Testing the Addition of Immunotherapy Before Surgery for Patients With Sarcomatoid Mesothelioma

Study Overview
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Brief Summary
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This phase II trial evaluates the safety and effectiveness of giving immunotherapy (nivolumab and ipilimumab) before surgery for controlling disease in patients with stage I-IIIa sarcomatoid mesothelioma. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving immunotherapy before surgery may be more effective at controlling disease in patients with sarcomatoid mesothelioma than giving immunotherapy alone.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the percentage of patients with potentially resectable non-epithelioid mesothelioma who are able to proceed with surgery after neoadjuvant ipilimumab and nivolumab. II. To determine the progression-free survival rate at 12 months after the initiation of neoadjuvant ipilimumab and nivolumab. SECONDARY OBJECTIVES: I. To determine the rate of intra-operative or post-operative complications following neoadjuvant immunotherapy. II. Best response per modified pleural Response Evaluation Criteria in Solid Tumors (RECIST). III. Major pathologic response rate. IV. Time to recurrence after surgery. EXPLORATORY OBJECTIVES: I. To evaluate the association between the change in peripheral T cell clonality relative to baseline and treatment response. II. To evaluate the association between PD-L1 expression at baseline and treatment response. III. To evaluate whether a novel mesothelioma immune signature identified by Dr. Mansfield's laboratory is predictive of response. OUTLINE: Patients receive nivolumab intravenously (IV), ipilimumab IV, and may undergo surgery on study. Patients also undergo computed tomography (CT) or magnetic resonance imaging (MRI) and positron emission tomography (PET) throughout the trial.

Official Title
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Official Title Neoadjuvant Immunotherapy in Sarcomatoid Mesothelioma

Conditions
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Pleural Biphasic Mesothelioma, Pleural Sarcomatoid Mesothelioma

Intervention / Treatment
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* Biological: Nivolumab
* Biological: Ipilimumab
* Procedure: Surgical Procedure
* Procedure: Computed Tomography
* Procedure: Magnetic Resonance Imaging
* Procedure: Positron Emission Tomography


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Sarcomatoid or sarcomatoid-dominant (> 50%) biphasic, pleural mesothelioma Stage: I-IIIA disease per Union for International Cancer Control (UICC) TNM Classification of Malignant Tumours 8th edition Measurable disease or non-measurable disease as defined No prior treatment which would be considered treatment for the primary neoplasm or impact the primary endpoint No treatment with hormones or other chemotherapeutic agents except for hormones administered for non-disease-related conditions (e.g., insulin for diabetes and or hormonal therapy for breast, prostate cancer etc.) Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown * Therefore, for women of childbearing potential only, a negative pregnancy test done =< 14 days prior to registration is required Age >= 18 years Eastern Cooperative Oncology Group (ECOG) performance status =< 2 or Karnofsky >= 60% Absolute neutrophil count (ANC) >= 1,000/mm^3 Leukocytes >= 2,000/mm^3 Platelet count >= 100,000/mm^3 Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance >= 40 mL/min Total bilirubin =<1.5 x ULN, except patients with Gilbert Syndrome who can have total bilirubin < 3.0 mg/dl Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3.0 x ULN Alkaline (alk) phosphatase (phos) =< 3.0 x ULN No active, known or suspected autoimmune disease except for vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger No active systemic infection requiring therapy, as well as positive tests for hepatitis B surface antigen or hepatitis C antibody No history of any other condition that may require the initiation of anti-tumor necrosis factor alpha (TNFalpha) therapies or other immunosuppressant medications during the study Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial STEP 2 ELIGIBILITY CRITERIA: Completion of at least 1 cycle of treatment and not have an unresolved adverse event that would preclude surgery STEP 2 ELIGIBILITY CRITERIA: No evidence of progression that would preclude resection STEP 2 ELIGIBILITY CRITERIA: ECOG performance status =< 2 or Karnofsky >= 60% STEP 2 ELIGIBILITY CRITERIA: Predicted forced expiratory volume in 1 second (FEV1) > 35% and postoperative predicted diffusion capacity of the lung for carbon monoxide (DLCO) > 35% STEP 2 ELIGIBILITY CRITERIA: Registration to step 2 no less than 21 days and no more than 90 days after the last dose of neoadjuvant therapy Exclusion Criteria: No patients deemed to be unresectable or poor surgical candidates No patients with chest wall invasion, peritoneal spread, contralateral pleural involvement, mediastinal organ involvement, vertebral involvement, or metastases to contralateral intrathoracic lymph nodes, or any supraclavicular nodes No patients with a history of symptomatic interstitial lung disease

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (nivolumab, ipilimumab, surgery)<br>Patients receive nivolumab IV, ipilimumab IV, and may undergo surgery on study. Patients also undergo CT or MRI and PET throughout the trial. | Biological: Nivolumab<br>* Given IV<br>* Other names: 946414-94-4, BMS-936558, CMAB819, MDX-1106, NIVO, NIVOLUMAB, Nivolumab, Nivolumab Biosimilar CMAB819, ONO-4538, Opdivo;Biological: Ipilimumab<br>* Given IV<br>* Other names: 477202-00-9, Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, IPILIMUMAB, ipilimumab, Ipilimumab Biosimilar CS1002, MDX-010, MDX-010, MDX-CTLA4, Yervoy;Procedure: Surgical Procedure<br>* Undergo surgery<br>Procedure: Computed Tomography<br>* undergo CT<br>* Other names: CAT, CAT Scan,;Procedure: Magnetic Resonance Imaging<br>* Undergo MRI<br>* Other names: MRI;Procedure: Positron Emission Tomography<br>* Undergo PET<br>* Other names: Medical Imaging, PET, Pet Scan;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Surgery Rate | The rate of surgery after neoadjuvant immunotherapy among the feasibility analysis population as well as the 80% and 95% exact Clopper-Pearson confidence intervals will be estimated. | immediately after the completion of neoadjuvant immunotherapy and surgery | 
| Progression free survival (PFS) | PFS will be determined per modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. The rate of PFS at 12 months after the initiation of neoadjuvant immunotherapy among the feasibility and efficacy analysis population as well as the 80% and 95% exact Clopper-Pearson confidence intervals will be estimated. | At 12 months after initiation of neoadjuvant immunotherapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | The type of adverse events, the frequency of each type and its grade will be summarized. The frequency and the percentage of severe adverse events will be presented in bar charts over treatment phase (neoadjuvant immunotherapy, surgery) to describe the change of adverse event or complication severity over time. The rates of the pre-operative or post-operative complications (within 30 days of surgery) will be estimated with its exact 95% confidence interval. | Up to 5 years | 
| Objective response rate | Will be determined per modified RECIST. Response rate will be reported with 95% exact confidence interval. | Up to 5 years | 
| Major pathologic response | Defined as =< 10% residual viable tumor in the resected lung and lymph node tissue. Response rates will be reported with 95% exact confidence interval. | Up to 5 years | 
| Time to recurrence | Time to recurrence will be estimated among those patients who receive surgery and will be characterized by estimating cumulative incidence function and conducting cause-specific and subdistribution hazard regression. | Time from surgery to disease relapse, progression, or second tumor, whichever occurs first, assessed up to 5 years |