Clinical trial NCT05041062
Conditions: Mesothelioma Peritoneal Mesothelioma
Keywords: chest cancer abdominal cancer lung cancer cancer in lining of lungs
Sponsor: University of Chicago
Start date: 2021-12-01; Completion date: 2023-04-13
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study is for individuals who have peritoneal mesothelioma, a cancer of the lining of your abdominal wall and organs (the peritoneum). Doctors leading the study would like to determine the effects of treating this cancer with immunotherapy drugs (nivolumab and ipilimumab - the two study drugs that will be used in this study) before and after surgery.

Doctors hope to learn if giving these two drugs before surgery will decrease the amount of viable (live) cancer cells that remain at the time of surgery and whether it will delay the time it could take for the cancer to regrow.

Detailed description:

Arms: arm 1: Individuals in this group will receive a combination of two immunotherapy drugs (nivolumab and ipilimumab) before and after surgery to remove their cancer. There will also be a follow up period to determine how well the drugs and surgery worked to get rid of your cancer. Your overall participation in this study (including drug treatment, surgery and follow up visits) will last for roughly one and a half years. All eligible participant who enroll in the study will participate in this group.
Interventions: intervention 1: Nivolumab intervention 2: Ipilimumab
Intervention descriptions: intervention 1: Nivolumab is an immunotherapy drug (a type of drug that helps your immune system fight cancer) that is often used with ipilimumab as the first treatment in adults with mesothelioma whose disease cannot be removed by surgery. The drug will be given as an IV infusion. intervention 2: Ipilimumab is a type of immunotherapy drug known as a checkpoint inhibitor, which helps your own immune system attack cancer cells.

Protocol documents:
Prot_SAP_000.pdf: 
 
1
SPONSOR: The University of Chicago 
 
PROTOCOL TITLE: A phase II prospective, open-label trial of perioperative combination 
nivolumab and ipilimumab in patients with resectable malignant peritoneal mesothelioma. 
 
Principal Investigator: 
Hedy Kindler, MD,  
Professor of Medicine 
Section of Hematology/Oncology, University of Chicago Medical Center 
Tel: 773-702-0360 
hkindler@medicine.bsd.uchicago.edu 
 
Co-Investigators: 
Divya Sood, MD 
Kiran Turaga, MD, MPH 
Aliya Husain, MD 
Oliver Eng, MD 
Samuel Armato, PhD 
Michael Drazer, MD 
Ankit Dhiman, MBBS 
Emily Fenton, PA 
Aytekin Oto, MD, MBA 
Carla Harmath, MD 
Aditya Juloori, MD 
 
Statistician: Mihai Giurcanu, PhD 
 
Amendment: 4 
Protocol Version Date: September 21, 2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
2
Table of Contents 
TRIAL SUMMARY ..................................................................................................................... 4 
1.0 
TRIAL DESIGN ................................................................................................................ 5 
1.1 
Trial Design ........................................................................................................................... 5 
1.2 
Trial Schema ......................................................................................................................... 6 
2.0 
OBJECTIVES ................................................................................................................... 6 
2.1 
Primary Objectives ................................................................................................................ 6 
2.2 
Secondary Objectives ............................................................................................................ 6 
2.3 
Exploratory Objectives .......................................................................................................... 7 
3.0 
BACKGROUND ............................................................................................................... 7 
3.1 
Pharmaceutical and Therapeutic Background ........................................................................ 7 
3.2 
Rationale .............................................................................................................................. 8 
3.2.1 
Rationale for the Trial and Selected Subject Populations ........................................................................ 8 
3.2.2 
Rationale for Endpoints ......................................................................................................................... 10 
4.0 
SUBJECT SELECTION AND WITHDRAWAL ..................................................................... 11 
4.1 
Number of Subjects ............................................................................................................ 11 
4.2 
Gender, Age, Racial and Ethnic Origin of Subjects ............................................................... 11 
4.3 
Inclusion Criteria ................................................................................................................. 11 
4.4 
Exclusion Criteria ................................................................................................................ 12 
4.5 
Subject Identification & Recruitment .................................................................................. 14 
4.6 
Location .............................................................................................................................. 14 
4.7 
Discontinuation of Study and Participant Withdrawal ......................................................... 14 
5.0 
TRIAL INTERVENTIONS ................................................................................................ 15 
5.1 
Pre‐intervention Testing ..................................................................................................... 15 
5.2 
Neoadjuvant Nivolumab and Ipilimumab ............................................................................ 15 
5.2.1 
Drug Supply ............................................................................................................................................ 15 
5.2.2 
Dose Selection ....................................................................................................................................... 15 
5.2.3 
Dose Modification .................................................................................................................................. 16 
5.3 
Surgical Intervention ........................................................................................................... 16 
5.4 
Adjuvant Nivolumab and Ipilimumab .................................................................................. 17 
6.0 
ADDITIONAL METHODOLOGY ...................................................................................... 17 
6.1 
Trial Blinding/Masking ........................................................................................................ 17 
6.2 
Randomization or Treatment Allocation ............................................................................. 17 


 
3
6.3 
Stratification ....................................................................................................................... 17 
6.4 
Concomitant Medications/Vaccinations (allowed & prohibited) ......................................... 17 
6.4.1 
Acceptable Concomitant Medications ................................................................................................... 17 
6.4.2 
Prohibited Concomitant Medications .................................................................................................... 18 
6.5 
Supportive Care Guidelines ................................................................................................. 18 
6.6 
Diet/Activity/Other Considerations .................................................................................... 21 
6.6.1 
Diet ........................................................................................................................................................ 21 
6.6.2 
Contraception ........................................................................................................................................ 21 
6.6.3 
Use in Pregnancy ................................................................................................................................... 21 
6.6.4 
Use in Nursing Women .......................................................................................................................... 22 
6.7 
Subject Withdrawal/Discontinuation Criteria ...................................................................... 22 
6.8 
Clinical Criteria for Early Trial Termination .......................................................................... 22 
7.0 
TRIAL PROCEDURES ..................................................................................................... 23 
7.1 
Flow Chart – Schedule of Events .......................................................................................... 23 
7.1.1 
Flow Chart for Screening, Neoadjuvant, and Surgery Phases ................................................................ 23 
7.1.2 
Flow Chart for Adjuvant and Post‐Treatment Phases ............................................................................ 25 
7.2 
Informed Consent ............................................................................................................... 26 
7.3 
Inclusion/Exclusion Criteria Review..................................................................................... 26 
7.4 
Medical History ................................................................................................................... 26 
7.5 
Prior and Concomitant Medications Review ........................................................................ 26 
7.5.1 
Prior Medications .................................................................................................................................. 26 
7.5.2 
Concomitant Medications...................................................................................................................... 27 
7.6 
Disease Details and Treatments .......................................................................................... 27 
7.6.1 
Disease Details ....................................................................................................................................... 27 
7.6.2 
Prior Treatment Details ......................................................................................................................... 27 
7.6.3 
Subsequent Anti‐Cancer Therapy Status ............................................................................................... 27 
7.7 
Adverse Event (AE) Monitoring ........................................................................................... 27 
7.8 
Full Physical Exam ............................................................................................................... 27 
7.9 
Vital Signs ........................................................................................................................... 27 
7.10 
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........................................ 28 
7.11 
Tumor Imaging and Assessment of Disease ......................................................................... 28 
7.12 
Tumor Tissue Collection and Correlative Studies Blood Sampling ........................................ 28 
7.13 
Laboratory Procedures/Assessments .................................................................................. 28 
7.14 
Safety Follow‐Up Visit ......................................................................................................... 29 
7.15 
Follow‐up Visits .................................................................................................................. 29 
7.16 
Survival Follow‐up .............................................................................................................. 29 


 
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7.17 
Assessing and Recording Adverse Events ............................................................................ 29 
7.17.1 
Adverse Event Characteristics ........................................................................................................... 29 
7.17.2 
Adverse Event Definitions ................................................................................................................. 30 
7.17.3 
Evaluating Adverse Events................................................................................................................. 31 
7.17.4 
Responsibility for Reporting Adverse Events ..................................................................................... 33 
8.0 
STATISTICAL ANALYSIS PLAN ....................................................................................... 33 
8.1 
Primary Endpoint ................................................................................................................ 33 
8.2 
Secondary Endpoints .......................................................................................................... 33 
8.3 
Exploratory Endpoints ......................................................................................................... 33 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ...................... 34 
9.1 
Investigational Product ....................................................................................................... 34 
9.2 
Packaging and Labeling Information .................................................................................... 34 
9.3 
Clinical Supplies Disclosure ................................................................................................. 34 
9.4 
Storage and Handling Requirements ................................................................................... 34 
10.0  ADMINISTRATIVE AND REGULATORY DETAILS ............................................................ 34 
10.1 
Confidentiality .................................................................................................................... 34 
10.2 
Compliance with Financial Disclosure Requirements ........................................................... 34 
10.3 
Compliance with Law, Audit and Debarment ...................................................................... 35 
10.4 
Compliance with Trial Registration and Results Posting Requirements ................................ 35 
10.5 
Quality Management System .............................................................................................. 35 
10.6 
Data Management .............................................................................................................. 35 
11.0  REFERENCES ................................................................................................................ 35 
12.0  APPENDIX ................................................................................................................... 40 
12.1 
ECOG Performance Status ................................................................................................... 40 
12.2 
Common Terminology Criteria for Adverse Events V5.0 (CTCAE) ......................................... 40 
12.3 
Prescribing Information ...................................................................................................... 40 
12.3.1 
Nivolumab ......................................................................................................................................... 40 
12.3.2 
Ipilimumab......................................................................................................................................... 40 
12.4 
EORTC QOL‐C30 Quality of Life Survey ................................................................................ 40 
 
 
 
TRIAL SUMMARY 
Abbreviated Title 
Nivolumab and Ipilimumab in resectable peritoneal mesothelioma 


 
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Trial Phase 
Phase II 
Clinical Indication 
Malignant peritoneal mesothelioma 
Trial Type 
Treatment 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups  
1 
Number of trial subjects 
37 subjects 
Estimated enrollment period 
24 months 
Estimated duration of trial 
42 months 
Duration of Participation 
18 months 
 
 
 
 
1.0 TRIAL DESIGN 
1.1 
Trial Design  
This is a single institution, single-arm, phase II trial of perioperative combination immunotherapy 
(nivolumab + ipilimumab) in patients with resectable malignant peritoneal mesothelioma. All 
patients will undergo pretreatment cross-sectional imaging (CT or MRI) for clinical staging, as 
well as a laparoscopy to stage the peritoneum, assess resectability, and acquire pretreatment tissue, 
all of which is part of standard of care. Enrolled patients will then receive neoadjuvant combination 
immunotherapy, which will include 2 doses of nivolumab (3 mg/kg IV every 21 days) and 1 cycle 
of ipilimumab (1 mg/kg IV ). Repeat cross-sectional imaging (CT or MRI) will be performed to 
assess response to neoadjuvant immunotherapy. Surgical intervention via cytoreductive surgery 
(CRS) and hyperthermic intraperitoneal chemoperfusion (HIPEC) with mitomycin-C will occur 2-
6 weeks following the last dose of the neoadjuvant therapy, at which point additional pathologic 
assessments will be made. About 6-8 weeks following surgery and after new baseline cross-
sectional imaging is completed, patients will receive adjuvant ipilimumab (2 cycles; 1mg/kg IV 
every 6 weeks) + nivolumab (1 year). Restaging cross sectional scans will be obtained to assess 
response every 6 weeks while on adjuvant therapy and every 3 months for an additional year after 
completing therapy.  
The primary objective of the study is to assess the rate of major pathologic response (MPR), 
defined as 10% residual viable tumor (RVT) in the resected surgical specimen following 
neoadjuvant nivolumab + ipilimumab. Secondary objectives include assessment of the safety 
profile and feasibility of the neoadjuvant regimen, radiologic response rate, and overall and 
progression-free survival. Samples will be obtained pretreatment via laparoscopy and after 
nivolumab + ipilimumab treatment at surgical resection. Additional correlatives will be assessed 
including immune status/infiltration of the tumor, CA-125 serum levels, serum SRMP (soluble 
mesothelin-related peptide), circulating tumor cells, as well as radiologic correlatives. 
 


 
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1.2 
Trial Schema 
 
 
2.0 OBJECTIVES 
2.1 
Primary Objectives 
1. To determine pathologic response of the tumor to neoadjuvant treatment with 
nivolumab + ipilimumab via Major Pathologic Response (MPR), defined as ≤10% 
residual viable tumor (RVT) cells, as well as grade, necrosis, and Ki67. 
2.2 
Secondary Objectives  
1. To determine the safety profile of neoadjuvant nivolumab + ipilimumab, as defined 
by rate of grade III/IV adverse events according to CTCAE v5.0, occurring up to 30 
days post-operatively.  
2. To determine feasibility of neoadjuvant nivolumab + ipilimumab, as measured by the 
number of participants who complete neoadjuvant treatment with nivolumab + 
ipilimumab and proceed to surgery without extended treatment-related delay (> 6-
week delay) or progression precluding surgery.  
 
3. To determine the Overall Survival (OS) effect from neoadjuvant nivolumab + 
ipilimumab, defined as time from enrollment on study to death from any cause.   
 
4. To determine the Progression-free Survival (PFS) effect from neoadjuvant nivolumab 
+ ipilimumab, defined as time from enrollment on study to disease progression or 
death.  
 
Malignant 
Peritoneal 
Mesothelioma
All histologies
18 yrs
ECOG < 2
No IO/chemo within 4 
weeks
EXCLUSION:
Not a candidate for 
CRS/HIPEC
Visceral metastases
Baseline 
imaging, labs
Staging 
laparoscopy 
and biopsy
E
N
R
O
L
L
M
E
N
T
Neoadjuvant 
IO
Nivolumab IV 
3mg/kg Q3wks x2 + 
Ipilimumab 1mg/kg 
Q6wks x1
Restaging
Radiologic 
reassessment after 
Nivo x2 and Ipi x1
Restaging 
Radiologic 
assessment (ORR by 
RECIST 1.1)
CRS/HIPEC
Pathologic 
assessment (MPR, 
grade, necrosis, 
Ki67, immune 
infiltrate)
Adjuvant 
IO
Nivolumab IV 
3mg/kg Q3wks 
x1yr + 
Ipilimumab 
1mg/kg Q6wks
x2 cycles
Follow‐up
H&P, Labs, 
Imaging Q3mo 
x1 yr


 
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5. To determine the safety profile of adjuvant nivolumab + ipilimumab after 
cytoreductive surgery and HIPEC.  
 
6. To determine the radiologic response to neoadjuvant nivolumab + ipilimumab 
utilizing RECIST 1.1 pre- and post-treatment. 
 
7. To determine the effect of neoadjuvant nivolumab + ipilimumab on peritoneal 
carcinomatosis index (PCI).  
 
2.3 
Exploratory Objectives 
1. To determine immune status/infiltration of the tumor in response to neoadjuvant 
nivolumab + ipilimumab, including the change in presence of TILs/macrophages 
(CD3, CD4, CD8, CD11b, CD68, CD20) and PDL1 status.  
 
2. To determine blood-based changes with nivolumab + ipilimumab treatment, 
including PBMC inflammation expression profile, serum mesothelin (SMRP), 
osteopontin, CA-125, and circulating tumor cells. 
 
3. To evaluate health-related quality of life (HRQoL) for patients with peritoneal 
mesothelioma undergoing perioperative immunotherapy, measured by the EORTC 
QLQ C30, which was developed specifically to assess quality of life in patients with 
cancer.  
 
4. To correlate radiologic tumor measurements based on RECIST 1.1 and tumor volume 
with patient survival.  
 
5. To relate pathologic assessment of immune infiltrate with pre-operative image-based 
tumor signatures.  
 
6. To assess the response of neoadjuvant immunotherapy in those with BAP1 mutations 
identified on next-generation sequencing.  
 
3.0 BACKGROUND 
3.1 
Pharmaceutical and Therapeutic Background  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / 
FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in 
many solid tumors (Facciabene, 2012).  
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 


 
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healthy conditions, is to down-regulate unwanted or excessive immune responses.  PD-1 is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).   
PD-1 was shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ 
T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells.  The ligands for PD-1 are constitutively expressed or can be induced in a variety of 
cell types, including non-hematopoietic tissues as well as in various tumors.  Binding of either PD-
1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.   
Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to 
express abundant levels of this T-cell inhibitor.  PD-1 has been suggested to regulate tumor-
specific T-cell expansion in subjects with melanoma, consistent with the understanding that the 
PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and thereby is an attractive 
target for therapeutic intervention. 
Nivolumab is a potent human immunoglobulin G4 (IgG4) monoclonal antibody (mAb) that binds 
to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, releasing PD-1 pathway-
mediated inhibition of the immune response, including the anti-tumor immune response. 
The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct from 
that of CTLA-4 as both molecules regulate an overlapping set of signaling proteins.  CTLA-4 is 
a negative regulator of T-cell activity. Ipilimumab is a monoclonal antibody that binds to CTLA-
4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86. Blockade of CTLA-4 has 
been shown to augment T-cell activation and proliferation, including the activation and 
proliferation of tumor infiltrating T-effector cells. Inhibition of CTLA-4 signaling can also 
reduce T-regulatory cell function, which may contribute to a general increase in T cell 
responsiveness, including the anti-tumor immune response. 
 
Combined nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) mediated inhibition has also 
been shown to result in enhanced T-cell function that is greater than the effects of either antibody 
alone, suggesting a synergistic effect of the combination, and results in improved anti-tumor 
responses in metastatic melanoma and advanced RCC. In murine syngeneic tumor models, dual 
blockade of PD-1 and CTLA-4 resulted in increased anti-tumor activity (Fiegle, 2019). 
 
3.2 
Rationale 
3.2.1 Rationale for the Trial and Selected Subject Populations 
Around 500-800 new cases of peritoneal mesothelioma occur every year in the United States 
(Miura, 2014). In contrast to pleural mesothelioma, an antecedent exposure to asbestos cannot 
always be found in patients with this disease. However, we previously demonstrated that germline 
mutations (with BAP1 mutations being most common) are found in as many as 25% of peritoneal 
mesothelioma patients, compared to only 7% of those with pleural disease (Panou, 2018), implying 
that inherited susceptibility may play a larger role in peritoneal mesothelioma. Patients generally 
present with ascites or malignant bowel obstructions, which are significantly life limiting due to 
the resulting malnutrition and inanition. Cross sectional imaging such as CT scans or MRIs are 


 
9
utilized in the diagnosis of peritoneal mesothelioma but they generally underestimate the burden 
of disease. There are 3 major histologic subtypes of mesothelioma: epithelial, sarcomatoid, and 
mixed or biphasic (Husain, 2009).  Pathologic subtype is one of the most important prognostic 
indicators in this disease, so an accurate determination of pathology is essential (Rusch, 2012).  
The prognosis of patients with peritoneal mesothelioma is rather dismal in the absence of 
treatment, with a median survival of 12 months (Alexander, 2013). The standard of care for 
patients with peritoneal mesothelioma is the performance of cytoreductive surgery (CRS) and 
hyperthermic intra-peritoneal chemotherapy (HIPEC). The surgery consists of extirpation of 
peritoneal tumor with parietal and visceral peritonectomy procedures and visceral resections as 
necessary. During the surgery, the burden of disease is assessed by the peritoneal cancer index 
(PCI score). This score is measured by dividing the abdomen into 13 zones (including 4 zones for 
the bowel) and ranges from 0-39 (39 being the most disease). At the end of the operation the 
residual tumor is assessed by the completeness of cytoreduction which is an important prognostic 
factor for the survival of these patients. Heated chemotherapy is then applied to the peritoneal 
surfaces for 90 minutes and circulated at 600 ml-1500ml/min at 42 0C (Turaga K 2016).  
Patients undergoing CRS+HIPEC have an overall median survival of 53 months, with a more 
favorable prognosis for patients that undergo a complete cytoreduction (CC-0/1)(Yan TD 2009). 
The agent of choice for the intra-operative chemotherapy is either platinum based 
(cisplatin/carboplatin) or mitomycin C (Helm, 2015). Grade III-IV complication rates after this 
surgery can be as high as 31-40% (Kepenekian 2016). Major complications include death, 
anastomotic leak, deep or superficial site infection, anemia, re-operations, organ failure including 
renal failure, cardiac failure or respiratory failure, neutropenia, thromboembolic events, 
dehydration and failure to thrive.  
Due to the relatively low incidence of peritoneal mesothelioma, there are no large randomized 
controlled trials for either surgery or chemotherapy to guide management, leaving no clear 
consensus on optimal treatment approach. Therefore, much of the management is extrapolated 
from the studies in pleural mesothelioma. Standard chemotherapy for pleural mesothelioma 
consists of pemetrexed plus cisplatin.  This regimen was FDA-approved for MM based on a single-
blind, placebo-controlled, phase III trial, which randomized 456 patients to cisplatin with or 
without pemetrexed. Patients who received the combination achieved a longer median overall 
survival (12.1 vs. 9.3 months, p = 0.020), a superior time to progression (5.7 vs. 3.9 months, 
p = 0.001), and a higher objective response rate (41% vs. 17%, p < 0.001) than patients who 
received cisplatin alone (Vogelzang, 2003).  
 
However, the benefits of cytotoxic chemotherapy for peritoneal mesothelioma are less clear and 
alternative therapies such as immunotherapy warrant investigation. PD-1/PD-L1 and CTLA4 are 
immune checkpoints that mediate immune evasion in a wide spectrum of tumors. While the normal 
function of PD-1 and CTLA4 is to counteract excessive immune responses directed against normal 
tissues, various types of cancer have manipulated this function by up-regulating the natural ligands 
of these checkpoints to evade immune recognition. The critical role of this pathway became 
evident with the promising results of clinical trials of PD-1/PD-L1 and CTLA4 inhibitors, such as 
pembrolizumab (Hamid, 2013), nivolumab (Wolchok, 2013), and MPDL3280A (Powderly, 2013). 
While immune checkpoint blockers have not been evaluated in mesothelioma in the neoadjuvant 
setting, they are being used safely in the preoperative setting in a variety of tumor types. 


 
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In an analysis presented at ASCO 2014 (Kindler, 2014), we analyzed gene expression data on 44 
malignant mesothelioma tumors (Gordon, 2005), applied a melanoma-derived signature of T-cell 
inflammation (Harlin, 2009), and analyzed other immune response related genes. We identified 
that 32% of malignant mesotheliomas showed high CD8 gene expression, and a T-cell inflamed 
phenotype analogous to melanomas was present in multiple tumors. 
 
We evaluated MM tumor tissues from patients by multi-color immunohistochemistry (IHC), 
staining for CD68 (macrophages), CD8 (tumor infiltrating lymphocytes), and PD-L1 (immune 
checkpoint, MTA: Lieping Chen) We observed PD-L1 expression in 75% of MM tumors tested, 
which was 2-3+ in 37.5%, and 1+ in 37.5%. Patchy higher level PD-L1 expression was observed 
in stromal or CD68 cells located close to CD8+ cells. CD8 tumor infiltrating lymphocytes (TILs) 
were present in all epithelial tumors. Prominent CD68 infiltration was seen in all tumors.  
Thus, we identified high PDL-1 expression, a CD8 infiltrative pattern with a T-cell inflamed 
expression, and presence of PD-1/PD-L1 immune checkpoints in a subset of MM (approximately 
1/3 of MM tumors) similar to the phenotype found in other tumors such as melanoma that benefit 
from immune checkpoint blockade.  Furthermore, we recently identified a marked heterogeneity 
in PD-L1 expression specifically in peritoneal mesothelioma associated with either systemic or 
intraperitoneal chemotherapy administration (White, 2020). This demonstrates the pliability of 
PD-L1 as a biomarker, indicating that a low PD-L1 status at a single timepoint should not preclude 
patients from immune checkpoint inhibition therapy. 
 
Based on these and other studies, MM is an ideal target disease for anti-PD-1 therapy, and further 
investigation of the biology of this agent in this disease is warranted. This hypothesis is further 
supported by the recently reported data from the CheckMate 743 study. This was a randomized, 
open-label trial in patients with unresectable malignant pleural mesothelioma, with a primary 
endpoint of overall survival. Patients were randomized to receive either combination 
immunotherapy with nivolumab + ipilimumab for up to 2 years or standard chemotherapy with 
pemetrexed + either cisplatin or carboplatin for 6 cycles. The trial demonstrated a statistically 
significant improvement in OS for patients randomized to immunotherapy compared to 
chemotherapy. While it was efficacious in all histologies, there was a greater benefit noted in the 
sarcomatoid subgroup. The results of this trial have established a new standard of care in the 
treatment of malignant pleural mesothelioma, with immunotherapy now considered first line 
therapy. (Baas 2020). 
 
Therefore, we expect to see a similar response to immunotherapy in the peritoneal disease setting, 
and with this study we aim to evaluate that response. Of note, while resection is typically offered 
only to patients with non-sarcomatoid histology, in this trial we plan to include sarcomatoid 
histologies as well. Due to the robust response in the CheckMate 743 trial, which demonstrated 
that immunotherapy allowed for an equivalent survival in the sarcomatoid cohort to the epithelioid 
cohort, we anticipate that the sarcomatoid peritoneal patients will have a similar response, making 
their disease more amenable to cytoreduction.  
 
3.2.2 Rationale for Endpoints 
Tumor response is a surrogate marker of benefit from immune therapies that has been used for 
studies with nivolumab, ipilimumab, and other immune therapies. Response is considered a 
reliable marker of benefit for malignant mesothelioma and correlates with a survival benefit 


 
11
(Blayney, 2012). Response in pleural mesothelioma is generally assessed via the modified 
RECIST 1.1 criteria for assessment of response in mesothelioma (Armato 2018).  However, 
radiologic assessments of tumor response in peritoneal disease are poor and usually underestimate 
the burden of disease. 
Retrospective analyses have revealed that Major Pathologic Response (MPR) after neoadjuvant 
chemotherapy was related to improved overall survival and disease-free survival. Chaft et 
al. examined neoadjuvant chemotherapy for non-squamous NSCLC (non-small cell lung cancer) 
and reported that 22% of tumors showed MPR, with these responses being associated with long-
term survival. Furthermore, MPR has since been used in several prospective and randomized 
studies and has now been recommended as a surrogate endpoint specifically in the context of 
neoadjuvant immunotherapy (Hellmann, 2014). Pathologic responses, such as MPR and 
pathologic complete response are to date the most commonly used metrics for assessing response 
to neoadjuvant immunotherapy, and have been used in trials for melanoma, colon cancer, NSCLC, 
muscle-invasive bladder cancer, and several others (Chalabi, 2020; Yang, 2020). Patients with 
non-small cell lung cancer who received neoadjuvant nivolumab were found to have a 45% rate 
of MPR (Bott, 2019), and 30% of those with resectable stage III/IV melanoma who received just 
a single dose of pembrolizumab had MPR, 100% of which had a durable disease-free survival at 
24 months (Huang, 2019). This pathologic response is seen not only in those with known 
susceptibility to immunotherapy, such as those with mismatch repair deficient (dMMR) tumors. 
In the NICHE study, though colorectal cancer patients with dMMR tumors had a 95% MPR rate, 
those with MMR-proficient tumors still had a robust response with 20% MPR rate (Chalabi, 2020).  
 
4.0 SUBJECT SELECTION AND WITHDRAWAL 
4.1 
Number of Subjects 
This is a single-center phase II study and will enroll 37 patients for a total of 42 months. The 
University of Chicago will attempt to enroll 18-19 patients each year for two consecutive years. 
4.2 
Gender, Age, Racial and Ethnic Origin of Subjects 
Both male and female patients who are at least 18 years of age, of any ethnic or racial background, 
are included. Children (≤18 years of age) will be excluded from this study to limit variability in 
the study population and avoid this vulnerable population. There is no restriction on the racial or 
ethnic origin of subjects. Please see the inclusion and exclusion criteria for full details. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
4.3 
Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have a diagnosis of histologically or cytologically confirmed peritoneal mesothelioma, of 
epithelial, biphasic, or sarcomatoid subtypes 
 
2. Have disease burden amenable to cytoreduction and hyperthermic intraperitoneal 
chemotherapy (HIPEC), as determined by a surgeon specializing in mesothelioma  


 
12
 
3. Have measurable or evaluable disease based on RECIST 1.1 or on laparoscopy 
 
4. Have no definitive evidence of visceral metastases by best staging 
 
5. Be willing to undergo laparoscopy or mini-laparotomy for peritoneal staging 
 
6. Demonstrate adequate organ function as determined by screening labs, with criteria 
defined in Table 1 
 
Table 1. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥ 1,500 /L 
Platelets 
≥ 100,000 / L 
Hemoglobin 
≥ 9 g/dL  
Renal 
 
Serum creatinine OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤ 1.5 X upper limit of normal (ULN) OR 
 
≥ 60 mL/min for subject with creatinine levels > 
1.5 X institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN   
Coagulation 
International Normalized Ratio 
(INR) or Prothrombin Time (PT) 
Activated Partial Thromboplastin 
Time (aPTT) 
 
≤ 1.5 X ULN. Patients on anticoagulation are 
expected to hold anticoagulation for at least 5 days 
prior to surgery. 
aCreatinine clearance should be calculated per institutional standard. 
 
7. Have an ECOG performance status of < 2 
 
8. Be  18 years of age on day of signing informed consent 
 
9. Be willing and able to provide written informed consent for the trial 
4.4 
Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject:  
1. Is currently participating in a study of an investigational agent and received an 
investigational agent within 4 weeks of the first dose of treatment on this protocol 
 
2. Has received any immunotherapy agents outside of this protocol within 4 weeks of the first 
dose of treatment on this protocol 
 


 
13
3. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (>10 
mg of prednisone daily or equivalent) or any other form of immunosuppressive therapy 
within 14 days prior to the first dose of study drug. 
 
4. Has a known history of active TB infection (Bacillus tuberculosis) 
 
5. Has active COVID-19 infection 
 
6. Has known history of, or any evidence of active, non-infectious pneumonitis that required 
steroids, or active pneumonitis 
 
7. Has a severe hypersensitivity to nivolumab or any of its excipients 
 
8. Has a severe hypersensitivity to ipilimumab or any of its excipients  
 
9. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs) 
 
10. Has a known additional malignancy that is progressing or required active treatment within 
the 3 years prior to enrollment - exceptions include basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially curative therapy or in 
situ cervical cancer or other tumors that will not affect life expectancy 
 
11. Has an active infection requiring systemic therapy 
 
12. Has a known history of HIV, Hepatitis B, or Hepatitis C 
 
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit through 120 days after the 
last dose of trial treatment 
a. Female subjects of childbearing potential should have a negative urine 
or serum pregnancy within 72 hours prior to receiving the first dose of 
study medication.  If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.   
 
b. Female subjects of childbearing potential should be willing to use 2 
methods of birth control or be surgically sterile, or abstain from 
heterosexual activity for the course of the study through 120 days after 
the last dose of study medication (Reference Section 5.8.2).  Subjects of 
childbearing potential are those who have not been surgically sterilized 
or have not been free from menses for > 1 year.  
 


 
14
c. Male subjects should agree to use an adequate method of contraception 
starting with the first dose of study therapy through 120 days after the 
last dose of study therapy. 
 
15. Is on anticoagulation that cannot be discontinued in the perioperative period 
 
16. Has received a live vaccine within 30 days of planned start of study therapy 
4.5 
Subject Identification & Recruitment  
Patients will be identified during the initial medical oncology or surgical oncology appointment. 
Patients will be screened for the appropriate inclusion and exclusion criteria and recruited to the 
trial as appropriate. There will be no use of advertisements, but it will be listed on the Cancer 
Center website. Patients will not be identified through medical records.  
4.6 
Location  
This trial will be a single institution study. Recruitment of all patients will happen at the University 
of Chicago main site. Patients will undergo all interventions at the University of Chicago main 
site, but may receive the immunotherapy at the satellite sites.  
4.7 
Discontinuation of Study and Participant Withdrawal  
Discontinuation of study intervention does not represent withdrawal from the study. 
As data on clinical events beyond study intervention discontinuation may be important to the study, 
they must be collected through the participant’s last scheduled follow up, even if the participant 
has discontinued study intervention. Therefore, all participants who discontinue study intervention 
prior to completion of the protocol-specified treatment period will still continue to participate in 
the study. 
 
Participants may discontinue study intervention at any time for any reason or be discontinued from 
the study intervention at the discretion of the investigator should any untoward effect occur. Also, 
a participant may be discontinued from study intervention by the investigator if study intervention 
is inappropriate, the study plan is violated, or for administrative and/or other safety reasons. 
A participant must be discontinued from study intervention but continue to be monitored in the 
study for any of the following reasons:  
1. The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.  
2. Any occurrence of another malignancy that requires treatment.  
3. Unacceptable AEs or toxicities  
4. The participant interrupts study intervention administration for >28 consecutive days  
5. The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator, placed the participant at unnecessary risk from continued administration 
of study intervention.  
6. The participant has a confirmed positive serum or highly-sensitive urine pregnancy test.  


 
15
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study. If a participant withdraws from the 
study, they will no longer receive study intervention or be followed at scheduled protocol visits.  
Lost to Follow-up 
If a participant fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the participant, the following procedures are to be performed:  
1. The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.  
2. The investigator must make every effort to regain contact with the participant at each 
missed visit (e.g. telephone calls and/or a certified letter to the participant’s last known 
mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.  
3. Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.  
5.0 TRIAL INTERVENTIONS 
5.1 
Pre-intervention Testing 
Once consent is obtained, if not already performed patients will have a CT or MRI of the Abdomen 
and Pelvis and a CT of the Chest to determine extent of disease. They will also undergo a 
laparoscopy or mini-laparotomy for peritoneal carcinomatosis index (PCI) staging and pre-
treatment tissue biopsy. The laparoscopic surgery is performed under general anesthesia, and 
involves inserting a 5 or 10 mm camera inside the peritoneal cavity to visually assess the peritoneal 
disease burden. Tissue biopsy is obtained by inserting a second 5 mm port and biopsying one or 
multiple areas of diseased peritoneum. Each biopsy site will be clearly marked by location for 
pathological identification. Patients with extensive prior surgery that precludes a safe laparoscopy 
could undergo a mini-laparotomy, in which a small incision is made to assess the burden of disease 
in the peri-incisional area. This laparoscopy or mini-laparotomy is standard of care for patients 
with peritoneal mesothelioma who are considered for CRS/HIPEC. 
 
5.2 
Neoadjuvant Nivolumab and Ipilimumab 
5.2.1 Drug Supply 
Both nivolumab and ipilimumab will be obtained through commercial drug supply.  
 
5.2.2 Dose Selection 
Neoadjuvant nivolumab is delivered at a dose of 3 mg/kg over 30 minutes every 21 days via IV 
infusion on day 1 and day 22 of each 42-day cycle for 2 doses (1 cycle). 


 
16
Neoadjuvant ipilimumab is delivered at a dose of 1 mg/kg over 30 minutes every 42 days via IV 
infusion on day 1 of each 42-day cycle for 1 dose (1 cycle). When given on the same day as 
nivolumab, ipilimumab is to be given following nivolumab infusion.  
 
5.2.3 Dose Modification 
Adverse events (both non-serious and serious) associated with nivolumab or ipilimumab exposure 
may represent an immunologic etiology. These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. No dose reduction for nivolumab or 
ipilimumab is recommended. In general, withhold nivolumab and ipilimumab for severe (Grade 
3) immune-mediated adverse reactions. Permanently discontinue the agents for life-threatening 
(Grade 4) immune-mediated adverse reactions, recurrent severe (Grade 3) immune-mediated 
reactions that require systemic immunosuppressive treatment, or an inability to reduce 
corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of 
initiating steroids.  
 
Dosage modifications for nivolumab or ipilimumab in combination for adverse reactions that 
require management different from these general guidelines are summarized in the prescribing 
information (Appendix). 
 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not 
related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or 
holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Principal Investigator. The reason for interruption 
should be documented in the patient's study record. 
 
5.3 
Surgical Intervention 
After completion of 2 cycles of nivolumab and 1 cycle of ipilimumab, patients will undergo 
restaging CT or MRI and labs to assess disease response. A surgical re-evaluation will be 
conducted to determine if patients remain suitable candidates for surgery. Surgical cytoreduction 
and HIPEC with mitomycin-C will be performed approximately 2-6 weeks after the last dose of 
nivolumab, to achieve an adequate cytoreduction of all residual gross tumor. CRS+HIPEC, which 
can be performed via a laparoscopic or an open laparotomy approach, includes but is not limited 
to peritonectomy procedures whereby the parietal peritoneum is resected, omentectomy and other 
visceral resections as necessary to reduce the tumor burden to minimal residual disease. 
Completeness of cytoreduction and PCI scores will be documented. The dose of intraperitoneal 
chemotherapy will be 40 mg of mitomycin in split dosing of 30mg at time 0 and 60 mg at time 60 
minutes, with a complete washout at 90 minutes. Tumor resections from matched sites of the 
original pre-neoadjuvant therapy biopsy will be marked clearly for pathological identification.  
 
Patients will be closely monitored for potential complications following surgery. Major 
complications include death, anastomotic leak, deep or superficial site infection, anemia, re-
operations, organ failure including renal failure, cardiac failure or respiratory failure, neutropenia, 
thromboembolic events, dehydration and failure to thrive. 
 


 
17
5.4 
Adjuvant Nivolumab and Ipilimumab 
Following surgery, patients will have 6-8 weeks of recovery prior to the initiation of adjuvant 
immunotherapy. Cross-sectional imaging will be obtained prior to starting adjuvant therapy and 
will be repeated every 6 weeks while on therapy. Adjuvant immunotherapy with nivolumab and 
ipilimumab will be administered according to the same dosing and schedule as it was given in the 
neoadjuvant phase, but with the first cycle to include nivolumab alone.  
The first 2 cycles in the adjuvant phase will include nivolumab delivered at a dose of 3 mg/kg over 
30 minutes every 21 days via IV infusion on day 1 and day 22 of each 42-day cycle for 4 doses (2 
cycles) and ipilimumab delivered at a dose of 1 mg/kg over 30 minutes every 42 days via IV 
infusion on day 22 of each 42-day cycle for 2 doses (2 cycles). When given on the same day as 
nivolumab, ipilimumab is to be given following nivolumab infusion. Following these first 2 
adjuvant cycles, nivolumab will be delivered alone at the same dose, route, and rate every 21 days 
on days 1 and 22 of each 42-day cycle, continuing until 1 year post-operatively.   
6.0 ADDITIONAL METHODOLOGY 
6.1 
Trial Blinding/Masking 
This is an open-label trial; therefore, the investigator and subject will know the treatment 
administered. 
6.2 
Randomization or Treatment Allocation  
There will be no randomization. All patients that meet criteria will be enrolled in the single arm. 
6.3 
Stratification  
No stratification will be done.  
6.4 
Concomitant Medications/Vaccinations (allowed & prohibited)  
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required. The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician.  
 
6.4.1 Acceptable Concomitant Medications 
All treatments that the treating investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the treating investigator in keeping with the community standards 
of medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 


 
18
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded as well. 
6.4.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Treatment Phase of this 
trial: 
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents not specified in this protocol 
 Radiation therapy  
 Live vaccines within 30 days prior to the first dose of trial treatment and while participating 
in the trial.  Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
 Systemic glucocorticoids while on nivolumab and ipilimumab for any purpose other than 
to modulate symptoms from an event of clinical interest of suspected immunologic 
etiology.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Principal Investigator. 
Subjects who, in the assessment by the treating investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the treating investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.5 
Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of adverse events with 
potential immunologic etiology are outlined below. Where appropriate, these guidelines include 
the use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory 
agents if symptoms do not improve with administration of corticosteroids.  Note that several 
courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the treating investigator determines the events 
to be related to the study treatment.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin 
photography as part of evaluation of the event.  


 
19
 Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 


 
20
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 


 
21
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
Management of Infusion Reactions: 
Discontinue nivolumab and ipilimumab in patients with severe (Grade 3) or life-threatening 
(Grade 4) infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild 
(Grade 1) or moderate (Grade 2) infusion-related reactions.  
6.6 
Diet/Activity/Other Considerations 
6.6.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
6.6.2 Contraception 
Nivolumab and ipilimumab may have adverse effects on a fetus in utero.  Furthermore, it is not 
known if nivolumab or ipilimumab have transient adverse effects on the composition of sperm.  
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to use 2 methods of 
birth control or are considered highly unlikely to conceive.  Highly unlikely to conceive is defined 
as 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥ 45 years of age and has not 
had menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should start 
using birth control from study Visit 1 throughout the study period up to 120 days after the last dose 
of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom (by 
the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progesterone agent (including oral, subcutaneous, intrauterine, or intramuscular 
agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in the 
study, they must adhere to the contraception requirement (described above) for the duration of the 
study and during the follow-up period. If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into the study. 
 
6.6.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on study, the subject will immediately be 
removed from the study.  The treating investigator and/or their designee will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Principal Investigator. 


 
22
If a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Principal Investigator and followed as described 
above. 
 
6.6.4 Use in Nursing Women 
There are no data on the presence of nivolumab or ipilimumab in human milk, the effects on the 
breastfed child, or the effects on milk production. Because of the potential for serious adverse 
reactions in breastfed children and since many drugs are excreted in human milk, subjects who are 
breast-feeding are not eligible for enrollment. 
 
6.7 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the principal and/or treating investigator should any untoward effect occur.  In 
addition, a subject may be withdrawn by the principal and/or treating investigator if enrollment 
into the trial is inappropriate, the trial plan is violated, or for administrative and/or other safety 
reasons.  Further details are described in Section 4.7. 
 
6.8 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
5. If 2 patient deaths attributed to the investigational drug are seen in the 30 days following 
surgery. The relationship of the investigational drug to the mortality will be determined by the 
treating medical oncologist and surgeon.  
6. Assuming a major complication rate of 10% from the combination immunotherapy (Taioli, 
2015), the trial will be halted if any major complication which is attributed to the 
investigational drug occurs in the first two patients, or in 3 cases among the first 11 patients, 
or in any 4 patients during the course of the trial. In order for the trial to be halted, these 
complications must be determined to result from the investigational drug as will be determined 
by the treating oncologist and surgeon. A composite adverse event of major complications 
defined as the occurrence of any ventricular arrhythmia requiring treatment, hemorrhage 
requiring re-operation, acute respiratory distress syndrome (ARDS), pneumonia, reintubation, 
placement of a tracheostomy, pulmonary embolus, empyema, sepsis, intra-abdominal sepsis, 
myocardial infarction and unexpected return to the operating room will be monitored 
sequentially.  


 
23
7.0 TRIAL PROCEDURES 
7.1 
Flow Chart – Schedule of Events 
7.1.1 Flow Chart for Screening, Neoadjuvant, and Surgery Phases 
Table 2. Trial Flow Chart of Screening, Neoadjuvant, and Surgery Phases 


 
24
 
 
Trial Phase: 
Screening 
Phase 
Neoadjuvant Treatment Phase 
Pre-Surgery 
Phase 
Surgery Phase 
Post-Surgery 
Recovery Phase 
 
Screening 
(Visit 1) 
C1 D1 
C1 D22C 
4 Weeks 
3 Weeks 
3-4 Weeks 
Scheduling Window (Days): 
-28 to -1 
 
± 3 
 
 
 
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
X 
X 
 
Demographics and Medical 
History 
X 
 
 
X 
X 
 
Prior and Concomitant 
Medication Review 
X 
X 
X 
X 
X 
 
Interventions 
Nivolumab Administration 
 
X 
X 
 
 
 
Ipilimumab Administration 
 
X 
 
 
 
 
Surgery 
 
 
 
 
X 
 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
 
 
Full Physical Examination 
X 
X 
X 
X 
X 
 
Height 
X 
 
 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
 
EORTC QOL C30 
X 
 
 
X 
 
X 
Surgeon Assessment 
X 
 
 
X 
 
 
Medical Oncology Assessment 
X 
X 
X 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory a 
Pregnancy Test – Urine or Serum 
-HCG 
X 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry 
Panel 
X 
X 
X 
X 
 
 
INR, PTT 
X 
 
 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
TSH (reflex T3, T4 if abnormal) 
X 
X 
 
X 
 
 
Efficacy Measurements b 
Tumor Imaging with CT/MRI 
X 
 
 
X 
 
 
CA-125 
X 
 
 
X 
 
 
Circulating tumor cells 
X 
 
 
X 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Laparoscopy for tissue and PCI 
score assessment 
X 
 
 
 
 
 
Correlative Studies Blood 
Collection c 
X 
X 
 
X 
X 
 
a. 
Screening lab tests to be performed within 14 days before first dose. After Cycle 1, pre‐dose lab procedures can be conducted <72 hours before dosing.  
b. 
For CT scans, scheduling window is +/‐ 7 days.  
c. 
Serum mesothelin and osteopontin will be obtained at the times of tumor imaging and upon tumor progression.  


 
25
7.1.2 Flow Chart for Adjuvant and Post-Treatment Phases 
Table 3. Trial Flow Chart of Adjuvant and Post-Treatment Phases 
Trial Period: 
Adjuvant Therapy Phase 
End of 
Treat-
ment 
Post-Treatment Phase 
Treatment Week/Title: 
 
 
 
 
Repeat x 1 year 
from surgery 
Discon 
Safety 
Follow-
up 
Follow 
Up 
Visits 
Survival 
Follow-Up 
C1 
D1 
C1 
D22 
C2 
D1 
C2 
D22 
C1 
D1 
C1 
D22 
C2 
D1 
C2 
D22 
Scheduling Window (Days)c: 
 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
At 
time of 
Discon 
30 days 
post 
discon 
Every 
12 wks 
post 
discon 
Every 12 
weeks 
Nivolumab Administration 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Ipilimumab Administration 
 
X 
 
X 
 
 
 
 
 
 
 
 
Prior and Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
 
 
X 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
EORTC QOL C30 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Laboratory Parameters 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Comprehensive Serum 
Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
TSH (reflex T3, T4 if 
abnormal) 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Efficacy Measurement 
Tumor Imaging with CT scan 
every 12 weeks c
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
CA-125 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Circulating tumor cells 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
Correlative Lab 
Correlative Studies Blood 
Collection a,b 
X 
 
 
 
X 
 
 
 
X 
 
 
 
a. 
Both tumor imaging and correlative studies to be repeated after every 6  weeks. 
b. 
Serum mesothelin and osteopontin will be obtained at the times of tumor imaging and upon tumor 
progression.  
c. 
For CT scans, the scheduling window is +/‐ 7 days 
 
The Trial Flow Chart summarizes the trial procedures to be performed at each visit.  Individual 
trial procedures are described in detail below.  It may be necessary to perform these procedures 
at unscheduled time points if deemed clinically necessary by the investigator. 


 
26
 
7.2 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to participating 
in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature on a consent form along with the dated signature of the person 
conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the subject before participation in 
the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent 
form that captures the subject’s dated signature or by the subject’s legally acceptable 
representative’s dated signature. 
 
The informed consent will adhere to IRB/ERC requirements and applicable laws and regulations. 
 
7.3 
Inclusion/Exclusion Criteria Review 
All inclusion and exclusion criteria will be reviewed by the treating investigator or qualified 
designee to ensure that the subject qualifies for the trial.  
7.4 
Medical History 
A medical history will be obtained by the treating investigator or qualified designee.  Medical 
history will include all active conditions, and any condition diagnosed within the prior 10 years 
that are considered to be clinically significant by the Investigator.  Details regarding the disease 
for which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.5 
Prior and Concomitant Medications Review 
7.5.1 Prior Medications 
The treating investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject within 
28 days before starting the trial.  Treatment for the disease for which the subject has enrolled in 
this study will be recorded separately and not listed as a prior medication.  
 


 
27
7.5.2 Concomitant Medications 
The treating investigator or qualified designee will record medication, if any, taken by the 
subject during the trial.   
 
7.6 
Disease Details and Treatments 
7.6.1 Disease Details 
The treating investigator or qualified designee will obtain prior and current details regarding 
disease status.  
 
7.6.2 Prior Treatment Details 
The treating investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
 
7.6.3 Subsequent Anti-Cancer Therapy Status 
The treating investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30-day Safety Follow-up visit should occur before the first 
dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will move 
into survival follow-up.  
7.7 
Adverse Event (AE) Monitoring 
The treating investigator or qualified designee will assess each subject to evaluate for potential 
new or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during the 
follow-up period according to CTCAE (v5.0). Toxicities will be characterized in terms regarding 
seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
7.8 
Full Physical Exam 
The treating investigator or qualified designee will perform a complete physical exam during the 
screening period and as indicated in the Trial Flow Chart.  Clinically significant abnormal findings 
should be recorded as medical history.   
7.9 
Vital Signs 
The treating investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in the 
Trial Flow Chart. Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 


 
28
7.10 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The treating investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment and discontinuation of trial treatment as specified in 
the Trial Flow Chart.   
7.11 Tumor Imaging and Assessment of Disease 
CT or MRI scans will be obtained at baseline. After completion of neoadjuvant nivolumab + 
ipilimumab treatment a CT or MRI imaging will again be repeated after completion of surgery 
(prior to starting adjuvant immunotherapy), and repeated every 6 weeks while on adjuvant therapy 
and every 3 months for 1 year after completing treatment. 
7.12 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Tumor tissue will be obtained at laparoscopy and at surgical resection. Correlative studies blood 
sampling for SRMP, osteopontin, CA-125, and circulating tumor cells will be obtained per Trial 
Flow Chart schedule.   
 
7.13 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 4.   
Table 4.  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human 
chorionic 
gonadotropin (β-hCG) 
† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PTT 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Total 
thriiodothyronine (T3) 
Red Blood Cell Count 
Carbon Dioxide (CO2 or bicarbonate) Microscopic exam (If abnormal 
results are noted) 
Free thyroxine (T4) 
Absolute Neutrophil Count 
Calcium 
Urine pregnancy test † 
Thyroid stimulating 
hormone (TSH) 
Absolute Lymphocyte Count 
Chloride 
 
Blood for correlative 
studies 
 
Glucose 
 
 
 
Potassium 
 
 
 
Sodium 
 
  
 
Total Bilirubin 
 
  
 
Total protein 
 
  


 
29
Hematology 
Chemistry 
Urinalysis 
Other 
 
Blood Urea Nitrogen 
 
  
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test 
will be required.   
 
Laboratory tests for screening should be performed within 14 days prior to the first dose of 
treatment.  After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to 
dosing.  Results must be reviewed by the treating investigator or qualified designee and found to 
be acceptable prior to each dose of trial treatment.  
 
7.14 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever comes 
first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  Subjects with an 
AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning 
of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur within 90 days of the 
end of treatment or before initiation of a new anti-cancer treatment should also be followed and 
recorded.   
 
7.15 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed every 3 months by radiologic imaging to monitor 
disease status.  Every effort should be made to collect information regarding disease status until 
the start of new anti-neoplastic therapy, disease progression, death, or end of the study. Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
 
7.16 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.  
7.17 Assessing and Recording Adverse Events 
7.17.1 Adverse Event Characteristics  
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 5.0.  A copy of the CTCAE 
version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm 
 
 Attribution of the AE: 


 
30
- 
Definite (5) – The AE is clearly related to the study treatment. 
- 
Probable (4) – The AE is likely related to the study treatment. 
- 
Possible (3) – The AE may be related to the study treatment. 
- 
Unlikely (2) – The AE is doubtfully related to the study treatment. 
- 
Unrelated (1) – The AE is clearly NOT related to the study treatment.  
 
7.17.2 Adverse Event Definitions 
7.17.2.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily have 
to have a causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of a medicinal product or protocol-specified procedure, whether 
or not considered related to the medicinal product or protocol-specified procedure.  Any worsening 
(i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting 
condition that is temporally associated with the use of the study treatment, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in frequency 
or severity from expected levels are not to be considered adverse events.  Examples of this may 
include, but are not limited to, teething, typical crying in infants and children and onset of menses 
or menopause occurring at a physiologically appropriate time. 
 
Adverse events may occur during the course of the use of the study treatment in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a 
result of a protocol-specified intervention, including washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is considered to 
be drug related by the treating investigator. 
 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets.  
 
7.17.2.2 Serious Adverse Event  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death 
2) Life-threatening (e.g. places subject at immediate risk of death, this does not include events 
that might have caused death if they occurred a greater severity) 
3) Inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 hours  


 
31
4) A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions  
5) A congenital anomaly/birth defect.  
 
7.17.2.3 Adverse Reactions 
An adverse event is considered to be an adverse reaction if there is evidence to suggest a causal 
relationship to the study agent.  This may include a single occurrence of an event strongly 
associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more occurrence of an 
event otherwise uncommon is the study population, or an aggregate analysis of specific events 
occurring at greater than expected frequency. 
 
7.17.3      Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 5.0. Any adverse event which 
changes CTCAE grade over the course of a given episode will have each change of grade recorded 
on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.


 
 
 
 
 


 
 
 
 
7.17.4 Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.  
 
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Primary Endpoint 
The primary endpoint in this study is Major Pathologic Response (MPR), defined as presence of 
<=10% residual viable tumor in the resected surgical specimen. The proportion of patients who 
achieve an MPR will be reported (MPR rate), along with an exact 95% confidence interval. 
Sample size considerations: A total of 37 patients will be enrolled, with the goal to enroll 18-19 
patients per year in 2 consecutive years. This sample size will provide 80% power to detect a 
significant increase in MPR rate of at least 40% using the one-sided binomial test with the null 
hypothesis H0:p = 0.5 against the alternative hypothesis Ha:p > 0.5 corresponding to an actual MPR 
rate of ~0.7 or higher.  
 
8.2 
Secondary Endpoints  
Safety and feasibility will be assessed throughout the trial, especially in discussion with the 
surgeon performing the cytoreductive surgery. Adverse events will be summarized by type, grade, 
and relationship to the study drug.  The trial will be discontinued if the 30-day mortality occurs in 
two patients and the cause of death is determined to be related to the investigational agent by the 
treating medical oncologist and surgeon. Refer to section 6.8 for additional clinical criteria for 
early trial termination.  
 
Analyses to address the secondary objectives will be primarily descriptive in nature.  Progression-
free survival (PFS) and overall survival (OS) will be estimated using the Kaplan-Meier method 
with qualitative assessment of the emergence of a tail at the end of the curve as evidence of long-
term survival, which is not seen in this disease despite aggressive multimodality therapy.  Median 
event times will be determined as the time at which the Kaplan-Meier curve falls below 50%.   
The objective response rate to neoadjuvant nivolumab + ipilimumab based on cross-sectional 
imaging pre- and post-treatment will be determined along with an exact 90% confidence interval. 
8.3 
Exploratory Endpoints 
CD8 tumor infiltrating lymphocytes (TILs) will be assessed by % of tumor showing infiltration 
and calculation of CD8 TIL density in the pre- and post-treatment biopsy specimens. An increase 
in the TIL density will be termed a TIL-response and correlated with TCIP response using Pearson 
or Spearman rank correlation coefficients.  
Presence of additional pathologic markers, including CD3, CD4, CD68, and CD20 will be assessed 
in pre- and post-treatment tissue samples. Results will be descriptive and presented in tabular form.  
Changes in PD-L1 expression compared between the pre- and post-treatment tissue samples will 
be determined using IHC and mass spectrometry. Ordinal IHC data will be assessed using the 


 
 
 
 
Wilcoxon signed-rank test. Changes in other continuous immune response and biomarker values 
will be analyzed using paired t-tests.   
 
Analysis of variance for repeated measures will be performed to evaluate changes in serum 
mesothelin and osteopontin levels over time. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records 
and ensure appropriate supply, storage, handling, distribution and usage of investigational product 
in accordance with the protocol and any applicable laws and regulations. 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
9.3 
Clinical Supplies Disclosure 
This trial is open-label. Drug identity (name, strength) is included in the label text. 
 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions 
specified on the label.   
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial 
site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Individual patient medical information obtained as a result of this study is considered confidential 
and disclosure to third parties is prohibited with the exceptions noted below. Patient confidentiality 
will be ensured by using patient identification code numbers. Treatment data may be given to the 
patient’s personal physician or to other appropriate medical personnel responsible for the patient’s 
welfare. Data generated as a result of the study need to be available for inspection on request by 
the participating physicians, the Drug Manufacturer’s representatives, by the IRB and the 
regulatory authorities. 
 
10.2 Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration  


 
 
 
 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54) and will be 
implemented following institutional standards. 
10.3 Compliance with Law, Audit and Debarment 
The trial will be conducted in an efficient and diligent manner and in conformance with this 
protocol; generally accepted standards of Good Clinical Practice (e.g., International Conference 
on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use 
Good Clinical Practice: Consolidated Guideline and other generally accepted standards of good 
clinical practice); and all applicable federal, state and local laws, rules and regulations relating to 
the conduct of the clinical trial. 
10.4 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food 
and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible 
for determining whether the trial and its results are subject to the requirements for submission to 
the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.     
 
10.5 Quality Management System 
The Principal Investigator will ensure that trial is conducted and data are generated, documented, 
and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and 
all applicable federal, state, and local laws, rules and regulations relating to the conduct of the 
clinical trial.  
 
A quality assurance audit/inspection of this study may be conducted by regulatory authorities. The 
quality assurance auditor will have access to all medical records, the investigator’s study-related 
files and correspondence, and the informed consent documentation of this clinical study. 
The trial will be monitored in the weekly mesothelioma multidisciplinary conference.  
10.6 Data Management 
Data management will be provided via the cancer clinical trial infrastructure available at the 
University of Chicago (eVELOS). It is the responsibility of the investigators to record and verify 
the accuracy of subject data. 
 
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12.0 APPENDIX 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
12.2 Common Terminology Criteria for Adverse Events V5.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0 will be utilized for adverse event reporting. 
(https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_60) 
 
12.3 Prescribing Information 
12.3.1 Nivolumab 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125554s058lbl.pdf 
 
12.3.2 Ipilimumab 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125377s110lbl.pdf 
 
12.4 EORTC QOL-C30 Quality of Life Survey 
https://www.eortc.org/app/uploads/sites/2/2018/08/Specimen-QLQ-C30-English.pdf