDI-4736 and Tremelimumab, and after MEDI4736 alone will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.	at a surgery within one to six weeks after treatment
Ratio of Intratumoral Cytotoxic T Cells to Regulatory T Cells (CD8/Treg) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and Untreated Patients.	Tissue biomarker immune response of CD8 and Treg after MEDI-4736 and Tremelimumab, and at day 1 of untread will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The ratios of CD8/Treg are calculated by diving CD8 by Treg.	the untreated group(control) : at day 1, MEDI4736 + Tremelimumab: at a surgery within one to six weeks after treatment (MEDI4736+Tremelimumab) group
Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone	Tissue biomarker immune response of ICOS+ CD4 T cells after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI4736 alone will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.	at a surgery within one to six weeks after treatment
Percentage of Inducible T-cell Co-stimulator (ICOS) + CD4 T Cells in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients.	Tissue biomarker immune response of ICOS+ CD4 T cells after combination therapy (MEDI-4736 and Tremelimumab) and after untreated patients will be obtained using CytoF (time-of-flight mass cytometry) and/or flow cytometry. The percentages of ICOS+CD4 T cells are calculated by dividing by total cells.	Untreated group (control): at day 1, MEDI-4736 and Tremelimumab group: at a surgery within one to six weeks after treatment
Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Patients Treated With MEDI-4736 Alone.	Tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and after MEDI-4736 alone will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.	at a surgery within one to six weeks after treatment
Tumor Expression Programmed Death-ligand 1 (PD-L1) in Patients Treated With Combination Therapy (MEDI-4736 and Tremelimumab) and in Untreated Patients.	Tumor expression programmed death-ligand 1 (PD-L1) after combination therapy (MEDI-4736 and Tremelimumab) and before and at day 1 of untreate alone will be obtained by immunohistochemistry and CytoF. The unit of measure is MMI. MMI (mean metal intensity or mean mass intensity) is a signal intensity in time-of-flight mass cytometry (CyTOF), which is the same as MFI (mean fluorescent intensity) in flow cytometry. Mean metal intensity looks more common in CyTOF to tell it from the unit in mass spectrometry. Its range is from 0 to infinity.	Untreated arm (control): at day 1 after screening, MEDI4736 + Tremelimumab group: at a surgery within one to six weeks after treatment
Median Recurrence-free Survival (RFS)	RFS based on the Kaplan-Meier method is defined as the time between treatment and disease recurrence or censored and participants in either MEDI-4736 alone or MEDI-4736 plus Tremelimumab will be followed up for 2 years after surgery.	Participants will be followed up until disease recurrence or censor for 2 year after surgery
Median Overall Survival (OS)	OS based on the Kaplan-Meier method is defined as the time between treatment and death or censored and participants in either MEDI-4736 alone or MEDI-4736+Tremelimumab will be followed up for 2 years after surgery.	Participants will be followed up until death or censor for 2 year after surgery

Collaborators and Investigators

• Sponsor: Baylor College of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): May 11, 2016
• Primary Completion (Actual): August 6, 2019
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: October 19, 2015
• First Submitted That Met QC Criteria: October 29, 2015
• First Posted (Estimate): October 30, 2015

Study Record Updates

• Last Update Posted (Actual): September 29, 2022
• Last Update Submitted That Met QC Criteria: September 16, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab; Tremelimumab
• Other Study ID Numbers: H-36952

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No