Conditions: Hematopoietic and Lymphoid Cell Neoplasm Malignant Solid Neoplasm Steroid-Refractory Pneumonitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1
Healthy volunteers: no

Brief summary:
This phase II trial studies how well infliximab and intravenous immunoglobulin therapy work in treating patients with pneumonitis that does not respond to steroid treatment. Immunotherapy with monoclonal antibodies such as, infliximab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Intravenous immunoglobulin therapy may improve pneumonitis. It is not yet known whether giving infliximab and intravenous immunoglobulin therapy will work better in treating patients with pneumonitis.

Detailed description:
PRIMARY OBJECTIVE:

I. To assess pneumonitis response to additional immunosuppression (infliximab or intravenous immunoglobulin therapy \[IVIG\]) in patients with steroid-refractory pneumonitis at 28-days.

SECONDARY OBJECTIVES:

I. To assess functional parameters of steroid-refractory pneumonitis at day 1, 14-days and 28-days after day 1 of receipt of additional immunosuppression (infliximab or IVIG).

II. To assess radiologic parameters of steroid-refractory pneumonitis at day 1, 14-days and 28-days after day 1 of receipt of additional immunosuppression (infliximab or IVIG).

III. To assess patient-reported outcomes of steroid-refractory pneumonitis at day 1, 14-days and 28-days after day 1 of receipt of additional immunosuppression (infliximab or IVIG).

IV. To assess death after additional immunosuppression. V. To assess the rate of infections in the 28-day period after additional immunosuppression.

EXPLORATORY OBJECTIVES:

I. To examine lung tissue, bronchoalveolar lavage (BAL) and serial blood samples in patients who develop steroid-refractory pneumonitis.

II. To examine associations between BAL phenotypes and pneumonitis response, functional and radiologic parameters of pneumonitis.

III. To evaluate associations between pneumonitis and autoantibodies, T-cell expansion, and baseline cytokines in the blood.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM A: Patients receive infliximab intravenously (IV) on day 1 followed by prednisone taper IV or orally (PO) for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive an additional dose of infliximab IV on day 14 at the discretion of the treating physician.

ARM B: Patients receive intravenous immunoglobulin therapy IV over 2-5 days per institutional guidelines followed by prednisone taper IV or PO for 4-6 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 28, 42 and 56 days.

Arms:
arm 1: Patients receive infliximab IV on day 1 followed by prednisone taper IV or PO for 4-6 weeks in the absence of disease progression or unacceptable toxicity. Patients may receive an additional dose of infliximab IV on day 14 at the discretion of the treating physician. arm 2: Patients receive intravenous immunoglobulin therapy IV over 2-5 days per institutional guidelines followed by prednisone taper IV or PO for 4-6 weeks in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Infliximab intervention 2: Intravenous Immunoglobulin Therapy intervention 3: Prednisone intervention 4: Methylprednisolone
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV or PO intervention 4: Given IV or PO

Protocol document:
Prot_SAP_000.pdf: 
 
EAQ172 
1 
 
Optimizing Immunosuppression for Steroid-Refractory 
Anti-PD-1/PD-L1 Pneumonitis 
STUDY CHAIR: 
Jarushka Naidoo, MB, BCH 
STUDY STATISTICIAN: 
STUDY CO-CHAIR: 
IMAGING STATISTICIAN: 
Ju-Whei Lee, PhD 
Sheetal Kircher, MD 
JoRean Sicks, MS 
IMAGING CO-CHAIR: 
Mizuki Nishino, MD 
COMMUNITY CO-CHAIR: 
Kathleen J. Yost, MD 
TRANSLATIONAL RESEARCH CO-CHAIRS: 
Kellie N. Smith, PhD 
Franco Rafael D'Alessio, MD 
Peter B. Illei, MD 
Valsamo Anagnostou, MD, PhD 
Livia Casciola-Rosen, PhD 
SYMPTOM SCIENCE & TREATMENT TOXICITY 
SUBCOMMITTEE CHAIR: 
 
Sheetal Kircher, MD 
CANCER CONTROL AND SURVIVORSHIP 
COMMITTEE CHAIR: 
 
Lynne I. Wagner, PhD 
Version Date:  October 19, 2022 
STUDY PARTICIPANTS 
 
ACTIVATION DATE 
 
 
June 25, 2020 
ALLIANCE / Alliance for Clinical Trials in Oncology 
 
 
NRG / NRG Oncology 
 
Addendum #1 
SWOG / SWOG 
 
 
Addendum #2 
Addendum #3 
NCTN GROUP STUDY CHAMPIONS 
 
Addendum #4 
SWOG: David Page, MD  
 
Addendum #5 
ALLIANCE: Josephine Feliciano, MD  
 
 
NRG: Jarushka Naidoo, MB, BCH  
 
 
 
Agents 
NSC# 
Supply 
Infliximab 
728729 
Commercial 
Intravenous 
immunoglobulin (IVIG) 
621996 
Commercial 
Study Exempt from IND Requirements 
 


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Table of Contents 
Schema ...................................................................................................................... 7 
1. Introduction ........................................................................................................ 8 
1.1 Background ............................................................................................... 8 
2. Objectives ......................................................................................................... 18 
2.1 Primary Objective .................................................................................... 18 
2.2 Secondary Objectives .............................................................................. 18 
2.3 Exploratory Objectives ............................................................................ 18 
3. Selection of Patients ......................................................................................... 19 
3.1 Eligibility Criteria ..................................................................................... 19 
4. Registration and Randomization Procedures ................................................... 22 
4.1 Patient Registration ................................................................................ 26 
4.2 Eligibility Verification .............................................................................. 26 
4.3 Stratification Factors ............................................................................... 26 
4.4 Additional Requirements ........................................................................ 26 
4.5 Instructions for Patients Who Do Not Start Assigned Protocol Treatment29 
5. Treatment Plan ................................................................................................. 30 
5.1 Administration Schedule ......................................................................... 30 
5.2 Adverse Event Reporting Requirements ................................................. 33 
5.3 Dose Modifications ................................................................................. 37 
5.4 Supportive Care ....................................................................................... 37 
5.5 Duration of Therapy ................................................................................ 37 
5.6 Duration of Follow-up ............................................................................. 38 
6. Measurement of Effect ..................................................................................... 39 
6.1 Methods for Evaluation .......................................................................... 39 
6.2 Patient Reported Outcome Measurement ............................................. 40 
7. Study Parameters .............................................................................................. 42 
7.1 Therapeutic Parameters.......................................................................... 42 
7.2 Biological Sample Submissions ............................................................... 45 
8. Drug Formulation and Procurement ................................................................. 46 
8.1 Infliximab ................................................................................................. 46 
8.2 Intravenous Immunoglobulin (IVIG)........................................................ 50 
8.3 Prednisone .............................................................................................. 56 
8.4 Methylprednisolone ................................................................................ 57 
9. Statistical Considerations .................................................................................. 60 
9.1 Study Design ............................................................................................ 60 
9.2 Accrual Goal and Rate ............................................................................. 60 
9.3 Analysis Plan ............................................................................................ 60 
9.4 Monitoring Plan ...................................................................................... 63 
9.5 Gender and Ethnicity .............................................................................. 63 


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10. Specimen Submissions ...................................................................................... 64 
10.1 Tissue Submissions to the ECOG-ACRIN Central Biopathology and 
Pathology Facility .................................................................................... 64 
10.2 Submissions to the D’Alessio Laboratory ................................................ 65 
10.3 ECOG-ACRIN Sample Tracking System .................................................... 67 
10.4 Use of Specimens in Research ................................................................ 68 
10.5 Sample Inventory Submission Guidelines ............................................... 68 
11. Specimen Analyses: Diagnostic Review and Research Studies ......................... 69 
11.1 Blood: MANAFEST and AUTOFEST .......................................................... 69 
11.2 Blood: Autoantibody Analyses (MANDATORY) ....................................... 70 
11.3 Blood: Cytokine Analyses (MANDATORY) ............................................... 70 
11.4 Sample Inventory Submission Guidelines ............................................... 71 
11.5 Lab Data Transfer Guidelines .................................................................. 71 
12. Electronic Data Capture .................................................................................... 72 
13. Patient Consent and Peer Judgment ................................................................ 72 
14. References ........................................................................................................ 72 
Appendix I  Pathology Submission Guidelines ........................................................ 76 
Appendix II  Patient Thank You Letter ..................................................................... 80 
Appendix III  ECOG Performance Status .................................................................. 81 
Appendix IV   Calculation of PaO2/FiO2 Ratio ......................................................... 82 
Appendix V  PaO2/FiO2 Recording Form ................................................................ 85 
Appendix VI   Guidelines for Infliximab Administration .......................................... 86 
Appendix VII  Instructions for IVIG Administration ................................................. 87 
Appendix VIII  Patient Pill Calendar ......................................................................... 89 
Appendix IX  Patient Clinical Trial Wallet Card ........................................................ 92 
Appendix X  EAQ172 Collection and Shipping Kit Order Instructions ..................... 93 
 


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STUDY CHAIR 
Jarushka Naidoo, MB BCH MHS 
Beaumont Hospital Dublin 
Royal College of Surgeons Ireland 
Beaumont Rd 
Dublin 9 
Republic of Ireland 
Tel: +353877769288 
Fax: +35318092038 
Email: jnaidoo1@jhmi.edu 
 
STUDY CO-CHAIR 
Sheetal Kircher, MD 
Northwestern University  
Feinberg School of Medicine 
676 North Saint Clair Street 
Feinberg School of Medicine Suite 850 
Chicago, IL 60611 
Tel: 312-695-6180 
Email: sheetal.kircher@nm.org 
 
STUDY CHAIR LIASON 
Keith Egan 
Programme Manager 
Cancer Clinical Trials & Research Unit, Beaumont 
Hospital 
Tel: (+353) 18092010 
Fax: (+353) 18092038 
Email: keithegan2@beaumont.ie 
 
 
Rev. Add2 


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EAQ172 Co-Investigators 
Pulmonary Co-Investigators 
Erik Folch, M.D. 
(Massachusetts General Hospital) 
 
Colleen Keyes, M.D. 
(Massachusetts General Hospital) 
 
Lonny Yarmus, DO 
(Johns Hopkins Hospital) 
 
Karthik Suresh, M.D. 
(Johns Hopkins Hospital) 
 
David Feller-Kopman, M.D. 
(Johns Hopkins Hospital) 
 
M. Patricia Rivera, M.D. 
(UNC Chapel Hill) 
 
Chris Manley, M.D. 
(Fox Chase Cancer Center) 
 
Angela Argento, M.D. 
(Northwestern) 
 
Jennifer Possick, M.D. 
(Yale Cancer Center) 
 
Jason Beattie, M.D. 
(Memorial Sloan Kettering Cancer Center) 
 
Medical Oncology Co-Investigators 
Meghan Mooradian, M.D. 
(Massachusetts General Hospital) 
 
Hossein Borghaei, DO 
(Fox Chase Cancer Center) 
 
Barbara Burtness, M.D. 
(Yale Cancer Center) 
 
Jared Weiss, M.D. 
(UNC Chapel Hill) 
 
Sheetal Kircher, M.D. 
(Northwestern University) 
 
Allison Betof Warner, M.D. 
(Memorial Sloan Kettering Cancer Center) 
 
Oncology Pharmacy Co-Investigator 
Bryna Ewachiw, Pharm.D., BCOP 
(Johns Hopkins Bayview Medical Center 
The Sidney Kimmel Comprehensive Cancer 
Center) 
 
 
Rev. Add2 


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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data 
submission: 
Regulatory documentation 
must be submitted to the 
CTSU via the Regulatory 
Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, and 
select the Regulatory 
Submission sub-tab under the 
Regulatory tab.) 
Institutions with patients 
waiting that are unable to use 
the Portal should alert the 
CTSU Regulatory Office 
immediately at 1-866-651-
2878 to receive further 
instruction and support. 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 
for regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave.  Please 
see the data submission 
section of the protocol for 
further instructions. 
 
Do not submit study data or 
forms to CTSU Data 
Operations. Do not copy 
the CTSU on data 
submissions. 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org.  
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. 
Permission to view and download this protocol and its supporting documents is restricted and is based 
on person and site roster assignment housed in the CTSU Regulatory Support System (RSS). 
For clinical questions (i.e., patient eligibility or treatment-related) Contact the Study PI of the 
Coordinating Group. 
For non-clinical questions (i.e., unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Web site is located at   https://www.ctsu.org 
 


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Schema 
R
A
N
D
O
M
I
Z
A
T
I
O
N
1. A second dose of infliximab may be delivered 14-days after the first dose as per the treating investigator. If a second dose of infliximab is given, a prednisone taper will be 
restarted at Day 14.
2. IVIG may be delivered as either Privigen, Gammagard or Gamunex-C as per site standard of care.
3. Either as an inpatient or outpatient.
4. All patients will be followed up on both Days 42 and 56.
5. Required sample submission of 7 green top heparin tubes at Days 1, 14, and 28. Please see Section 7.2 for details.
Arm A1
Infliximab 5mg/kg IV on day 13,5 
followed by a 4-6 week 
corticosteroid taper, starting 
from a dose of prednisone 1-
2mg/kg (or methylprednisolone 
at a dose equivalent to 1-2mg/
kg of prednisone)
Grade 2+ Steroid 
Refactory
PD -1/PD -L1
Pneumonitis
Arm B2
IVIG 2g/kg divided as per 
institutional guidelines as an IV 
infusion,3,5 followed by a 4-6 
week corticosteroid taper from 
starting from a dose of 
prednisone 1-2mg/kg (or 
methylprednisolone at a dose 
equivalent to 1-2mg/kg of 
prednisone)
Pneumonitis 
Assessment 
Day 145
Pneumonitis 
Assessment 
Day 285
 F4
O
L
L
O
W
-
U
P
Accrual Goal = 36
Statification Factor
Severity of pneumonitis:
(Grade 4 vs. Grade 2-3)
 
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1. 
Introduction 
1.1 
Background 
1.1.1 
Immune-related Adverse Events 
Immune checkpoint inhibitor (ICI) therapy against programmed cell 
death1 (PD-1) and its ligand PD-L1 can lead to immune related 
adverse effects (irAEs).1 These toxicities have autoimmune etiology 
and require careful monitoring and specific management strategies. 
These include immune-related toxicities affecting nearly every organ 
system in the body, including dermatologic (rash and pruritus), 
gastrointestinal (diarrhea and colitis, hepatitis), endocrinopathies 
(hypophysitis and hypothyroidism) and pulmonary (pneumonitis) 
irAEs. Data regarding the incidence of irAEs comes mainly from large 
published clinical trials.2-8 The most common irAE associated with ICIs 
includes skin rash and/or pruritus. The latter has been reported in 
40% of patients treated with nivolumab or pembrolizumab. PD-1 
inhibitors have a lower incidence of irAEs compared with other ICIs 
that block other checkpoint molecules such as cytotoxic T-
lymphocyte-4 (CTLA-4), including such as ipilimumab or 
tremelimumab. Immune-related toxicities from anti-PD-1/PD-L1 ICIs 
are predominantly grade 1 or 2 in severity, with the incidence of grade 
3+ toxicity of < 20% across tumor types.1 Knowledge of the timing of 
onset of a suspected irAE may be helpful. For example, 
dermatological irAEs usually develop during the first few weeks on 
treatment, whereas diarrhea and colitis tend to occur between weeks 
5 and 10, liver toxicity from week 7 to 14, hypophysitis after the 6th 
week while pneumonitis may occur at anytime during the course of 
therapy.9 
Immune-related toxicities improve or resolve if treated promptly and 
appropriately with immunomodulatory medication. However, high-
grade irAEs can result in patient death (occurring in < 2% of cases) if 
unrecognized, or not appropriately managed. Specific management 
algorithms have been developed to guide the treatment of irAEs.1 
Treatment consists of immunosuppression, utilizing systemic 
corticosteroids in most cases. In patients who require a prolonged 
course of corticosteroids (20mg of prednisone or equivalent daily for 
more than 4 weeks), appropriate antimicrobial prophylaxis should be 
considered as per published irAE guidelines.1,10,11 A multi-disciplinary 
approach may be important to clarify the diagnosis and determine 
appropriate management. Other immunomodulatory medications used 
in specific irAEs include TNF-inhibition with Infliximab (CTLA-4 colitis), 
mycophenolate mofetil (MMF, hepatitis), intravenous Immunoglobulin 
(IVIG) or plasmapheresis (neurologic irAEs).1 
1.1.2 
Anti-PD/-PD-L1 Pneumonitis 
Pneumonitis is a potentially fatal irAE resulting from therapy with anti-
PD-1/PD-L1 affecting the lungs.1 It occurs in 2-5% of patients treated 
with PD-1/PD-L1 monotherapy, and up to 10% of patients who receive 
combinations such as PD-1/CTLA-4. Current recommendations for 


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the management of anti-PD-1/PD-L1 pneumonitis are based on 
clinical trial experience, published guidelines and algorithms. 
Based on National Cancer Institute (NCI) Common Toxicity Criteria for 
Adverse Events (CTCAE) grading of pneumonitis, anti PD-1/ PDL-1 
therapy should be withheld (grade 1) and corticosteroids administered 
(grade 2+).1-3 In grade 2+ cases, oral steroid treatment includes 
prednisone 1 to 2-mg/kg daily or methylprednisolone 0.5-10mg/kg 
daily. Corticosteroid taper should be initiated when the adverse 
reaction improves to ≤ Grade 1 and should be conducted over 4-6 
weeks. For pneumonitis that completely resolves or is grade 2 or less 
at diagnosis, treatment can be restarted when pneumonitis returns to 
≤ Grade 1 and the corticosteroid dose has been reduced to < 10 mg 
prednisone or equivalent per day. In moderate to severe (grade 2-3+) 
cases, a routine infectious evaluation is recommended to exclude 
infectious etiologies before starting immunosuppression. In severe 
cases (grade 3+), patients should be hospitalized and treatment 
should consist of high-doses of corticosteroids (i.e. 
methylprednisolone 1-4mg/kg/day).1-3 
Patients often improve with corticosteroids, however a significant 
group (~20%) become steroid-refractory.1 In published guidelines anti-
PD-1/PD-L1, steroid-refractory pneumonitis would have been defined 
as patients who do not sustain a clinical or functional improvement in 
pneumonitis, or worsening hypoxemia and clinical or radiographic 
appearances within 48-72 hours of high-dose corticosteroids.1-3 
Patients with steroid-refractory pneumonitis almost universally die 
from pneumonitis.1 Published guidelines suggest that patients with 
steroid-refractory pneumonitis should be treated with either infliximab, 
MMF, IVIG or cyclophosphamide after failure of corticosteroids.2,3 
However, there are no published data that demonstrate a benefit in 
pneumonitis with these agents. Likewise, there are no published data 
which may establish which agent may lead to the greatest benefit in 
pneumonitis. 
1.1.3 
Infliximab or Intravenous Immunoglobulin for Pneumonitis 
Infliximab is 
currently 
recommended 
based on its’ 
use in CTLA-
4-mediated 
colitis.1 
However, 3/5 
patients with 
infliximab-
treated 
pneumonitis died from infections related to prolonged 
immunosuppression, and another from pneumonitis itself, in a 
published series.12,13 Intravenous immunoglobulin (IVIG) has 
benefitted some patients with steroid refractory pneumonitis.14 In 
addition, it is a successful treatment for conditions similar to 
pneumonitis, such as paraneoplastic immune conditions,15 idiopathic 
     Mild (<25%)        Moderate (25-50%)      Severe (>50%)  
Figure 1: Radiographic Severity of PD-1/PD-L1 
Pneumonitis: % lung parenchymal involvement describes 
radiographic pneumonitis severity. Mild= 25% parenchyma 
involved, Moderate= 25-50%, Severe= >50% involvement. 


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pulmonary fibrosis,16 and autoantibody mediated conditions such as 
idiopathic thrombocytopenia purpura (ITP).17 Furthermore, IVIG has 
been used to successfully to treat PD-1induced neurologic irAEs,18,19 
and has minimal infection risk.  
When treating pneumonitis, quantitative measures that will help to 
objectively track clinical responses to immunosuppression are 
needed. Patient lung function testing may be such a measure, but has 
not been assessed in previous studies. Radiographically, the 
appearances of pneumonitis stratifies into 5 subtypes (e.g. 
cryptogenic-organizing pneumonia-like, ground glass opacities, 
hypersensitivity type, interstitial type and pneumonitis not otherwise 
specified).12,20 The percentage of lung parenchyma involved with 
pneumonitis at the time of the diagnosis has also been found to be 
associated with pneumonitis outcomes.12 In patients with other 
interstitial lung diseases that are similar to pneumonitis, high 
attenuation areas on chest CT scans (HAA:-600 - 250HU) are 
radiographic markers of lung function and inflammation.21 These 
quantitative imaging features may correlate with clinical response to 
immunosuppression in pneumonitis.  
The populations of immune cells present in core lung biopsies, 
obtained from 2 patients with PD-1 pneumonitis demonstrated 
lymphocytic and macrophage infiltrates, respectively (Fig. 2). 
Additionally, Johns Hopkins investigators identified that an elevated 
Th17/T-reg ratio in bronchoalveolar lavage fluid (BAL), is associated 
with early acute respiratory 
distress syndrome (ARDS), 
a similar process to PD-
1/PD-L1 pneumonitis.4 
The mechanisms that 
underlie the development 
of PD-1/PD-L1 pneumonitis 
are unknown. While 
autoantibody responses in 
irAEs have not yet been 
specifically linked to tumor immunity, autoantibody formation has been 
identified as a mechanism implicated in CTLA4-mediated 
hypophysitis23 and PD-1- thyroiditis.24 We now have newer tools that 
allow us to link autoantibody to T-cell responses, through detection of 
antigen specific T-cell clones by TCR sequencing, in both peripheral 
blood and tissue.25,26,27 In support of an autoantibody-mediated 
mechanism, cytokines (IL-17, IFN-γ, IL-4) are known to support 
humoral responses via Fc region switching and increased 
immunoglobulin production,28,29 and baseline IL17 levels were 
elevated in melanoma patients who developed CTLA4-colitis, in a 
neoadjuvant trial.30 
1.1.4 
Preliminary Data and Previous Experience 
Thirty-six NSCLC patients at Johns Hopkins University (JHU) 
developed PD-1/PD-L1 pneumonitis from 2013-2017, 6 of whom were 
steroid-refractory. Of these patients, we observed two with 
Figure 2: Pathologic Features of 
Pneumonitis: (A) Lymphocytic infiltrate (B) 
Macrophages, in pneumonitis lung tissue 
A 
B 
 


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radiographic improvement after infliximab, and one with improved 
oxygenation after IVIG.5 We evaluated BAL in 5 pneumonitis patients 
(Fig 3) and baseline sera in 3 pneumonitis patients (Table 1). In BAL, 
we identified lymphocyte, macrophage, and neutrophil populations 
(unpublished), and elevations in IL-17, IFN-γ and VEG-F in patient 
sera vs. non-irAE controls. 
 
 
 
 
 
 
 
 
 
 
 
Change in cytokine 
(pg/L) 
Pneumonitis 
(n=3) 
Control  
(n=6) 
VEG-F 
45.5 (3.4, 55.9) 
3.1 (-23.3, 10.3) 
IL-6 
-0.1 (-0.9, 12.0) 
0.7 (0.1, 2.4) 
IL-17A 
1.2 (0.8, 9.8) 
0.8 (0.0, 2.9) 
IFN-ɣ 
43.7 (7.5, 126.4) 
1.7 (-0.6, 3.2) 
Table 1: Cytokine profiles in sera from patients with 
pneumonitis, and controls: Baseline multi-parameter 
cytokine profiles in 3 pneumonitis patients and 6 control 
samples of NSCLC patients who did not develop irAEs 
Autoantibody discovery platforms have been previously utilized at 
JHU to describe an autoantibody-mediated link to the development of 
scleroderma in patients with POL3RA mutant cancers.6 In these 
cases, antibodies were identified using a novel immunoprecipitation 
(IP) assay followed by mass spectroscopy (MS) sequencing, using 
patient sera pre/post event (present post, absent pre),7 based on 
molecular weights in the initial IP step and rigorous candidate 
autoantigen validation.7-12 The linkage between antibody and T-cell 
responses, can then be evaluated through the novel sensitive and 
specific Functional Expansion of Specific T-cells (FEST) assays, 
developed at JHU. These assays experimentally and bioinformatically 
evaluate clonal expansion via next generation T cell receptor (TCR) 
sequencing of T cells, cultured with peptides representing candidate 
antigens. This approach has been used in NSCLC patients with 
acquired resistance to anti-PD-1, to detect peripheral T cell reactivity 
to mutation-associated neoantigens (MANAs) in resistant tumors, 
compared to pre-treatment specimens (MANAFEST).13 MANAFEST 
 
 
Figure 3: BAL obtained from patients 
with suspected PD-1 pneumonitis were 
centrifuged, cytospum and stained for 
cell differentials (n=5) 


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has also been used to detect and monitor antigen-specific immune 
responses. In patients with colon cancer who responded to 
pembrolizumab.14 MANAFEST can be adapted to evaluate CD4+ 
reactivity to autoantigens (AUTOFEST), together with MANAFEST 
evaluated CD-8 responses mutant peptides from patients’ tumors, 
identified through genomic sequencing of genes encoding identified 
autoantigens from tumor DNA. 
1.1.5 
Pneumonitis from Other Anti-Cancer Agents 
Pneumonitis is a rare but potentially lethal complication that may 
occur as a result of treatment with a number of chemotherapeutic 
agents.40 Patients who develop drug induced pneumonitis (or drug-
induced interstitial lung disease (DILD)) present clinically with acute or 
sub-acute breathlessness that is usually accompanied by new 
pulmonary infiltrates on chest imaging. DILD should be considered in 
all patients treated with a new anti-cancer therapy who present with 
acute or sub-acute dyspnea, dry cough, or fever. The diagnosis of 
DILD depends on a temporal association between the causative agent 
and the development of respiratory symptoms and signs. Bleomycin,41 
methotrexate,42 cyclophosphamide,43 mTOR inhibitors such as 
everolimus,44 as well as epidermal growth factor receptor tyrosine 
kinase inhibitors afatinib,15 gefitinib16 and erlotinib17 are the agents 
most frequently associated with pneumonitis, with an incidence of 1-
10%. Management of DILD in these cases involves withholding of the 
offending agent, and investigations to exclude competing differential 
diagnoses, including progressive malignancy in the lung, lung 
infection or pulmonary embolism. Treatment involves use of high-dose 
steroids (prednisone 60–100 mg/day) given promptly.45 
Bleomycin is the drug most commonly studied as a cause of DILD.41 
Larger studies have reported rates of 8-10%. Symptoms may develop 
earlier than 4 weeks and later than 10 weeks following chemotherapy. 
Potential risk factors for bleomycin pneumonitis include: age, 
underlying lung disease, smoking history, cumulative bleomycin dose, 
renal insufficiency, and prior radiation exposure. Typical radiologic 
changes include bibasilar infiltrates on chest radiographs and diffuse 
interstitial and ground glass opacities (GGO) HRCT. Bleomycin 
induced pneumonitis is thought to be related to the absence of the 
bleomycin-inactivating enzyme (bleomycin hydrolase) in the lung 
parenchyma or an excess of free oxygen radicals.41,46 
Other agents known to cause DILD include: cyclophosphamide, which 
causes early-onset interstitial lung disease with a low incidence of 
<1%,47 and everolimus-induced pneumonitis, which like PD-1/PD-L1 
pneumonitis has variable radiographic appearances, but has an 
incidence of up to 10%.  
1.1.6 
Clinical Assessment of Pneumonitis 
DILD may occur as an adverse event of chemotherapy, targeted 
therapy, as well as stem cell transplantation.15,16 The clinical 
presentation and evaluation of these pneumonitides has provided a 
framework from which we may begin to approach the characterization 
of pneumonitis associated with anti–PD-1/PD-L117 therapy. A 


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comprehensive patient history is crucial to establish symptom onset 
and associated manifestations, which will help to exclude alternative 
diagnoses such as tumor progression, infection or pulmonary 
embolism. Symptoms of pneumonitis include non-productive cough, 
dyspnea, and a low-grade fever. Additionally, patients with PD-1/PD-
L1 pneumonitis as with other agents, may be asymptomatic.1 Usually 
symptoms may become more pronounced as the pneumonitis 
worsens, and patients may develop tachypnea, dyspnea at rest, and 
hypoxia. Physical examination often reveals fine respiratory crackles, 
rhonchi and/or pleural rubs. Based on data from DILD and interstitial 
lung disease (ILD), the degree of dyspnea has been linked to disease 
severity and prognosis.15 
1.1.7 
Radiographic Assessment of Pneumonitis 
Radiographic assessment of pneumonitis is essential to diagnose and 
track the progress of PD-1/ PDL-1-associated pneumonitis during 
management. Chest imaging characterizes the appearance or pattern 
of pneumonitis, the severity of pneumonitis (percentage of lung 
parenchyma involved), the distribution of pneumonitis, and any other 
associated features.1 It is also useful to rule out competing diagnosis 
including progression of cancer, lung infection, pleural effusion or 
pulmonary embolism. In patients with known ILD and other interstitial 
lung processes these patients are evaluated radiologically with high 
resolution non contrast CT (HRCT) imaging of the chest.18 While 
chest radiographs may be easier to obtain, these tests may miss 
interstitial lung processes in a subset of cases. Radiologic features of 
PD-1/PD-L1 pneumonitis can be classiﬁed into ﬁve subtypes: (i) 
consolidative opacities predominantly in a peripheral distribution 
resembling cryptogenic organizing pneumonia (COP-like) (ii) ground 
glass opacities (GGO), (iii) interstitial infiltrates; (iv) hypersensitivity 
pneumonitis, and (v) ground glass opacities with interlobular septal 
thickening in basilar and peripheral distribution, mimicking nonspecific 
interstitial pneumonia (NSIP).1,19 Overall, the most common 
radiographic changes are GGOs and focal consolidation, 
predominantly in the lower lobes. Interestingly, HRCT findings have 
been suggested to reflect histological patterns of pneumonitis, thus 
predicting the prognosis and determining the most appropriate 
intervention.19 
1.1.8 
Functional Assessment of Pneumonitis 
Assessment of lung function with pulmonary function tests (PFTs) 
demonstrate a restrictive ventilatory deficit and impaired gas 
exchange in patients with known DILD or other forms of ILD.20 In 
patients who develop chemotherapy-induced pneumonitis (e.g. 
bleomycin) or those with ILD, diagnostic guidelines recommend PFT 
to assess respiratory limitations, severity of pneumonitis and monitor 
disease progression.20,21 PFTs provide objective, quantitative 
functional assessments of lung volume, spirometry (e.g., FVC and 
FEV1), and gas transfer at the alveolar level (DLCO). Specifically, 
FVC is a widely used measure of disease severity and a common 
endpoint in clinical trials in patients with idiopathic pulmonary fibrosis 
(IPF).22 Longitudinal change in serial FVCs is accepted as a reﬂection 


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of disease progression in patients with IPF.23 Several studies have 
also identiﬁed change in percent-predicted FVC as an independent 
predictor of mortality in patients with IPF. For example, Du Bois et all 
studied the reliability and validity of FVC in 1,156 randomized patients 
in two clinical trials of IFN-G1b, and found that FVC was a robust 
measure of clinical status in patients with IPF and the change in 
percent- predicted FVC was found to be highly predictive of 
mortality.24 Speciﬁcally, a decline in percent-predicted FVC >10% at 
24 weeks was associated with a nearly ﬁvefold increase in the risk of 
mortality. FVC has also been validated by its relationship to other key 
measures of disease severity including: disease extent on imaging, 
DLCO, 6MWT, oxygen saturation, symptoms and measures of quality 
of life (QOL). Both absolute reduction of 10% and relative reduction 
from 70% to 67% have been shown to confer a worse prognosis.55 
DLCO has also been used a prognostic parameter in patients with 
chemotherapy-induced pneumonitis, and strong correlated with 
changes in FVC.26 
PFTs are completed as a standard assessment for patients with 
suspected bleomycin induced pneumonitis. Zhao et al suggested that 
PFTs were a more sensitive measurement that could be used to 
diagnose bleomycin-induced pneumonitis, compared with respiratory 
symptoms or chest radiographs. Similarly, a 5-year cohort study of 
bleomycin-induced pneumonitis was performed in patients with 
testicular cancer, where PFTs were obtained in 565 patients before 
and after treatment with bleomycin. A significant proportion of patients 
discontinued therapy based on bleomycin induced pneumonitis (10%). 
The DLCO threshold used to determine discontinuation of treatment, 
was a 25% reduction in DLCO compared with pretreatment values. 
Even though PFTs can provide useful clinical and prognostic 
information, the feasibility to perform these studies is challenging in 
critically ill patients who have limited respiratory effort due to sedation, 
mechanical ventilation or prolonged critical care stay.36 Other 
limitations of using FVC include: 1) difficulty handling missing data 
since a proportion of patients will not be able to perform serial FVC 
measurements because of cough, worsening respiratory failure or 
inter-current infection. 2), a proportion of patients can have stable 
FVC prior to death and 3) measurement variation can be as much as 
5-9% between readings. 
1.1.9 
Functional Assessment of Pneumonitis: PaO2/FiO2 Ratio on Arterial 
Blood Gas Assessment 
The ratio of the partial pressure of arterial oxygen to the fraction of 
inspired oxygen (PaO2/FiO2 ratio) is a measure that represents 
patient oxygenation. This ratio is calculated from an arterial blood gas 
assessment obtained either from an arterial puncture or an arterial 
catheter to obtain a PaO2 result, and by the fraction of inspired 
oxygen (FIO2) the patient is receiving. For example, the FiO2 is 0.21 
if a patient is breathing room air, where the oxygen concentration is 
21%. The PaO2/FiO2 ratio is calculated by dividing the PaO2 by the 
FiO2. This is a practical, bedside test that can represent a patient’s 
arterial oxygenation.27,28 Higher ratios (from high PaO2 or lower FiO2) 


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represent easier oxygenation, whereas lower ratios represent difficulty 
in achieving arterial oxygenation. This measure has been widely used 
to monitor and predict mortality in patients with acute respiratory 
distress syndrome (ARDS), a clinical condition characterized by acute 
pulmonary inflammation that may be caused by a wide variety of 
clinical conditions, and is similar in clinical and radiologic appearance 
to PD-1/PD-L1 pneumonitis. The Berlin Definition for ARDS was a 
consensus definition developed in 2012 that focused on the feasibility, 
validity, reliability and reproducibility of defining and monitoring ARDS, 
and also represented the mortality risk from ARDS29. 
The initial draft definition proposed 3 mutually exclusive categories of 
ARDS based on the degree of patient hypoxemia: mild (PaO2/FIO2= 
201-300 mm Hg), moderate (PaO2/FIO2= 101-200 mm Hg), and 
severe (PaO2/FIO2 ≤ 100 mm Hg).29 The Berlin Definition was 
empirically evaluated using patient-level meta-analysis of 4188 
patients with ARDS from 4 multicenter clinical datasets, as well as 
269 patients with ARDS from 3 single-center datasets. Using this 
definition, the stages of mild, moderate, and severe ARDS were 
associated with increased mortality (27%; 95% CI, 24%-30%; 32%; 
95% CI, 29%-34%; and 45%; 95% CI, 42%-48%, respectively; 
p=0.001). 
Other potential measures of patient oxygenation have been proposed 
in ARDS and related literature. The measure of PaO2/FiO2 has been 
found to correlate with simple ambulatory oxygen saturation values 
(pulse oximetry) in studies with patients who have idiopathic 
pulmonary fibrosis (IPF).30 However, pulse oximetry values may not 
accurately measure patient oxygenation, as patient and procedural 
factors such as positioning, recent exertion, cold extremities, skin 
pigmentation, and receipt of vasopressor medications may alter this 
measurement.31 Similarly, the ratio of pulse oximetry to FiO2 
(SpO2/FiO2) has been explored as a measure of patient oxygenation. 
However, the relationship between SpO2 and PaO2 has been found 
to be non-linear, therefore this may not represent an accurate 
measure of patient oxygenation.31 
The PaO2/FiO2 measure has also been used as a primary outcome 
variable to assess benefit in acute lung injury in patients who require 
mechanical ventilation.32 To maximize reproducibility and 
interpretation of PaO2/FiO2 ratio in clinical trials, methods of oxygen 
delivery be standardized to minimize room air contamination (or 
entrainment) of oxygen. In addition, in patients who are being treated 
with mechanical ventilation, it is recommended to use standardized 
ventilator settings and a pulse oximetry goal of 90%.33 
1.1.10 
Laboratory Tests as an Assessment of Pneumonitis 
Although there are no specific laboratory tests that are 
pathognomonic for the diagnosis of pneumonitis, patients being 
assessed for pneumonitis according to standard algorithms,34 undergo 
routine complete blood cell count with differential, platelet count, 
erythrocyte sedimentation rate (ESR); and determination of serum 
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electrolyte levels, including calcium, serum urea nitrogen, and 
creatinine, liver function tests. 
1.1.11 
Patient-Reported Outcome Assessment of Pneumonitis 
The utility of health-related quality of life (HRQOL) assessments has 
been studied in patients with ILD such as IPF.50.51 This is of 
importance since a patient’s functional status and life expectancy is 
affected by interstitial processes such as pneumonitis. Several 
prospective clinical trials in the field of IPF have thus incorporated HR-
QOL measures as secondary endpoints in these studies. Several 
instruments have been designed to capture the effect of dyspnea on 
patients with lung disease. Among patients with ILD, HRQOL 
measures capture patient-reported dyspnea on physical inactivity, de-
conditioning, loss of independence, impaired emotional well-being and 
overall QOL. Questionnaires that assess dyspnea have not previously 
been used in clinical practice or as a research endpoint in studies for 
drug-induced pneumonitis.49,52,53 
A systemic review examining measures of breathlessness in patients 
with lung cancer, included 31 studies and examined 18 outcome 
measures.54 FACT-L was the most commonly used assessment.55 
This consists of a 36 item, self-assessment tool, developed to 
measure a lung cancer patient’s QOL over the last 7-day period, using 
a 0 to 4 Likert scale. The four sub-sections assess: emotional, 
functional, physical, and social /family well-being. The fifth sub scale 
queries the patient’s additional concerns. 
Measuring dyspnea intensity associated provides insights into 
dyspnea-limited exercise capacity, and it’s a fundamental tool used to 
evaluate treatment outcomes for various pulmonary conditions in 
several clinical trials. The most widely used instrument to measure 
perceived exertion or exercise intensity is the Borg scale which was 
initially described in 1982.56 Since then, several modifications have 
been made. The American Thoracic Society (ATS)/American College 
of Chest Physicians (ACCP)57 recommends the use of modified Borg 
Scale (MBS) for quantifying dyspnea in several pulmonary conditions 
including ILD, COPD and asthma. Research on this scale has focused 
on how it relates to a variety of physiological measures (e.g. heart 
rate, ventilatory drive, blood lactate concentration, creatine) and 
psychologic perception of wellbeing.57 This is 0 to 10 rated scale 
which has been used in several clinical trials. Moreover, the MBS has 
been shown to be feasible, reliable and valid in patients with dyspnea. 
1.1.12 
Rationale for the Proposed Study 
Immune checkpoint blockade is now standard therapy for patients 
with multiple malignancies However, in 5% of patients treated with 
anti-PD-1/PD-L1 monotherapy, and up to 10% with anti-PD-1/PD-L1-
based combinations, pneumonitis will occur.1-3 In 20% of these cases, 
pneumonitis that develops is refractory to corticosteroids, and can 
result in death from pneumonitis itself, or infections in the context of 
prolonged/profound immunosuppression.2,4 While the incidence may 
seem low, the absolute numbers of patients with solid tumors treated 
with anti-PD-1/PD-L1 alone or in combination, either as standard-of-


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care or on clinical trials, is high. There is thus an unmet clinical need 
to identify efficacious immunosuppression for these patients, and 
improve our understanding of the underlying mechanisms of this 
toxicity. So far, no standard immunosuppressive agent beyond 
steroids has proved efficacious for anti-PD-1/PD-L1 pneumonitis, and 
biospecimens from these patients are not routinely obtained. We aim 
to identify an efficacious immunosuppressive agent for steroid-
refractory anti-PD-1/PD-L1 pneumonitis, by completing a randomized 
study of infliximab vs. IVIG, two promising therapies for this 
phenomenon. We will collect pre and post-immunosuppression 
clinical, radiologic, functional parameters and biospecimens with the 
goal of characterizing the mechanisms of this phenomenon.  
 


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2. 
Objectives 
2.1 
Primary Objective 
2.1.1 
To assess pneumonitis response to additional immunosuppression 
(infliximab or IVIG) in patients with steroid-refractory pneumonitis at 
28-days.  
2.2 
Secondary Objectives 
2.2.1 
To assess functional parameters of steroid-refractory pneumonitis on 
Days 1, 14, and 28 of receipt of additional immunosuppression 
(infliximab or IVIG). 
2.2.2 
To assess radiologic parameters of steroid-refractory pneumonitis on 
Days 1, 14, and 28 of receipt of additional immunosuppression 
(infliximab or IVIG). 
2.2.3 
To assess patient-reported outcomes of steroid-refractory 
pneumonitis on Days 1, 14, and 28 of receipt of additional 
immunosuppression (infliximab or IVIG). 
2.2.4 
To assess death in the 28-day period after additional 
immunosuppression. 
2.2.5 
To assess the rate of infections after additional immunosuppression. 
2.3 
Exploratory Objectives 
2.3.1 
To examine serial blood samples in patients who develop steroid-
refractory pneumonitis. 
2.3.2 
To evaluate associations between pneumonitis and autoantibodies, T-
cell expansion, and baseline cytokines in the blood. 
 
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3. 
Selection of Patients 
Each of the criteria in the checklist that follows must be met in order for a patient to be 
considered eligible for this study. Use the checklist to confirm a patient’s eligibility. For 
each patient, this checklist must be photocopied, completed and maintained in the 
patient’s chart.  
In calculating days of tests and measurements, the day a test or measurement is 
done is considered Day 0. Therefore, if a test is done on a Monday, the Monday 
four weeks later would be considered Day 28.  
ECOG-ACRIN Patient No. ____________________________ 
Patient’s Initials (L, F, M) _______________________ 
Physician Signature and Date ___________________ 
NOTE: 
CTEP Policy does not allow for the issuance of waivers to any protocol 
specified criteria 
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
Therefore, all eligibility criteria listed in Section 3 must be met, without 
exception. The randomization of individuals who do not meet all criteria listed 
in Section 3 can result in the participant being censored from the analysis of 
the study, and the citation of a major protocol violation during an audit. All 
questions regarding clarification of eligibility criteria must be directed to the 
Group's Executive Officer (EA.ExecOfficer@jimmy.harvard.edu) or the 
Group's Regulatory Officer (EA.RegOfficer@jimmy.harvard.edu). 
NOTE: 
Institutions may use the eligibility checklist as source documentation if it has 
been reviewed, signed, and dated prior to randomization by the treating 
physician. 
3.1 
Eligibility Criteria 
3.1.1 
Patient must be ≥ 18 years of age. 
3.1.2 
Patient must be English-speaking and have the ability to understand 
and the willingness to sign a written informed consent document. 
Patients with impaired decision-making capacity (IDMC) who have a 
legally authorized representative (LAR) or caregiver and/or family 
member available will also be considered eligible. 
English Speaking? ______ (Yes or No)  
Date of Written Informed Consent: _______ 
3.1.3 
Patient must be willing and able to undergo arterial blood gas 
assessment as per the treating investigator. Patient must not have 
contraindication for arterial blood gas assessment. 
3.1.4 
Women must not be pregnant or breast-feeding due to the potential 
risk to the fetus with infliximab or IVIG. 
All females of childbearing potential must have a blood test or urine 
test within 14 days prior to randomization to rule out pregnancy. 
A female of childbearing potential is defined as any woman, 
regardless of sexual orientation or whether they have undergone tubal 
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ligation, who meets the following criteria: 1) has achieved menarche 
at some point, 2) has not undergone a hysterectomy or bilateral 
oophorectomy; or 3) has not been naturally postmenopausal for at 
least 24 consecutive months (i.e., has had menses at any time in the 
preceding 24 consecutive months). 
Female of child bearing potential? ______ (Yes or No) 
Date of blood test or urine study: ___________ 
3.1.5 
Women of childbearing potential and sexually active males must not 
conceive or father children by using accepted and effective method(s) 
of contraception or to abstain from sexual intercourse for a minimum 
of 56 days (the duration of their participation in the study). 
3.1.6 
Patient must have an ECOG Performance Status of 0-3. Please see 
Appendix III. 
PS: ______ (0, 1, 2, or 3) 
3.1.7 
Patient with any solid tumor or hematologic malignancy is eligible. 
NOTE: 
Patient may have received any number of lines of prior 
systemic therapy. 
3.1.8 
Patient must have received treatment with an anti-PD-1/PD-L1 agent 
either alone or in combination with another anti-cancer agent, as their 
most recent therapy prior to development of pneumonitis. 
NOTE: 
Patient may have received anti-PD-1/PD-L1 therapy as 
standard-of-care or part of a clinical trial. 
Prior Anti-PD-1 or PD-L1: _______ (Yes or No)  
If yes, list agent and date of last dose: ___________________ 
3.1.9 
Patient must not be receiving anti-PD-1/PD-L1 agent in combination 
with any of the following anti-cancer agents: docetaxel, 
cyclophosphamide, gefitinib, erlotinib, osimertinib, crizotinib, 
bleomycin, afatinib. 
3.1.10 
Patient must have steroid-refractory pneumonitis defined as:  
• 
Grade 2 pneumonitis that has not improved by a CTCAE grade in 
greater than 72 hours or maximum of 21 days or 
• 
Grade 3 or higher pneumonitis that has not clinically improved by 
a CTCAE grade in greater than 48 hours or maximum of 21 days 
with high dose corticosteroids (methylprednisolone or prednisone 
1-4mg/kg/equivalent) as their most recent treatment for 
pneumonitis, as determined by the treating investigator. 
3.1.11 
Patient must have had pathogen-negative infectious diagnostic 
evaluation within 21 days prior to randomization, and at a minimum 
these should include: blood culture, urine culture, sputum culture, and 
viral panel: rapid flu and RSV (respiratory syncytial virus). Empiric 
antibiotics for culture negative infections are not an exclusion for study 
entry. 
Date of pathogen-negative infectious diagnostic evaluation: ________ 
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3.1.12 
Patient must not have clinical evidence of cardiac dysfunction (as 
determined by the treating investigator) as an alternative diagnosis to 
steroid-refractory pneumonitis. 
3.1.13 
Patient must not be receiving concurrent radiation therapy to the 
chest. 
Concurrent radiation therapy: __________ (Yes or No) 
If yes, provide site(s): _____________________ 
3.1.14 
Patient must not be deemed to have radiation pneumonitis. Patients 
with a history of stable radiation pneumonitis not requiring 
corticosteroid therapy within the last 3 months prior to randomization 
will be allowed on study. 
Date of last corticosteroid therapy: _________ 
3.1.15 
Patient must not have pre-existing interstitial lung disease or 
pneumonitis requiring corticosteroid therapy from any other cause, as 
determined by the treating investigator. 
3.1.16 
Patient must not have an absolute contraindication to IVIG or 
infliximab, including: clinical history of severe hypersensitivity reaction, 
selective IgA deficiency, active hepatitis B, active tuberculosis, active 
human immunodeficiency virus/acquired immunodeficiency syndrome 
(HIV/AIDS) where a study subject has a CD4 count of ≤ 200 at 
screening, or drug interaction as detailed in Section 8.1.8 and 8.2.9. 
3.1.17 
Patient must have a negative tuberculosis assessment (TB spot test, 
quantiferon gold or tuberculin skin test) within 21days prior to 
randomization and either negative or low clinical suspicion. 
Date of negative TB test: ___________ 
3.1.18 
Patient must have chest CT scan with or without contrast performed 
≤14 days before randomization. Patient must not have a 
contraindication for CT. 
Date of CT chest: ___________ 
 
 
 
 
Physician Signature 
 
Date 
OPTIONAL: 
This signature line is provided for use by institutions wishing to 
use the eligibility checklist as source documentation. 
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4. 
Registration and Randomization Procedures 
Cancer Therapy Evaluation Program Investigator Registration Procedures 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) 
policy require all individuals contributing to NCI-sponsored trials to register and to renew 
their registration annually. To register, all individuals must obtain a Cancer Therapy 
Evaluation Program (CTEP) Identity and Access Management (IAM) account at 
https://ctepcore.nci.nih.gov/iam. In addition, persons with a registration type of 
Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) at (https://ctepcore.nci.nih.gov/rcr).  
RCR utilizes five person registration types. 
• 
IVR — MD, DO, or international equivalent; 
• 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level 
researchers (e.g., PhD); 
• 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU 
applications such as the Roster Update Management System (RUMS), OPEN, Rave, 
acting as site primary contact, or with consenting privileges; 
• 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored 
trials; and 
• 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
 
 
 
 
 
Financial Disclosure Form 
 
 
 
 
 
NCI Biosketch (education, 
training, employment, license, 
and certification) 
 
 
 
 
 
GCP training 
 
 
 
 
 
Agent Shipment Form (if 
applicable) 
 
 
 
 
 
CV (optional) 
 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to 
access all CTEP and Cancer Trials Support Unit (CTSU) websites and applications. In 
addition, IVRs and NPIVRs must list all clinical practice sites and IRBs covering their 
practice sites on the FDA Form 1572 in RCR to allow the following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
In addition, all investigators act as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the 
DTL must be rostered at the enrolling site with a participating organization. Additional 
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information can be found on the CTEP website at 
<https://ctep.cancer.gov/investigatorResources/default.htm>. For questions, please 
contact the RCR Help Desk by email at <RCRHelpDesk@nih.gov>. 
CTSU Registration Procedures 
Permission to view and download this protocol and its supporting documents is restricted 
and is based on person and site roster assignment housed in the CTSU Regulatory 
Support System (RSS). 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
IRB Approval 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National Clinical 
Trials Network (NCTN) and NCI Community Oncology Research Program (NCORP) 
Research Bases after March 1, 2019, all U.S.-based sites must be members of the NCI 
Central Institutional Review Board (NCI CIRB). In addition, U.S.-based sites must accept 
the NCI CIRB review to activate new studies at the site after March 1, 2019. Local IRB 
review will continue to be accepted for studies that are not reviewed by the CIRB, or if 
the study was previously open at the site under the local IRB. International sites should 
continue to submit Research Ethics Board (REB) approval to the CTSU Regulatory 
Office following country-specific regulations.  
Sites participating with the NCI CIRB must submit the Study Specific Worksheet for 
Local Context (SSW) to the CIRB using IRBManager to indicate their intent to open the 
study locally. The NCI CIRB’s approval of the SSW is automatically communicated to the 
CTSU Regulatory Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI CIRB 
approvals across their Signatory Network. Site preferences can be set at the network or 
protocol level. Questions about establishing site preferences can be addressed to the 
CTSU Regulatory Office by email or calling 1-888-651-CTSU (2878). 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of the 
IRB/REB approval record to be completed: 
• 
Holds an active CTEP status; 
• 
Rostered at the site on the IRB/REB approval (applies to US and Canadian sites 
only) and on at least one participating roster; 
• 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
• 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 in the 
RCR profile; and 
• 
Holds the appropriate CTEP registration type for the protocol. 
Additional Requirements 
Additional requirements to obtain an approved site registration status include: 
• 
An active Federal Wide Assurance (FWA) number; 
• 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
• 
Compliance with all protocol-specific requirements (PSRs). 


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Downloading Site Registration Documents 
• 
Download the site registration forms from the protocol-specific page located on the 
CTSU members’ website. Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. To 
participate, the institution and its associated investigators and staff must be 
associated with the LPO or a Protocol Organization (PO) on the protocol. One way to 
search for a protocol is listed below. Log in to https://www.ctsu.org and log in to the 
members’ area using your CTEP-IAM username and password. 
• 
Click on the Protocols tab in the upper left of your screen. 
• 
Enter the protocol # in the search field at the top of the protocol tree, or 
• 
Click on the By Lead Organization folder to expand then select ECOG-ACRIN 
and protocol number EAQ172. 
• 
Click on Documents, select Site Registration, and download and complete the 
forms provided. (Note: For sites under the CIRB, IRB data will load automatically 
to the CTSU.) 
Protocol Specific Requirements for EAQ172 Site Registration 
• 
Site-designated personnel must attest to the below requirements by signing the Site 
Registration Attestation Form submitted via the CTSU Regulatory Submission Portal. 
• 
Sites must be able to comply with the below requirements as part of the patient’s 
standard of care: 
• 
Have a medical oncology co-PI at each site to provide oversight of study 
procedures. 
• 
IVIG must be available in the treating institution. 
Submitting Regulatory Documents 
Submit required forms and documents to the CTSU Regulatory Office via the Regulatory 
Submission Portal on the CTSU website. 
To access the Regulatory Submission Portal log in to the CTSU members’ website, go to 
the Regulatory section and select Regulatory Submission. 
Institutions with patients waiting that are unable to use the Regulatory Submission Portal 
should alert the CTSU Regulatory Office immediately at 1-866-651-2878 in order to 
receive further instruction and support. 
Required Protocol Specific Regulatory Documents 
1. Copy of IRB Informed Consent Document. 
NOTE:  
Any deletion or substantive modification of information concerning risks or 
alternative procedures contained in the sample informed consent 
document must be justified in writing by the investigator and approved by 
the IRB. 
2. A.  CTSU IRB Certification Form. 
 
Or 
B.  Signed HHS OMB No. 0990-0263 (replaces Form 310). 
 
Or 
 
C.  IRB Approval Letter 
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NOTE:  
The above submissions must include the following details: 
• 
Indicate all sites approved for the protocol under an assurance 
number. 
• 
OHRP assurance number of reviewing IRB 
• 
Full protocol title and number 
• 
Version Date 
• 
Type of review (full board vs. expedited) 
• 
Date of review. 
• 
Signature of IRB official 
3. Site Certification Form (See Section 
) 
Checking Your Site’s Registration Status: 
Site’s registration status may be verified on the CTSU members’ website. 
• 
Click on Regulatory at the top of your screen; 
• 
Click on Site Registration; and  
• 
Enter the site’s 5-character CTEP Institution Code and click on Go 
• 
Additional filters are available to sort by Protocol, Registration Status, Protocol 
Status, and/or IRB Type. 
NOTE: 
The status shown only reflects institutional compliance with site registration 
requirements as outlined above. It does not reflect compliance with protocol 
requirements for individuals participating on the protocol or the enrolling 
investigator’s status with the NCI or their affiliated networks. 
Patient Enrollment 
Patients must not start protocol treatment prior to randomization. 
Treatment must start within seven days after randomization.  
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the Lead Protocol Organization (LPOs) registration/randomization systems or 
Theradex Interactive Web Response System (IWRS) for retrieval of patient 
registration/randomization assignment. OPEN will populate the patient enrollment data in 
NCI’s clinical data management system, Medidata Rave. 
Requirements for OPEN access: 
• 
A valid CTEP-IAM account; 
• 
To perform enrollments or request slot reservations: Be on a LPO roster, ETCTN 
Corresponding roster, or PO roster with the role of Registrar. Registrars must hold a 
minimum of an AP registration type; 
• 
Have an approved site registration for a protocol prior to patient enrollment. 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. 
Prior to accessing OPEN, site staff should verify the following: 
• 
Patient has met all eligibility criteria within the protocol stated timeframes; and 


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• 
All patients have signed an appropriate consent form and HIPAA authorization form 
(if applicable). 
NOTE: 
The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. You may print this confirmation for 
your records.  
Access OPEN at https://open.ctsu.org or from the OPEN link on the CTSU members’ 
website. Further instructional information is provided on the OPEN tab of the CTSU 
website at https://www.ctsu.org or at https://open.ctsu.org. For any additional questions 
contact the CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
4.1 
Patient Registration 
The following information is to be provided at time of registration. 
4.1.1 
Protocol Number  
4.1.2 
Site/Investigator Identification 
• 
Institution CTEP ID 
• 
Treating Investigator 
• 
Consenting Person 
• 
Site Registrar 
• 
Network Group Credit 
• 
Credit Investigator 
4.1.3 
Patient Identification  
• 
Patient’s initials (first and last) 
• 
Patient’s Hospital ID and/or Social Security number 
• 
Sex 
• 
Birth date (mm/dd/yyyy) 
• 
Race 
• 
Ethnicity 
• 
Nine-digit ZIP code 
• 
Method of payment 
• 
Country of residence 
4.2 
Eligibility Verification 
Patients must meet all of the eligibility requirements listed in Section 3.1. 
4.3 
Stratification Factors 
Severity of pneumonitis: (Grade 4 vs. Grade 2-3) 
4.4 
Additional Requirements  
4.4.1 
Patients must provide a signed and dated, written informed consent 
form. 
NOTE: 
Copies of the consent are not collected by the ECOG-
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4.4.2 
Biospecimens are to be submitted as indicated in Section 7.2 and 
Section 10 
4.4.3 
Site Requirements 
• 
Site-designated personnel must attest to the below requirements 
by signing the Site Registration Attestation Form submitted via the 
CTSU Regulatory Submission Portal. 
• 
Sites must be able to comply with the below requirements as part 
of the patient’s standard of care: 
• 
Have a medical oncology co-PI at each site to provide 
oversight of study procedures. 
• 
IVIG must be available in the treating institution. 
4.4.4 
Medidata Rave is a clinical data management system being used for 
data collection for this trial/study. Access to the trial in Rave is 
controlled through the CTEP-IAM system and role assignments. 
Requirements to access Rave via iMedidata: 
• 
A valid CTEP-IAM account; and 
• 
Assigned a Rave role on the relevant LPO or PO roster at the 
enrolling site of: Rave CRA, Rave Read Only, Rave CRA 
(LabAdmin), Rave SLA, or Rave Investigator. Rave CRA or Rave 
CRA (Lab Admin) role must have a minimum of an Associate Plus 
(AP) registration type; 
• 
Rave Investigator role must be registered as a Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
• 
Rave Read Only role must have at a minimum an Associates 
(A) registration type.  
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for 
registration types and documentation required. 
Upon initial site registration approval for the study in Regulatory 
Support System (RSS), all persons with Rave roles assigned on the 
appropriate roster will be sent a study invitation e-mail from iMedidata. 
To accept the invitation, site users must log into the Select Login 
(https://login.imedidata.com/selectlogin) using their CTEP-IAM 
username and password, and click on the “accept” link in the upper 
right-corner of the iMedidata page. Site staff will not be able to access 
the study in Rave until all required Medidata and study specific 
trainings are completed. Trainings will be in the form of electronic 
learnings (eLearnings) and can be accessed by clicking on the link in 
the upper right pane of the iMedidata screen. If an eLearning is 
required and has not yet been taken, the link to the eLearning will 
appear under the study name in iMedidata instead of the Rave EDC 
link; once the successful completion of the eLearning has been 
recorded, access to the study in Rave will be granted, and a Rave 
EDC link will display under the study name. 
Site staff that have not previously activated their iMedidata/Rave 
account at the time of initial site registration approval for the study in 
RSS will receive a separate invitation from iMedidata to activate their 
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account. Account activation instructions are located on the CTSU 
website in the Data Management section under the Rave resource 
materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on 
the CTSU members’ website in the Data Management > Rave section 
at www.ctsu.org/RAVE/ or by contacting the CTSU Help Desk at 1-
888-823-5923 or by e-mail at ctsucontact@westat.com. 
4.4.5 
Data Quality Portal 
The Data Quality Portal (DQP) provides a central location for site staff 
to manage unanswered queries and form delinquencies, monitor data 
quality and timeliness, generate reports, and review metrics.  
The DQP is located on the CTSU members’ website under Data 
Management. The Rave Home section displays a table providing 
summary counts of Total Delinquencies and Total Queries. DQP 
Queries, DQP Delinquent Forms and the DQP Reports modules are 
available to access details and reports of unanswered queries, 
delinquent forms, and timeliness reports. Review the DQP modules 
on a regular basis to manage specified queries and delinquent forms. 
The DQP is accessible by site staff that are rostered to a site and 
have access to the CTSU website. Staff that have Rave study access 
can access the Rave study data using a direct link on the DQP. 
To learn more about DQP use and access, click on the Help icon 
displayed on the Rave Home, DQP Queries, and DQP Delinquent 
Forms modules. 
NOTE: 
Some Rave protocols may not have delinquent form details 
or reports specified on the DQP. A protocol must have the 
Calendar functionality implemented in Rave by the Lead 
Protocol Organization (LPO) for delinquent form details 
and reports to be available on the DQP. Site staff should 
contact the LPO Data Manager for their protocol regarding 
questions about Rave Calendaring functionality. 
4.4.6 
Digital Radiation Therapy (RT) Data Submission Using Transfer of 
Radiation Images and Data (TRIAD) 
Transfer of Images and Data (TRIAD) is the American College of 
Radiology’s (ACR) image exchange application. TRIAD provides sites 
participating in clinical trials a secure method to transmit images. 
TRIAD anonymizes and validates the images as they are transferred. 
TRIAD Access Requirements: 
• 
A valid CTEP-IAM account. 
• 
Registration and Credential Repository (RCR) registration type of: 
Associate (A), Associate Plus (AP), Non-Physician Investigator 
(NPIVR), or Investigator (IVR). Refer to CTEP Registration 
Procedures section for instructions on how to request a CTEP-
IAM account and complete registration in RCR. 
• 
TRIAD Site User role on an NCTN or ETCTN roster.  


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• 
All individuals on the Imaging and Radiation Oncology Core 
provider roster have access to TRIAD and may submit images for 
credentialing purposes, or for enrollments to which the provider is 
linked in OPEN. 
TRIAD Installations: 
To submit images, the individual holding the TRIAD Site User role will 
need to install the TRIAD application on their workstation. TRIAD 
installation documentation is available at 
https://triadinstall.acr.org/triadclient/. 
This process can be done in parallel to obtaining your CTEP-IAM 
account and RCR registration. 
For questions, contact TRIAD Technical Support staff via email at 
TRIAD-Support@acr.org or 1-703-390-9858. 
4.5 
Instructions for Patients Who Do Not Start Assigned Protocol Treatment  
If a patient does not receive any assigned protocol treatment, baseline and 
follow-up data will still be collected and must be submitted through Medidata 
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5. 
Treatment Plan 
5.1 
Administration Schedule 
Patients will be randomized to one of two possible immunosuppressive 
treatments as per the study schema. These will include: 
5.1.1 
Arm A Treatment 
Infliximab 5mg/kg IV on day 1 followed by a 4-6 week corticosteroid 
taper, starting from a dose of prednisone 1-2mg/kg (or 
methylprednisolone at a dose equivalent to 1-2mg/kg of prednisone) 
either orally or intravenously in divided doses, and determined by the 
treating investigator. The date of commencement of the corticosteroid 
taper will be from Day 1 of the first infliximab dose. A second dose of 
infliximab may be delivered 14-days after the first dose as per the 
treating investigator. If a second infliximab dose is administered, 
corticosteroid taper will be restarted from a dose of prednisone 1-
2mg/kg either orally or intravenously in divided doses at Day 14, at 
the discretion of the treating investigator. Dosing will be based on 
actual patient body weight. Treatment may be delivered either as an 
outpatient or an inpatient at the discretion of the treating investigator. 
Patient may receive infliximab as per locally obtainable formulation. 
Patient should be under assessment for latent or active tuberculosis 
as per local institutional guidelines. (Appendix VI) 
5.1.2 
Arm B Treatment 
IVIG 2g/kg divided as per institutional guidelines as an IV infusion, 
followed by a 4-6 week corticosteroid taper, starting from a dose of 
prednisone 1-2mg/kg (or methylprednisolone at a dose equivalent to 
1-2mg/kg of prednisone) either orally or intravenously in divided 
doses, determined by the treating investigator. The date of 
commencement of the corticosteroid taper will be from Day 1 of the 
first IVIG dose. Dosing will be based on actual patient body weight. 
Treatment may be delivered either as an outpatient or an inpatient at 
the discretion of the treating investigator. (Appendix VII) 
5.1.3 
Corticosteroids and Pill Calendar 
Patients will keep a pill calendar as per Appendix VIII to record 
administration of corticosteroids after receipt of study therapy, if given 
orally. Corticosteroids will be tapered over a 4-6 week period as 
deemed appropriate by the treating investigator. Administration of 
corticosteroids will be confirmed at days 14 and 28 visits as per the 
study calendar in Section 7. Patients in both Arm A and Arm B will 
need this pill calendar. 
5.1.4 
Recommendations for chest CT58-60 
All patients will undergo a chest CT during study screening, and days 
1, 14 and 28. 
5.1.4.1 
Chest CT Techniques 
• 
Diagnostic chest CT taken in a spine position at end-
inspiration (as routinely done for clinical chest CT). 


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• 
Contiguous axial slices with slice thickness of 3 mm or 
less 
• 
Reconstructed with 1) lung algorithm and 2) 
mediastinum/soft tissue algorithm 
• 
IV contrast is not necessary to diagnose pneumonitis, 
but OK to be present if clinically indicated. 
• 
Use the same techniques on the serial scans in the 
same patient as much as possible. 
5.1.4.2 
Assessment of Pneumonitis on CT 
• 
Assessment is done primarily using the contiguous 
axial images reconstructed with lung algorithm 
displayed on a lung window setting. 
• 
Other image series (soft tissue reconstructions, 
coronal/sagittal images if available) can be reviewed if 
necessary to differentiate pneumonitis and other 
findings. 
5.1.4.3 
Assessment of Chest CT scan at each timepoint (study 
screening, days 1, 14, and 28 of study therapy 
administration) 
• 
Assessment is done primarily using the contiguous 
axial images reconstructed with lung algorithm 
displayed on a lung window setting. 
• 
Other image series (soft tissue reconstructions, 
coronal/sagittal images if available) can be reviewed if 
necessary to differentiate pneumonitis and other 
findings. 
Abnormal pulmonary as consistent with the published 
Fleischner criteria outlined in Johkoh et al, Radiology 2021 
and Chest 2021.  Abnormal findings indicative pneumonitis 
are evaluated for: 
1) Extent in upper, middle and lower lungs using a 6-point 
scale; 
1a) Upper lung: 0: none, 1: 1-5%, 2: 6-25%, 3: 26-
50%, 4: 51%-75%, 5: 76-100% 
1b) Middle lung: 0: none, 1: 1-5%, 2: 6-25%, 3: 26-
50%, 4: 51%-75%, 5: 76-100% 
1c) Lower lung: 0: none, 1: 1-5%, 2: 6-25%, 3: 26-
50%, 4: 51%-75%, 5: 76-100% 
NOTE: 
Visually evaluate the extent of pneumonitis 
involvement in upper, middle, and lower 
lungs. “Upper” is from the apices to the level 
of carina, “middle” is from the level of carina 
to the level of inferior pulmonary veins (at 
the junction with atrium), and “lower” is 
below the level of inferior pulmonary veins. 
Assess both lungs together, on contiguous 
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axial slices. For example, there is diffuse 
GGO all over in all or most slices in the 
upper lung, that is 5 (76-100%) for the 
upper lung. Note this is a qualitative score 
based on visual assessments, and no 
quantification image processing necessary. 
2) Distributions in terms of (pick one each for 2a and 2b; 
based on the predominant distribution of the 
abnormalities of pneumonitis): 
2a) peripheral, diffuse, central, mixed* 
2b) upper, lower, diffuse, multifocal, focal 
* Two or more of the other three patterns co-exist 
without definite predominance 
3) Lobar involvement (involved/not involved): 
• 
Right upper lobe (RUL) 
• 
Right middle lobe (RML) 
• 
Right lower lobe (RLL) 
• 
Left upper lobe (LUL) 
• 
Lingula 
• 
Left lower lobe (LLL) 
4) Specific CT findings (present/absent): 
• 
Traction bronchiectasis 
• 
Consolidation 
• 
Reticular opacities 
• 
Ground glass opacities (GGOs) 
• 
Centrilobular nodularity 
• 
Honeycombing 
NOTE:  
Fleischner Society: glossary of terms for 
thoracic imaging. Radiology. 2008 
Mar;246(3):697-722. 
5) Lung volumes (qualitative assessment by visual 
evaluation, in references to what is expected in normal 
cases, paying attention to the entire lung volume and 
expansions, as well as the presence of traction 
bronchiectasis) 
1: Definitely decreased, 
2: Probably decreased, 
3: Within expected normal range, 
4: Probably increased, 
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5.1.4.4 
Chest CT scans at days 14 and 28 are additionally 
assessed for the following in comparison with the prior 
scans*: 
1) Overall findings of pneumonitis: 
1: Definitely decreased, 
2: Probably decreased, 
3: No significant change, 
4: Probably increased, 
5: Definitely increased 
2) Lung volumes (qualitative assessment by visual 
evaluation) 
1: Definitely decreased, 
2: Probably decreased, 
3: No significant change, 
4: Probably increased, 
5: Definitely increased 
* Day 14 scan compared with day 1 scan 
* Day 28 scan compared with pre-therapy/baseline scan 
and with 14-day scan (two assessments) 
5.1.4.5 
Data Collection 
CT scans are to be submitted. Please refer to Section 
4.4.5 for digital RT data submission using TRIAD. 
5.2 
Adverse Event Reporting Requirements 
All toxicity grades described throughout this protocol and all reportable 
adverse events will be graded using the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 5.0. 
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 website (http://ctep.cancer.gov). 
5.2.1 
Purpose 
Adverse event (AE) data collection and reporting, which are a 
required part of every clinical trial, are done so investigators and 
regulatory agencies can detect and analyze adverse events and risk 
situations to ensure the safety of the patients enrolled, as well as 
those who will enroll in future studies using similar agents. 
5.2.2 
Routine Reporting of Adverse Events (Medidata Rave) 
Adverse events are reported in a routine manner at scheduled times 
during a trial using the Medidata Rave clinical data management 
system. Please refer to Section 4 of the protocol for more information 
on how to access the Medidata Rave system and the EAQ172 forms 


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packet for instructions on where, when and what adverse events are 
to be reported routinely on this protocol. 
5.2.3 
Expedited Reporting of Adverse Events (CTEP-AERS) 
In addition to routine reporting, certain adverse events must be also 
reported in an expedited manner for timelier monitoring of patient 
safety and care. The remainder of this section provides information 
and instructions regarding expedited adverse event reporting. 
5.2.4 
Terminology 
• 
Adverse Event (AE): Any untoward medical occurrence 
associated with the use of an agent in humans, whether or not 
considered agent related. Therefore, an AE can be ANY 
unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered 
related to the medicinal product. 
• 
Attribution: An assessment of the relationship between the 
adverse event and the protocol treatment (Arm A or Arm B), using 
the following categories. 
ATTRIBUTION 
DESCRIPTION 
Unrelated 
The AE is clearly NOT related to treatment 
administered in Arm A or B. 
Unlikely 
The AE is doubtfully related to treatment 
administered in Arm A or B. 
Possible 
The AE may be related to treatment 
administered in Arm A or B. 
Probable 
The AE is likely related to treatment 
administered in Arm A or B. 
Definite 
The AE is clearly related to treatment 
administered in Arm A or B. 
• 
CTCAE: The NCI Common Terminology Criteria for Adverse 
Events provides a descriptive terminology that is to be utilized for 
AE reporting. A grade (severity) is provided for each AE term.  
• 
Expectedness: Expected events are those that have been 
previously identified as resulting from administration of the agent. 
An adverse event is considered unexpected, for expedited 
reporting purposes, when either the type of event or the severity of 
the event is NOT listed in the protocol or drug package insert. 
• 
Life Threatening Adverse Event: Any AE that places the patient 
at immediate risk of death from the AE as it occurred. 
5.2.5 
Expedited Adverse Event Reporting Procedure 
Adverse events requiring expedited adverse event reporting will use 
CTEP’s Adverse Event Reporting System (CTEP-AERS). CTEP’s 
guidelines for CTEP-AERS can be found at http://ctep.cancer.gov. 
A CTEP-AERS report must be submitted electronically via the CTEP-
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that ECOG-ACRIN and all appropriate regulatory agencies will be 
notified of the event in an expeditious manner. 
In the rare event when Internet connectivity is disrupted a 24-hour 
notification is to be made by telephone to  
• 
the AE Team at ECOG-ACRIN (857-504-2900) 
• 
the FDA (1-800-FDA-1088) 
An electronic CTEP-AERS report MUST be submitted immediately 
upon re-establishment of internet connection. 
Supporting and follow up data: Any supporting or follow up 
documentation must be uploaded to the Supplemental Data Folder in 
Medidata Rave within 48-72 hours. In addition, supporting or follow up 
documentation must be faxed to the FDA (800-332-0178) in the same 
timeframe.  
CTEP Technical Help Desk: For any technical questions or system 
problems regarding the use of the CTEP-AERS application, please 
contact the NCI Technical Help Desk at ncictephelp@ctep.nci.nih.gov 
or by phone at 1-888-283-7457. 
Many factors determine the requirements for expedited reporting of 
adverse events on each individual protocol. The instructions and 
tables in the following sections have been customized for protocol 
EAQ172 and outline the specific expedited adverse event reporting 
requirements for study EAQ172. 


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5.2.6 
Steps to determine if an event is to be reported in an expedited 
manner 
 
Identify the type and grade of the event 
using the CTCAE. 
Determine if the event is related to the 
protocol treatment (attribution). 
With this information, review the chart in 
Section 5.2.7 to determine if event 
requires expedited reporting. 
Refer to footnote b in 
Section 5.2.7 to determine 
if the event meets the 
protocol specific reporting 
requirements for this 
study. If so, report the 
event in CTEP-AERS. 
Is the event 
reportable? 
No 
Yes 
Report the event in CTEP-AERS. 
Determine the expectedness of the 
event. An unexpected event is defined as 
one where the type of severity of the 
event is not listed in the investigator’s 
brochure, package insert or protocol for 
the agents being used on this study. 


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5.2.7 
Expedited Reporting Requirements on protocol EAQ172 
Commercial Agents: Infliximab and Intravenous Immunoglobulin 
(IVIG)  
Expedited reporting requirements for adverse events experienced by patients on protocol EAQ172 
Attribution 
Grade 4 
Grade 5a 
ECOG-ACRIN and 
Protocol-Specific 
Requirements 
Unexpected 
Expected 
Unexpected 
Expected 
See footnote  
(b) for special 
requirements. 
Unrelated or Unlikely 
 
 
7 calendar 
days 
7 calendar 
days 
Possible,  
Probable,  
Definite 
7 calendar 
days 
 
7 calendar 
days 
7 calendar 
days 
7 Calendar Days: Indicates a full CTEP-AERS report is to be submitted within 7 calendar days of learning of the 
event. 
a 
A death occurring while on study or within 30 days of the last dose of treatment requires both routine and 
expedited reporting, regardless of causality. Attribution to treatment or other cause must be provided. 
NOTE:  A death due to progressive disease should be reported as a Grade 5 “Disease progression” 
under the System Organ Class (SOC) “General disorder and administration site conditions”. 
Evidence that the death was a manifestation of underlying disease (e.g. radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 
NOTE: Any death that occurs > 30 days after the last dose of treatment on this study and is attributed 
possibly, probably, or definitely to the treatment on this study must be reported within 7 
calendar days of learning of the event. 
b 
Protocol-specific expedited reporting requirements: The adverse events listed below also require expedited 
reporting for this trial: 
Serious Events: Any event following treatment that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported in CTEP-AERS within 7 calendar 
days of learning of the event. For instructions on how to specifically report these events in 
CTEP-AERS, please contact the AEMD Help Desk at aemd@tech-res.com or 301-897-
7497. This will need to be discussed on a case-by-case basis. 
5.2.8 
Other recipients of adverse event reports and supplemental data. 
Adverse events determined to be reportable via CTEP-AERS must 
also be reported by the institution, according to the local policy and 
procedures, to the Institutional Review Board responsible for oversight 
of the patient. 
5.3 
Dose Modifications  
There are no dose modifications of study agents in this study. If a dose of study 
medication is missed at the time of administration specified in Section 5.1 and/or 
Appendices VI-VII, this will be recorded and considered missed. Study treatment 
will not be made up at a later date. 
5.4 
Supportive Care  
All supportive measures consistent with optimal patient care will be given 
throughout the study. 
5.5 
Duration of Therapy  
Patients will receive protocol therapy unless: 
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• 
Extraordinary Medical Circumstances: If at any time the constraints of this 
protocol are detrimental to the patient's health, protocol treatment should be 
discontinued. In this event submit forms according to the instructions in the 
EAQ172 Forms Completion Guidelines, accessible under the Case Report 
Forms tab of the EAQ172 page on the CTSU website. 
• 
Patient withdraws consent. 
• 
Patient experiences unacceptable toxicity deemed related to or possibly-
related to study therapy. 
• 
Patient develops progressive cancer during the study time period and this is 
deemed to be of greater clinical significance than pneumonitis and requiring 
cancer therapy. (Patient will be replaced with a new one in this case). 
• 
Patient develops worsening pneumonitis, defined as worsening pneumonitis 
symptoms despite protocol-directed therapy, or an escalation in the level of 
clinical care for pneumonitis, as deemed by the treating investigator. 
• 
Non-protocol therapies are administered. 
5.6 
Duration of Follow-up  
For this protocol, all patients, including those who discontinue protocol therapy 
early, will be followed until day 28 for pneumonitis response, and up to day 56 for 
other assessments (refer to table in Section 7.1). 
 


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6. 
Measurement of Effect 
For the purposes of this study, patients will be re-evaluated for response to protocol-
directed therapy at Days 14 and 28, compared with an assessment at Day 1 of study 
therapy administration. 
Evaluation of response in patients with pneumonitis will be assessed by PaO2/FiO2 ratio 
at Days 1, 14 and 28 of the study period. For the purposes of evaluating the primary 
objective of the study, pneumonitis response will be defined as an improvement of ≥20% 
in PaO2/FiO2 ratio, at Day 28 compared with Day 1. 
6.1 
Methods for Evaluation  
All measurements should be taken and recorded using mmHg for PaO2 on an 
arterial blood gas assessment as in Section 6.1.1. FiO2 will be calculated based 
on patient inspired oxygen as per Section 6.1.2. 
• 
All Day 1 evaluations should be performed as closely as possible to the 
administration of study therapy (+/-5 days of commencement of study therapy 
as per Study Calendar).  
• 
All Day 14 evaluations will be done on day 14 (+/-5 days) after the day of 
administration of study therapy.  
• 
All Day 28 evaluations will be done on day 28 (+/-5 days) after the day of 
administration of study therapy.  
To the extent that is possible, the same method of assessment, same machine 
and the same technique should be used to evaluate each patient at each 
timepoint. 
6.1.1 
PaO2 calculation 
An arterial blood gas assessment will be performed as outlined in 
Appendix IV. 
6.1.2 
FiO2 calculation 
FiO2 will be calculated as per the fraction of inspired oxygen the 
patient is receiving, to maintain their pulse oximetry reading at 92-
94%. This will be calculated based on if a patient is receiving oxygen 
either by: 1. room air, 2. supplemental oxygen delivery (facemask or 
mouthpiece with nose clip, only), 3. non-invasive ventilation, or 4. 
invasive ventilation. Patients who are receiving supplemental oxygen 
by nasal cannula or who cannot maintain oxygen saturations (SpO2) 
of 92-94% on room air for 20 minutes, will be switched to receiving 
oxygen delivered either by facemask or mouthpiece/nose clip for 20-
30 minutes, to ensure accuracy of the FiO2 measurement, as defined 
in Appendix IV. 
Examples: 
1. Room air: 21% oxygen on room air: FiO2= 0.21 
2. High-flow humidified oxygen by facemask (e.g. 60% oxygen 
delivered to maintain SpO2 of 92-94%): FiO2= 0.60 
3. 100% Oxygen delivered by mouthpiece with one-way valve and 
nose clip (100% oxygen delivered to maintain SpO2 of 92-94%): 
FiO2=1.0 


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4. Oxygen delivery by non-invasive ventilation (e.g. 60% oxygen 
delivered to maintain SpO2 of 92-94%): FiO2= 0.6 
5. Oxygen by mechanical ventilation (e.g. 80% oxygen delivered to 
maintain SpO2 of 92-94%): FiO2= 0.80 
The fraction of inspired oxygen (FiO2) will be recorded by a member 
of the study team as outlined in Appendix V. The oxygen saturation 
will also be recorded at the time the supplemental oxygen liter volume 
is recorded. 
6.1.3 
Measurement of Infection 
The proportion of patients who develop a confirmed bacterial, viral or 
fungal infection after immunosuppression, using standard infective 
evaluation as per the treating investigator. 
6.2 
Patient Reported Outcome Measurement 
6.2.1 
Quality of Life Instruments to be Administered 
Improvement in pneumonitis symptoms will be assessed using the 
FACT-L scale and the Borg Dyspnea Score. 
6.2.2 
Quality of Life Assessment Schedule 
Patients will be assessed according to the following schedule: 
1) Day 1 (up to 5 days before Day 1 or on Day 1, as per study 
calendar) 
2) Day 14 (+/- 5 days, as per study calendar) 
3) Day 28 (+/- 5 days as per study calendar) 
These patient-reported outcome assessment time points correspond 
to standard clinic office visits of routine care to minimize participant 
burden. 
PRO 
Baseline (up to 5 days 
before Day 1 or on Day 1) 
Day 14 (+/- 
5 days) 
Day 28 (+/- 
5 days) 
FACT-L 
Questionnaire 
X 
X 
X 
Borg Dyspnea 
Score 
X 
X 
X 
6.2.3 
Quality of Life Administration Instructions 
6.2.3.1 
The questionnaires must be administered at the time 
points listed above. The patient should be instructed to 
respond to the questionnaires in terms of their experience 
during the timeframe specified on each questionnaire.  
6.2.3.2 
The baseline questionnaire (up to 5 days before Day 1 or 
on Day 1) must be completed prior to administration of 
study treatment. 
6.2.3.3 
The patient should be asked to read the instructions at the 
beginning of each questionnaire and complete all the 
items.  
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6.2.3.4 
The questionnaires must be reviewed by the protocol 
nurse or research coordinator as soon as the patient 
completes them to ensure all items were marked 
appropriately. If more than one answer was marked, the 
patient should be asked to choose the answer which best 
reflects how they are feeling. If a question was not 
answered, the patient should be asked if they would like to 
answer it. The patient should always have the option to 
refuse. If the patient refuses, it should be indicated on the 
questionnaire that they declined to answer the item. 
6.2.3.5 
If the patient cannot complete a questionnaire, or if the 
patient refuses to complete the questionnaire, the reason 
should be noted according to the instructions in the 
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7. 
Study Parameters 
7.1 
Therapeutic Parameters  
1. Pre-treatment Standard of Care CT scans must be done ≤14 days before randomization 
2. Pre-study CBC (with differential and platelet count) should be done ≤ 14 days before randomization 
3. All required pre-study chemistries should be done ≤ 14 days before randomization 
Study Calendar 
Trial Period 
Study Screening 
(Prior to Randomization)10 
Treatment Phase 
Follow-Up 
Treatment Day 
≤21 days before randomization 
Day 110 
Day 14 
Day 28 
Days 42 and 
56 
Scheduling Window (days) 
 
+/-5 
+/-5 
+/-5 
+/-5 
Clinical Procedures/Assessments 
Patient demographics/Age 
X 
 
 
 
 
Medical and Surgical History 
X 
 
 
 
 
Pregnancy test1 
X 
 
 
 
 
Prior and concomitant medications 
X 
X 
X 
X 
X 
Review of Adverse Events 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
X 
X 
X 
X 
Vital Signs2 
X 
X 
X 
X 
X 
Supplemental Oxygen Use3 
X 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
Weight/BMI 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
EKG 
X13 
X 
X 
X 
 
Infliximab or IVIG administration 
 
X 
X 
 
 
Corticosteroids Administration 
 
X 
X 
X 
 
Arterial Blood Gas (PaO2/FiO2 ratio)3 
 
X 
X 
X 
 
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Trial Period 
Study Screening 
(Prior to Randomization)10 
Treatment Phase 
Follow-Up 
Treatment Day 
≤21 days before randomization 
Day 110 
Day 14 
Day 28 
Days 42 and 
56 
Scheduling Window (days) 
 
+/-5 
+/-5 
+/-5 
+/-5 
Clinical Procedures/Assessments 
Pill counts 
 
 
X 
X 
X7 
Laboratory Procedures/Assessments 
Hematology labs12 
X 
X 
X 
X 
X 
Serum chemistries, Liver function tests12 
X 
X 
X 
X 
X 
Coagulation Profile (PT, INR) 
X9 
 
 
 
 
ESR (erythrocyte sedimentation rate) 
 
X 
X 
X 
X 
Pulmonary Function Tests4 
X 
X 
X 
X 
 
Tuberculosis test8 
X 
 
 
 
 
Hepatitis B serology 
X 
 
 
 
 
Blood culture 
X9 
 
 
 
 
Urine culture 
X9 
 
 
 
 
Viral Panel including rapid flu and RSV 
X9 
 
 
 
 
Sputum Culture 
X9 
 
 
 
 
Radiologic Assessments 
CT chest with or without contrast11 
X 
X 
X 
X 
 
Patient-Reported Outcome Assessments 
FACT-L Questionnaire 
 
X14 
X 
X 
 
Borg scale 
 
X14 
X 
X 
 
Biological Sample Submissions: See Sections 7.2 and 10 
1. All females of childbearing potential must have a negative blood test or urine test within 14 days prior to randomization to rule out 
pregnancy. 
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3. Response Assessment will be performed by assessment of PaO2/FiO2 ratio. To calculate this, patients will need an arterial blood gas 
assessment obtained from an arterial puncture or an indwelling arterial catheter, and a recording of the fraction of inspired oxygen received, 
as outlined in Appendices IV and V. 
4. Pulmonary Function Tests include: FVC, FEV1, DLCO, Total Lung Capacity (TLC) and Flow-volume loops without bronchodilator use. 
These only need to be completed if the patient is clinically able to complete this assessment. Selected patients (such as those on a 
ventilator) may not be able to complete this test. Raw values and the percent predicted for FEV1, FVC, DLCO and TLC should be collected. 
5. Arm A: If corticosteroids taper is given for 6 weeks or is re-commenced for another 4-6 weeks after day 14 administration of infliximab. 
6. Tuberculosis test must be completed as per local practices, and may refer to either: TB spot test, quantiferon gold or tuberculin skin test as 
per eligibility criteria. Patient must have a negative tuberculosis assessment within 21 days of randomization and either negative or low 
clinical suspicion. 
7. Patients must have pathogen-negative infectious diagnostic evaluation within 21 days of randomization, at a minimum these should 
include: blood culture, sputum culture, and viral panel (including rapid flu and RSV). Perform urine culture and coagulation profile as 
clinically indicated. 
8. All study screening assessments must be completed within ≤21 days prior to randomization. If screening tests are done within 5 days of 
day 1, assessments that are also required on day 1 do not need to be repeated. 
9. IV contrast is not necessary to diagnose pneumonitis, but OK to be present if clinically indicated. Please refer to Section 5.1.4 for imaging 
guidelines and Section 4.4.6 for digital RT data submission using TRIAD. 
10. Hematology tests are to include a CBC with differential (i.e., WBC, ANC, platelet, Hgb, Hct). Serum chemistry tests are to include: sodium, 
potassium, calcium, magnesium, glucose (non-fasting), creatinine, creatinine clearance (CrCl; calculated with the Crockcroft-Gault 
formula), bilirubin, alkaline phosphatase, aspartate aminotransferase (AST or SGOT), alanine aminotransferase (ALT or SGPT), blood urea 
nitrogen (BUN). 
11. Perform screening EKG as clinically indicated. 
12. Patient-reported outcome assessments should be completed up to 5 days before Day 1 or on Day 1 
Rev. Add4 


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7.2 
Biological Sample Submissions 
Biospecimens are to be submitted for research studies as outlined in Section 10. 
The submission of biospecimens is mandatory for use in the correlative studies 
described in Section 11. 
All samples submitted must be logged and tracked in the ECOG-ACRIN Sample 
Tracking System (STS). 
Material 
Pre-
Study 
Day 13 
Day 
143 
Day 
283 
Ship To: 
MANDATORY 
Peripheral blood, 7 Heparin tubes3 
 
X 
X 
X 
D’Alessio Laboratory 
Johns Hopkins 
Per Participant Consent: If collected, these will be submitted from patients who answer “Yes” to “I 
agree that my samples and related health information may be used for the laboratory studies 
described above.” 
Tumor Tissue, FFPE2 
X 
 
 
 
 
1. Tissue collected during previous standard of care (SOC) procedures prior to trial entry are requested 
to be submitted to the Central Biorepository and Pathology Facility (CBPF) – MDACC Life Sciences 
Plaza as outlined in Section 10 with 4 weeks following randomization. The associated pathology and 
related reports are to be submitted with all tissue submissions. 
2. Blood is to be collected within +/- 5 days of the timepoints indicated. Research blood samples are 
not to be collected or shipped on Fridays or a day before a holiday, as the receiving laboratory is 
closed on Saturdays and holidays. Samples must be shipped the day of collection as they are 
required to be processed within 36 hours of sample collection. To order kits, please see Appendix X. 
Kit supplies are limited and are available for US and Canadian sites only. Institutional supplies are 
requested to be used if kits are not available. 
 
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8. 
Drug Formulation and Procurement 
This information has been prepared by the ECOG-ACRIN Pharmacy and Nursing 
Committees. Biosimilars and other formulations of infliximab or IVIG not stated below, 
will not be permitted. 
8.1 
Infliximab 
8.1.1 
Other Names 
Infliximab is also known as Remicade (Janssen Biotech Inc., PA). 
8.1.2 
Classification 
Infliximab neutralized the biologic activity of TNF-alpha, by binding 
with high affinity to the soluble and transmembrane forms of TNF 
alpha, and inhibits blocking of TNFalpha with its receptions. Infliximab 
is an FDA-approved treatment for a number of immunologic 
conditions, including but not limited to: ulcerative colitis, Crohn’s 
disease, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis 
and plaque psoriasis. 
8.1.3 
Mode of Action 
Infliximab is a chimeric monoclonal antibody that inhibits binding of 
the inflammatory cytokine tumor necrosis factor alpha (TNF-a) to its 
receptor. Infliximab is an FDA-approved tumor necrosis factor (TNF) 
modifier marketed in the U.S. targeted against tumor necrosis factor-
alpha (TNF-alpha). Biological activities attributed to TNFalpha include 
induction of pro-inflammatory cytokines such as interleukin (IL)-1 and 
IL-6; enhancement of leukocyte migration by increasing endothelial 
layer permeability; expression of adhesion molecules by endothelial 
cells and leukocytes; activation of neutrophil and eosinophil functional 
activity; fibroblast proliferation; synthesis of prostaglandins; and 
induction of acute phase and other liver proteins. Preclinical studies 
have implicated TNF-alpha as an important effector molecule in the 
development of lung injury. This has led to the application of TNF-
alpha inhibitors in different clinical scenarios. For example, etanercept 
has been used (46) in idiopathic pneumonia syndrome (IPS), which 
like PDL-1 induced pneumonitis is triggered by immunologic factors. 
Specifically, murine IPS models have suggested that the lung is a 
target of distinct immune-mediated injury pathways that include 
soluble inﬂammatory effectors such as TNF-alpha and antigen 
speciﬁc T-cell which synergize to cause inﬂammation, cellular injury 
and pulmonary dysfunction. Based on infliximab use in CTLA 4-
mediated colitis, prior studies have used infliximab in steroid refractory 
pneumonitis.57 However, infliximab may be implicated in the 
development of infections leading to poor outcomes in these patients 
and more recently the number of reported cases of ILD triggered by 
anti TNF-alpha agents is increasing. Given that infliximab may be 
implicated in the development of severe infections (renal and hepatic), 
other alternatives have been explored for the treatment of anti 
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8.1.4 
Storage and Stability 
Store unopened infliximab vials in a refrigerator at 2-8C. Do not use 
infliximab beyond the expiration date on the carton or vial. This 
product contains no preservatives. Unopened vials may be stored up 
to 30C for a single period for up to 6 months, but not exceeding the 
expiration date. 
8.1.5 
Dose Specifics 
Refer to Section 5.1.1. 
8.1.6 
Preparation 
Infliximab is a chimeric IgGk monoclonal antibody composed of 
human constant and murine variable regions specific to human tumor 
necrosis factor-alpha (TNFalpha). Infliximab is produced by a 
recombinant cell line cultured by continuous perfusion and is purified 
by a series of steps that includes measures to inactivate and remove 
viruses. 
Infliximab is supplied as a sterile white lypholized powder for 
intravenous infusion. Following reconstitution with 10ml of sterile 
water for injection, the resulting pH is 7.2. 
8.1.7 
Route of Administration 
Infliximab is administered intravenously. It is predominantly distributed 
within the vascular compartment. The elimination half-life of infliximab 
is 8-9.5 days. When single infusions of infliximab 1 - 20 mg/kg are 
given, a linear relationship exists between the dose administered and 
the Cmax and AUC. A single infusion of 5 mg/kg IV results in a 
median Cmax of 118 mcg/m. The standard recommended dose for 
PD-1/PDL1 pneumonitis is 5mg/kg.  
Prior to initiating infliximab therapy, patients must be evaluated for 
latent tuberculosis as per institutional policies (tuberculin skin test, TB 
spot test, or Quantiferon test). Prior to IV infusion, infliximab will be 
administered as outlined in Appendix VI. 
• 
The IV infusion should begin within 3 hours of reconstitution and 
dilution. 
• 
Do not administer the solution if visibly opaque particles, 
discoloration, or other foreign particles are observed. 
• 
Do not infuse the infliximab solution concomitantly in the same 
intravenous line with other agents. 
• 
Infuse IV over a period of not less than 2 hours. Use an infusion 
set with an in-line, sterile, non-pyrogenic, low-protein-binding filter 
(pore size of 1.2 microns or less). Discard any unused portion. 
Laboratory monitoring should include: 
• 
CBC with differential 
• 
Hepatitis B serology 
• 
Assessment for Active/Latent Tuberculosis (as per local 
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• 
Cytochrome p450 (CYP450) substrates: advised to monitor drug 
concentrations or the effects of drugs that are known to be 
CYP450 substrates such as warfarin, cyclosporine and 
theophylline. 
Treatment of Infliximab infusion reactions 
Infusion reactions may occur within 2 hours of an infliximab infusion in 
up to 20% of patients. Infusion-related reactions include flushing (9%), 
headache (18%), and rash (10%). Among infliximab infusions in 
reported clinical trials, 3% were accompanied by non-specific 
symptoms such as fever or chills, and 1% were accompanied by 
cardiopulmonary reactions such as chest pain (unspecified), 
hypotension, hypertension, or dyspnea. Less than 1% were 
accompanied by itching, urticaria, or the combined symptoms of 
itching/urticaria and cardiopulmonary reactions. Serious acute infusion 
related reactions including anaphylactic shock, convulsions, 
erythematous rash, and hypotension occurred in < 1% of adults 
treated during clinical trials. 
If infusion reactions occur, sites should follow local institutional 
protocols for management of infusion reactions. For example, mild to 
moderate infusion reactions should prompt slowing of infusion rate or 
temporary discontinuation of the infusion. Upon resolution of the 
reaction, reinitiate administration at a lower infusion rate and/or the 
prescriber may order treatment with antihistamines, acetaminophen, 
and/or corticosteroids, in accordance with local infusion reaction 
guidelines For patients that do not tolerate the infusion following these 
interventions, infliximab should be discontinued. Infliximab would be 
discontinued if severe hypersensitivity reactions occur. Medications 
for the treatment of hypersensitivity reactions (e.g., acetaminophen, 
antihistamines, corticosteroids and/or epinephrine) should be 
available for immediate use in the event of a serious reaction. 
8.1.8 
Incompatibilities  
Contraindications 
Infliximab at doses >5mg/kg should not be administered to patients 
with moderate to severe heart failure. Infliximab should not be re-
administered to patients who have experienced a severe 
hypersensitivity reaction to infliximab. Additionally, patients should not 
receive infliximab if they have known hypersensitivity to any 
components of the product or murine proteins. 
Drug Interactions: 
• 
Anakinra or Abatacept: Increased risk of serious infections were 
seen in clinical studies of these agents with infliximab.  
• 
Tocilizumab: this combination should be avoided due to increased 
risk of infection or immunosuppression. 
• 
Methotrexate: concomitant use my increase infliximab 
concentrations 
• 
Live vaccines: These should not be given concurrently with 
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Pregnancy 
It is not known whether infliximab may cause fetal harm. Patients will 
be strongly encouraged to use contraception during this study, if of 
child-bearing potential. Infliximab should not be given to breastfeeding 
mothers as the penetration of the agent into breast milk is unknown. 
8.1.9 
Availability  
The drug will be provided by the treating investigator at the study site. 
Infliximab is included in national guidelines (American Society of 
Clinical Oncology (ASCO), Society for Immunotherapy of Cancer 
(SITC), and National Comprehensive Cancer Network (NCCN)), and 
will be billed to the patient’s insurance. This study will not be 
conducted under an IND. 
8.1.10 
Side Effects 
Common AEs include: rash (10%), abdominal pain (12%), nausea 
(21%), headache (18%), cough 12%, pharyngitis (12%), sinusitis 
(14%), upper respiratory infection (32%), fatigue (9%). 
Side effects by organ system are annotated below: 
• 
Cardiovascular: Hypertension (5%), Acute coronary syndrome, 
Bradyarrhythmia (≥ 0.2%), Hypotension, Heart failure, Systemic 
vasculitis (Rare) 
• 
Dermatologic: Pruritis (7%), Erythema multiforme, Stevens-
Johnson syndrome, Toxic epidermal necrolysis 
• 
Gastrointestinal: Abdominal pain (12%), Diarrhea (12%), 
Dyspepsia (10%), Bowel obstruction ( 0.2%) 
• 
Hematologic: Hemolytic anemia ( 0.2%), Leukopenia (Adult,  
 0.2%; pediatric, 9%), Neutropenia (Pediatric, 7%), Pancytopenia 
( 0.2%), Thrombocytopenia ( 0.2%) 
• 
Hepatic: Autoimmune hepatitis (Rare), Hepatic failure, acute 
(Rare), Hepatitis ( 0.2%), Hepatotoxicity (Rare) 
• 
Immunologic: Allergic reaction ( 0.2%), Anaphylaxis, 
Hepatosplenic T-cell lymphoma (Rare), Hypersensitivity reaction, 
Malignant lymphoma, Sarcoidosis ( 0.2%) 
• 
Infectious: Infliximab-associated infection ranges from 5.3 -56% in 
incidence. The infections most frequently reported include: upper 
respiratory tract infections (32%), e.g. sinusitis (14%), pharyngitis 
(12%), bronchitis (10%) urinary tract infections (8%). Reported 
serious infections: pneumonia (0.2%), cellulitis (0.2%), sepsis 
(0.2%), skin ulcer, abscess, bacterial infections.  
• 
Neurologic: Demyelinating disease of central nervous system, 
Change in vision (Rare) 
• 
Respiratory: Dyspnea (1%), Pulmonary edema ( 0.2%), 
Tuberculosis (0.4% ) 
• 
Other: Cancer, Histoplasmosis, Infectious disease (Adult, 36-50%; 
pediatric, 38-74%), Infusion reaction (Adult,  20%; pediatric, 13-
18%), Mycosis fungoides. 
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8.1.11 
Nursing/Patient Implications 
Advise the patient to read the FDA-approved packaging 
information/labelling for this agent (medication guide). Patients and 
caregivers should be advised of the potential risks and side effects of 
this agent. Patients should be informed that infliximab may lower the 
effects of their immune system, and the ability to fight infection. 
Patients should be counselled on an increased risk of lymphoma and 
other malignancies. Advise patients to report any new or worsening 
heart failure, neurologic disease or autoimmune toxicity. 
8.1.12 
References 
Remicade (Infliximab) package insert 2013.  
Janssen Biotech, Inc. 
Horsham, PS 19044 
8.2 
Intravenous Immunoglobulin (IVIG) 
8.2.1 
Other Names 
Intravenous immunoglobulin (IVIG) may also be known by a number 
of commercial names/brands. For the purposes of this study, the 
following IVIG formulations may be used: Privigen (CSL Beyring AG, 
Bern, Switzerland), Gammagard Liquid (Baxalta Us Inc, Westlake 
Village, CA, USA). Gamunex-C (Grifols USA, Research Triangle Park, 
NC, USA) may be used as an alternative IVIG formulation in the event 
either Privigen or Gammagard are not available from the 
manufacturer due to production shortages. 
8.2.2 
Classification 
IVIG is an intravenous solution composed primarily of human 
immunoglobulin G (IgG), with trace amounts of IgA and IgM. IVIG is 
derived from the pooled human plasma of thousands of donors, 
ensuring a diversified collection of antibodies with variable antigen 
binding regions. All samples undergo human immunodeficiency virus 
(HIV), hepatitis B, and hepatitis C testing. IVIG is an FDA-approved 
treatment for a number of immunologic conditions, including but not 
limited to: primary humoral immunodeficiency, chronic immune 
thrombocytopenia purpura ITP), chronic inflammatory demyelinating 
polyneuropathy (CIDP). 
8.2.3 
Mode of Action 
IVIG is a well-established anti-inflammatory and immunomodulatory 
agent that primarily contains intact monomeric IgG with only trace 
amounts of IgA, IgM, and IgE. IVIG exerts its effects through multiple 
mechanisms: modulation of macrophage Fc receptor expression and 
function; alteration of T cell and B cell function; inhibition of 
pathogenic autoantibodies; inhibition of inflammatory cytokines and 
inhibition of complement activation.  
Within 24 hours, up to 30% of a dose may be removed by catabolism 
and distribution. IVIG appears to distribute throughout intravascular 
(60%) and extravascular (40%) spaces. The exact fate of IVIG is not 


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well defined, but the serum half-life is that of immune globulin (IgG), 
approximately 21 to 29 days. High variability exists for the half-life of 
IgG. Fever, infection, or high IgG concentrations appear to coincide 
with a shortened half-life whereas immunodeficiency appears to be 
associated with a longer half-life of IgG. For example, the apparent 
half-life of IgG after Octagam is approximately 40 days (range, 23 to 
84 days) in immunosuppressed patients. Peak serum concentrations 
occur immediately after IV injection and are dose-related. Following 
infusion, IVIG products show a biphasic decay curve. The initial phase 
is characterized by an immediate post-infusion peak in serum IgG and 
is followed by rapid decay due to equilibration between the plasma 
and extravascular fluid compartments. The second phase is 
characterized by a slower and constant rate of decay. After receipt of 
300 to 450 mg/kg of IVIG every 4 weeks, the mean total IgG serum 
concentration decreased approximately 47% to 55% over 28 days. 
The mean trough total IgG concentration after 6 or 7 infusions of 
Octagam was 766 to 871 mg/dL. The concentrations were similar to 
the patient's baseline trough total concentrations (883 to 986 mg/dL) 
on other IVIG products (59). 
The use of IVIG for the treatment of ILD is limited to case series, 
exploratory trials and anecdotal reports. As such, it has been used 
primarily as salvage therapy when traditional immunosuppression has 
either failed or been poorly tolerated. IVIG is a known therapy for 
multiple autoimmune, paraneoplastic immune conditions, steroid-
resistant polymyositis and severe idiopathic pulmonary fibrosis (IPF) 
(59). Donahoe and colleagues reported that patients who received 
IVIG in addition to rituximab and plasma exchange had a more 
durable response in terms of mortality and improvement in PFTs 
compared to rituximab and plasma exchange alone(60).  
8.2.4 
Storage and Stability 
Privigen, Gammagard Liquid and Gamunex-C are supplied in a 
single-use tamper-evident vial containing a labelled amount of 
functionally active IVIG. Packing components are not made with 
rubber latex. Privigen, Gammagard Liquid and Gamunex-C should be 
kept in its original carton to protect it from light. Each vial has an 
integral suspension band and a label with two peel off strips showing 
product name, lot number and expiration date. When stored at room 
temperature (up to 25C, or 77F). Privigen is stable for up to 36 
months and Gammagard is stable for up to 24 months respectively. 
Gamunex-C may be stored under refrigeration for up to 36 months at 
2-8 C (36-46 F). 
8.2.5 
Dose Specifics 
Refer to Section 5.1.2. The dose of IVIG varies depending on the 
condition it is being administered. For patients receiving privigen as 
part of this study: patients will be treated with 2g/kg per day in divided 
doses, and the initial infusion rate will commence as outlined in 
Appendix VII. For patients receiving Gammagard Liquid and 
Gamunex-C as part of this study: patients will be treated with 2g/kg in 


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divided doses, and the initial infusion rate will commence as outlined 
in Appendix VII. 
8.2.6 
Preparation 
Do not mix immune globulin products of different formulations or from 
different manufacturers. Do not shake vials to avoid excessive 
foaming. Do not use IVIG (products beyond their expiration date on 
the label). Privigen, Gammagard Liquid and Gamunex-C vials are for 
single-use only and contain no preservative. Discard any partially 
used vials or unused product according to institutional requirements. If 
large doses are to be administered several vials can be pooled using 
aseptic technique. IVIG products can be diluted with D5W only, do not 
use NS to further dilute. May flush the infusion line with NS or D5W 
for either IVIG product. 
8.2.7 
Dosage Forms and Description 
IVIG is ready-to-use sterile 10% protein liquid preparation of 
polyvalent human immunoglobulin G (IgG) for intravenous use 
Privigen and Gammagard Liquid has a purity of at least 98% IgG 
consisting primarily of monomers. Privigen contains 250mmol/L 
(range 210-290) of L proline as a stabilizer and trace amounts of 
sodium. Gammagard Liquid contains 250mmol/L of glycine as a 
stabilizer and buffering agent. Privigen and Gammagard Liquid 
contain no carbohydrate stabilizers or preservatives. Privigen, 
Gammagard Liquid and Gamunex-C are supplied in single-use 
tamper-evident vials containing a labelled amount of functionally 
active IVIG. Packing components are not made with rubber latex.  
8.2.8 
Route of Administration  
IVIG is administered intravenously, and will be administered as 
outlined in Appendix VII. 
Severe adverse events may be related to infusion rate; it is important 
to follow recommendations closely. Administer at the minimum 
infusion rate possible for patients at risk for renal dysfunction or 
thromboembolic events. Thrombotic events have been associated 
with the administration of IVIG, particularly in patients with renal 
dysfunction. Therefore, the investigators must ensure adequate 
hydration prior to infusion, particularly in patients with preexisting 
renal insufficiency or those at risk of thrombosis.  
The following laboratory parameters, should be monitored daily before 
and after initiation of IVIG: 
• 
Evaluate for signs and symptoms of thrombotic events during 
administration 
• 
Assess renal function, including BUN and serum creatinine  
• 
Monitor glucose levels in patients with diabetes 
• 
Consider assessing baseline blood viscosity in patients at risk for 
hyperviscosity, including those patients with cryoglobulins, fasting 
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• 
Hemoglobin and hematocrit, given risk of hemolysis after the 
infusion and within 36 to 96 hours post-infusion 
• 
If transfusion-related acute lung injury (TRALI) is suspected, 
conduct appropriate tests to check for anti-neutrophil antibodies 
and anti-HLA antibodies in both the product and patient's serum 
• 
Conduct cerebrospinal fluid studies if symptoms of meningitis 
occur. 
The following signs and symptoms should be monitored during, and 
after infusion: 
• 
Signs and symptoms of thrombotic events  
• 
Urine output periodically in patients with an increased risk of acute 
renal failure (i.e., preexisting renal dysfunction, diabetes mellitus, 
volume depletion, sepsis, paraproteinemia, age 65 years, and 
those receiving concomitant nephrotoxic agents) 
• 
Signs of infusion reaction, including fever, chills, nausea, and 
vomiting,  
• 
Signs and symptoms of hemolysis 
• 
Pulmonary adverse reactions. If transfusion-related acute lung 
injury (TRALI) is suspected, conduct appropriate tests to check for 
anti-neutrophil antibodies and anti-HLA antibodies in both the 
product and patient's serum  
• 
Monitor vital signs during the IV infusion 
• 
Monitor for signs and symptoms of volume overload  
• 
Perform a neurological exam if meningitis symptoms occur 
Diagnosis and Treatment of IVIG ‐Related Infusion Reactions 
Infusion reactions generally appear 30 minutes to 1 hour after 
initiation of the infusion and might also be associated with flushing of 
the face, tightness in the chest, chills, fever, dizziness, nausea, 
vomiting, diaphoresis, and hypotension or hypertension. The 
investigators will closely monitor for adverse reactions throughout the 
infusion. IVIG may cause a precipitous fall in blood pressure and 
clinical manifestations of anaphylaxis, which appear to be related to 
the rate of IVIG infusion; do not exceed the recommended rate of 
infusion. 
If infusion reactions occur, sites should follow local institutional 
protocols for management of infusion reactions. For example, if 
flushing and changes in blood pressure, temperature or pulse occur 
with the infusion, slow or temporarily stop the infusion. In some cases, 
when symptoms subside the infusion may be resumed at a rate that is 
comfortable for the patient. The infusion will be stopped immediately if 
anaphylaxis or other severe reactions occur. Immediate AEs can be 
treated by the slowing or temporary discontinuation of the infusion and 
symptomatic therapy with analgesics, nonsteroidal anti-inflammatory 
drugs, antihistamines, and glucocorticoids in more severe reactions. 
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hydration, especially in high-risk patients, may prevent renal failure, 
thromboembolic events, and aseptic meningitis. 
Risk of Transmissible Agents with IVIG: 
IVIG is a derivative of human blood. As with other products derived 
from or purified with human blood components, the remote possibility 
of contamination with bacterial or viral infection, including hepatitis, or 
Creutzfeldt-Jakob disease (CJD) exists in patients receiving IVIG. 
Screening plasma donors for prior exposure to certain viruses, testing 
for the presence of viruses, and inactivating and/or reducing viruses 
has reduced the risk of transmission of infectious agents; however, 
none of the processes are completely effective. Some viruses, such 
as parvovirus B19, are particularly difficult to remove or inactivate.  
8.2.9 
Incompatibilities  
Contraindications: 
IVIG should not be administered to patients with a history of 
anaphylaxis or severe systemic reaction to human immune globulin. 
This agent is contraindicated in patients with hyperprolinemia because 
it contains the stabilizer L-proline. Privigen, Gammagard Liquid and 
Gamunex-C are contraindicated in IgA-deficient patients with 
antibodies to IgA and a history of hypersensitivity. 
• 
Drug Interactions: 
• 
Hypersensitivity: As outlined above, if this occurs stop IVIG and 
institute appropriate supportive treatment 
Pregnancy 
It is not known whether IVIG may cause fetal harm. Patients will be 
strongly encouraged to use contraception during this study, if of child-
bearing potential. IVIG should not be given to breastfeeding mothers 
as the penetration of the agent into breastmilk is unknown. 
8.2.10 
Availability 
The drug will be provided by the treating investigator at the study site. 
IVIG is included in national guidelines (ASCO, SITC, and NCCN), and 
will be billed to the patient’s insurance. This study will not be 
conducted under an IND. 
8.2.11 
Side Effects 
Adverse reactions have been reported in approximately 2-25% of all 
IVIG infusions, in reported clinical studies and post-marketing 
evaluations. The majority of adverse reactions associated with IVIG 
are minor, transient, and infusion-related. However, serious systemic 
reactions affecting renal, cardiovascular, central nervous system, 
integumentary, and hematological systems have been reported. 
Potential risk factors affecting the risk and intensity of adverse events 
include the underlying condition and pre-existing cardiovascular or 
renal disease, as well as IVIG formulation, lot number, dose, 
concentration, and rate of infusion. Conservative product-specific 
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closely throughout each infusion. Particular care should be taken 
when patients are IVIG-naïve. 
Adverse events following IVIG infusions may be classified as 
immediate (occurring during the infusion itself) or delayed (occurring 
after the infusion has ceased). The rate of IVIG infusions should be 
low at the beginning and increased every 15-30 min, based on the 
patient's tolerance. 
Common adverse effects of IVIG include: hypertension (6-8%), 
hypotension (11%), increased heart rate (11-22% ), edema (8.2%), 
injection site reaction (5-98%), pruritus (6-8%), rash (4.1-7.8%), 
urticaria (5-8.2%), increased body temperature (2-4%), diarrhea (6-
28%), nausea (5- 26%), vomiting (7- 23%), arthralgia (3.9-13%), 
myalgia (5-20%), limb pain (6.4-11.5%), asthenia (5-10% ), dizziness 
( 13.1%), headache (8-64.9%), otalgia (6.4-18% ), asthma (8.5-
29%), cough (6-26%), nasal congestion (13-15% ), throat pain (6.4-
6.8%). 
Reported serious side effects of IVIG by organ system include:  
• 
Cardiovascular: Chest discomfort (5-9%), Chest pain (5-11%), 
Myocardial infarction, Tachycardia (5% - 22% ) 
• 
Endocrine metabolic: Hyponatremia 
• 
Hematologic: Hemolysis, Hemolytic anemia, Thrombosis (Primary 
humoral immunodeficiency, 2%; immune thrombocytopenic 
purpura, 22% ) 
• 
Hepatic: Hepatitis C 
• 
Immunologic: Anaphylaxis/Hypersensitivity reactions 
• 
Musculoskeletal: Backache (3.9-28%) 
• 
Neurologic: Aseptic meningitis (0.02%) 
• 
Renal: Acute renal failure, Hypokalemic nephropathy 
• 
Respiratory: Pulmonary embolism (0.9%), Transfusion-related 
acute lung injury 
8.2.12 
Nursing/Patient Implications 
Patients should be informed that IVIG is made from human blood and 
may contain infectious agents that can cause disease, such as 
viruses and CJD. Explain that the risk of transmission of an infection 
through Privigen, Gammagard Liquid and Gamunex-C have been 
reduced by screening plasma donors and testing donated plasma. 
Patients should be informed that IVIG may interfere with a response 
to live vaccines. 
8.2.13 
References 
Privigen package insert 
CSL Behring AG, Bern, Switzerland. 
Gammagard Liquid package insert 
Baxalta US Inc., Westlake, CA, USA 
Gamunex-C package insert 


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Grifols USA, Research Triangle Park, NC, USA 
8.3 
Prednisone 
8.3.1 
Other Names 
Deltasone, Orasone, Medicorten, Panasol-S, Liquid-Pred, others  
8.3.2 
Classification 
Adrenal corticosteroid. 
8.3.3 
Mode of Action 
Prednisone is a potent synthetic glucocorticoid that affects almost 
every body system. It has anti-inflammatory, immunosuppressant, and 
minimal mineralocorticoid activity, and antineoplastic properties. As an 
antineoplastic agent, prednisone may bind to specific proteins 
(receptors) within the cell forming a steroid-receptor complex. Binding 
of the receptor-steroid complex with nuclear chromatin alters mRNA 
and protein synthesis within the cell. 
8.3.4 
Storage and Stability 
The drug is stored at room temperature in a dry place. Refer to the 
package insert from the manufacturer for storage specifics. 
8.3.5 
Dose Specifics 
4-6 week corticosteroid taper, starting from a dose of prednisone 1-
2mg/kg either orally or intravenously in divided doses, and determined 
by the treating investigator.  
8.3.6 
Administration 
Prednisone is taken orally (with food or a meal) or intravenously in 
divided doses, as determined by the treating investigator. A pill 
calendar will be provided to patients. See Appendix VIII. 
8.3.7 
Availability 
Commercially available in 1, 2.5, 5, 10, 20, 25 and 50 mg tablets. Also 
available as a 1 mg/ml oral solution or syrup and as a 5 mg/mL oral 
solution. 
8.3.8 
Side Effects 
1. Gastrointestinal: Nausea, vomiting, anorexia; increased appetite 
and weight gain; peptic ulceration. 
2. Dermatologic: Rash; skin atrophy; facial hair growth, acne, facial 
erythema; ecchymoses. 
3. Genitourinary: Menstrual changes (amenorrhea, menstrual 
irregularities), urinary frequency. 
4. Neurologic: Insomnia; muscle weakness; euphoria, psychosis, 
depression; headache, vertigo, seizures. 
5. Cardiovascular: Fluid retention and edema; hypertension. 
6. Ocular: Cataracts; increased intraocular pressure; exophthalmos. 


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7. Metabolic: Hyperglycemia; decreased glucose tolerance; 
aggravation or precipitation of diabetes mellitus; adrenal 
suppression; Cushingoid features; hypokalemia. 
8. Hematologic: Leukocytosis. 
9. Other: Osteoporosis (and resulting back pain); serious infections 
including herpes zoster, varicella zoster, fungal infections, 
pneumocystis carinii, tuberculosis; muscle wasting; delayed 
wound healing; suppression of reactions to skin tests. 
8.3.9 
Nursing Implications 
1. Instruct patients to take prednisone after meals. Should not be 
taken too close to bedtime to avoid insomnia. A mild sedative may 
be required. 
2. GI symptoms should be treated symptomatically. 
3. Monitor blood glucose levels. 
4. Educate patient concerning potential mood swings. 
NOTE: 
Please refer to the commercially-available package 
labeling for more information. 
8.3.10 
References 
1. Pickup ME: Clinical pharmacokinetics of prednisone and 
prednisolone. Clin Pharmacokinet 4:111-128, 1979. 
2. The Boston Collaborative Drug Surveillance Program: Acute 
reactions to prednisone in relation to dosage. J Clin Pharmacol 
13:694-698, 1972. 
3. Ling MHM, Perry PJ, Tsuang MT: Side effects of corticosteroid 
therapy: Psychiatric aspects. Arch Gen Psychiatry 38:471-477, 
1981. 
8.4 
Methylprednisolone 
8.4.1 
Other Names 
Methylprednisolone sodium succinate (Solu-Medrol), 
methylprednisolone acetate (Depo-Medrol), Methylprednisolone 
(Medrol), others. 
8.4.2 
Classification 
Adrenal corticosteroid 
8.4.3 
Mode of Action 
Methylprednisolone is a potent synthetic glucocorticoid that affects 
almost every body system. It has anti-inflammatory, 
immunosuppressant, and minimal mineralocorticoid activity, and 
antineoplastic properties. As an antineoplastic agent, 
methylprednisolone may bind to specific proteins (receptors) within 
the cell forming a steroid-receptor complex. Binding of the receptor-
steroid complex with nuclear chromatin alters mRNS and protein 
synthesis within the cell. 
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8.4.4 
Storage and Stability 
The intact vials are stored at room temperature. After reconstitution, 
the solution is stable for 48 hours at room temperature. When further 
diluted in dextrose 5% or normal saline, concentrations of < 0.25 
mg/ml are stable for 24 hours when refrigerated; concentrations 
> 0.25 mg/ml are stable for 4 hours when refrigerated. 
8.4.5 
Dose Specifics 
4-6 week corticosteroid taper, starting from a dose of 
methylprednisolone at a dose equivalent to 1-2mg/kg of prednisone 
either orally or intravenously in divided doses, and determined by the 
treating investigator. Methylprednisolone 0.8mg/kg either orally or 
intravenously is the equivalent of 1mg/kg of prednisone. 
8.4.6 
Preparation 
The 40 mg vial of methylprednisolone sodium succinate is 
reconstituted with 1 ml of the provided diluent or bacteriostatic water, 
resulting in a concentration of 40 mg/ml. The 125 mg, 500 mg, and 1 
gm vials are reconstituted with 2, 8, and 16 ml, resulting in a 
concentration of 62.5 mg/ml. The 2 gm vials are reconstituted with 30 
ml, resulting in a concentration of 65.3 mg/ml. 
8.4.7 
Route of Administration 
Methylprednisolone sodium succinate is administered intravenously 
over one to several minutes or intramuscularly. Methylprednisolone 
sodium succinate is administered intramuscularly, intra-articularly, or 
intralesionally. Methylprednisolone may also be administered orally 
taken with food or a meal. 
8.4.8 
Incompatibilities 
Stability with intravenous fluids and additives varies with 
concentration; consult your pharmacist for specific information. Drugs 
that induce hepatic microsomal enzymes (phenytoin, barbiturates, 
rifampin) accelerate the metabolism of methylprednisolone. 
8.4.9 
Availability 
The sodium succinate salt is commercially available as a powder for 
injection with provided diluent in 40, 125, 500, 1000, and 2000 mg 
vials. The acetate salt is available in 20, 40, and 80 mg/ml vials. Oral 
methylprednisolone is available in 2, 4, 8, 16, and 32 mg tablets. 
8.4.10 
Side Effects 
1. Hematologic Leukocytosis 
2. Gastrointestinal: Nausea, vomiting, anorexia; increased appetite 
and weight gain; peptic ulceration. 
3. Dermatologic: Rash; skin atrophy; facial hair growth, acne, facial 
erythema; ecchymoses. 
4. Genitourinary: Menstrual changes (amenorrhea, menstrual 
irregularities). 
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5. Neurologic: Insomnia; muscle weakness; euphoria, psychosis, 
depression; headache, vertigo, seizures. 
6. Cardiovascular: Fluid retention and edema; hypertension; 
hypokalemia. 
7. Ocular: Cataracts; increased intraocular pressure; exophthalmos. 
8. Metabolic: Hyperglycemia; decreased glucose tolerance; 
aggravation or precipitation of diabetes mellitus; adrenal 
suppression; redistribution of body fat (truncal obesity, moon 
facies, cervical fat deposition). 
9. Musculoskeletal: Muscle wasting, osteoporosis (and resulting 
back pain). 
10. Other: Serious infections including herpes zoster, varicella zoster, 
fungal infections, pneumocystis carinii, tuberculosis; muscle 
wasting; delayed wound healing. 
8.4.11 
Nursing Implications 
1. GI symptoms should be treated symptomatically. 
2. Monitor blood glucose levels and blood pressure. 
3. Educate patient concerning potential mood swings. 
4. If used longer than 1-2 weeks, educate patient about long-term 
side effects. 
5. If used longer than 1-2 weeks, doses should be tapered prior to 
withdrawal. 
8.4.12 
References 
1. Derendorf H et al.  Kinetics of methylprednisolone and its 
hemisuccinate ester.  Clin Pharmacol Ther 37:502-7, 1985. 
2. The Boston Collaborative Drug Surveillance Program.  Acute 
reactions to prednisone in relation to dosage.  J Clin Pharmacol 
13:694-698, 1972. 
3. Ling MHM, Perry PJ, Tsuang MT.  Side effects of corticosteroid 
therapy: psychiatric aspects.  Arch Gen Psychiatry 38:471-477, 
1981. 
 


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9. 
Statistical Considerations 
This is a study with 1-step registration and two randomized arms. The main interest of 
this study is to assess pneumonitis response to an additional immunosuppressive agent 
(either infliximab or IVIG) in patients with steroid-refractory pneumonitis in order to 
inform future more definitive research. This study is not designed to compare infliximab 
vs. IVIG due to the rarity of the patient population, however a randomized design will 
ensure balance between patients enrolled in each arm.  
The primary outcome, pneumonitis response, is defined as an improvement of ≥ 20% in 
the PaO2/FiO2 ratio at Day 28 compared to Day 1 of the protocol treatment. This is 
assessed as in Section 6.1. This is measured by arterial blood gas assessment 
(obtained by arterial puncture, or from an indwelling arterial catheter), and recording of 
the fraction of inspired oxygen the patient is receiving. For the assessment of the 
primary outcome of the study, this ratio will be calculated at Day 28 after receipt of 
additional immunosuppression (infliximab or IVIG), and compared with the PaO2/FiO2 
calculated on Day 1 of receipt of additional immunosuppression. Secondary outcome 
include radiologic and functional measurement of pneumonitis, patient-reported 
outcome, death, and infection. Exploratory outcomes include blood/serum biomarkers for 
steroid-refractory pneumonitis. 
9.1 
Study Design 
For either immunosuppression arm, 16 patients will be needed in order to detect 
an improvement in pneumonitis response from 5% to 25%, using one sample 
exact binomial test with type I error (one-sided) of 4.3% for the null and power of 
80.3% for the alternative. Assuming a 10% ineligibility rate, 18 patients will be 
enrolled into each arm. If at least three patients are reported with pneumonitis 
response on Day 28 after the initiation of study treatment among the 16 eligible 
and treated patients, the new agent will be considered promising. 
9.2 
Accrual Goal and Rate 
For either arm, 18 patients will be enrolled, leading to the accrual of 36 patients 
in total for this study. With the expectation of approximately 1-2 patients per 
month to this trial, it is estimated that the accrual for this study will take 
approximately 24 months. 
9.3 
Analysis Plan 
The analysis plan described below will be performed on eligible and treated 
patients only unless specified otherwise. 
9.3.1 
Primary Objective 
The primary outcome of this study is pneumonitis response to 
infliximab or IVIG therapy. In all enrolled patients, pneumonitis 
response will be defined as an improvement in PaO2/FiO2 of ≥20% 
measured by arterial blood gas assessment (PaO2) and recording of 
the fraction of inspired oxygen (FiO2) received by the patient at the 
time of the arterial blood gas assessment, on Day 28 compared with 
Day 1. In patients who discontinue protocol therapy early or cannot 
complete an arterial blood gas assessment on either Day 1 or Day 28, 
this will be deemed as a failed event. However, if a patient develops 
progressive cancer during the study time period and this is deemed to 
be of greater clinical significance than pneumonitis and requiring 
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discontinuation from the protocol therapy for cancer therapy, this 
patient will be replaced and excluded from the primary objective 
analysis. This response rate will be reported with a proportion and its 
90% confidence interval for each treatment arm. A comparison on the 
pneumonitis response rate between the two arms (infliximab vs. IVIG) 
will be performed using Fisher’s exact test. However, this comparison 
will be exploratory as steroid-refractory pneumonitis is a rare 
phenomenon and the current study is not designed to detect any 
significant difference between arms. 
9.3.2 
Secondary Objectives 
Radiologic features of steroid-refractory pneumonitis will be assessed 
by the extent and distributions of the parenchymal abnormalities and 
the qualitative assessment of the lung volumes on CT. These 
outcomes will be assessed three times – first at Day 1 of study 
treatment, second Day 14 after initiation of study treatment, and the 
last on Day 28 after the initiation of study treatment. On review of the 
scans taken on Day 14 and Day 28, comparisons will be made 
between the current scan and the on from Day 1. The pneumonitis 
and lung volume will be graded “Definitely decreased”, “Probably 
decreased”, “No significant change”, “Probably increased” and 
“Definitely increased”. Response to study therapy will be defined by 
combining the categories “Definitely decreased” and “Probably 
decreased”. The response rate will be compared between the arms 
using Fisher’s exact test.  
Functional features and patient-reported outcomes of pneumonitis will 
be assessed three times as well - first at baseline (Day 1 of study 
treatment), second on Day 14 after the initiation of study treatment, 
and the last on Day 28 after the initiation of study treatment. 
Functional features of pneumonitis will be assessed by spirometry 
(FVC, FEV1), diffusion capacity of the lung (DLCO) and oxygen 
saturation on room air at rest, collected as part of the vital signs; 
These quantitative measures will be reported descriptively (by 
median, mean, and range) by timepoints and treatment arms. 
Pneumonitis improvement (from Day 1 to Day 14 and from Day 1 to 
Day 28) by each measure will be evaluated using the Wilcoxon 
signed-rank tests, by arm, without statistical adjustments. 
Patient-reported outcomes of pneumonitis will be measured by 
questionnaires (FACT-L (version 4) and the Borg scale). FACT-L 
consists of 5 subscales - physical well-being (PWB, 7 items), 
social/family welling-being (EWB, 7 items), emotional well-being 
(EWB, 6 items), functional well-being (FWB, 7 items), and additional 
concerns (10 items, but subscale score is computed based on the 7 
symptom items only). Each FACT-L subscale score will be computed 
separately (per the guidelines posted at https://www.facit.org). The 
primary outcome from FACT-L is the Trial Outcome Index (TOI), 
which is the sum of the scores from PWB, FWB, and lung-symptom (7 
items) Subscales. The lung-symptom subscale score is the sum of 7 
symptom items from the Additional Concerns Subscale, excluding the 
ones related with hair loss and smoking). All FACT-L questions 
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Likert scale (ranging from 0 “not at all” to 4 “very much”). Negatively 
worded items will be reversely scored. The TOI score will thus range 
from 0-84, with higher scores representing better QOL. The one-item 
Borg Dyspnea score is ranging from 0 “Nothing at all” to 10 “maximal”, 
with higher rating signifying more intensity or severity of 
breathlessness. These quantitative measures will be reported 
descriptively (by median, mean, and range) by timepoints and 
treatment arms. Pneumonitis improvement (from Day 1 to Day 14 and 
from Day 1 to Day 28) by each measure will be evaluated using the 
Wilcoxon signed-rank tests, by arm, without statistical adjustments. 
Death reported in the 28-day period after additional 
immunosuppression will be tabulated by treatment arm, and classified 
as pneumonitis-related, immunosuppression-related, disease-related 
or other. 
The number and severity of treatment-related adverse events from 
infections in any organ system by the CTCAE reported in the 28-day 
period after additional immunosuppression, will be tabulated by 
treatment arm. This analysis will include all patients starting protocol 
therapy regardless of eligibility. 
9.3.3 
Correlative Objectives 
Potential blood/serum biomarkers for pneumonitis will be assessed 
from serially collected blood/serum in accrued patients (on Days 1, 14 
and 28 after study treatment) and controls, whose blood/serum will be 
obtained as part of a parallel tissue-collection protocol. Assays for 
these samples will include: cytokine assays, autoantibody assays, 
MANAFEST assay and AUTOFEST assay. Autoantibodies, T-cell 
expansions (negative/positive), and cytokine levels (e.g., IFN-ɣ, IL-17, 
and VEG-F) will be summarized descriptively in patients with 
pneumonitis vs. controls, by timepoint and treatment arm (when 
appropriate). Fisher’s exact test will be used to evaluate associations 
of pneumonitis (Yes/No) with autoantibodies, T-cell expansions 
(negative/positive), and baseline cytokines (dichotomized by the 
median of each cytokine). 
Given the phenomenon of steroid-refractory pneumonitis is rare and a 
small number of these patients will be accrued to this trial, all the 
correlative analyses performed in this study will be explorative in 
nature. 
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9.4 
Monitoring Plan 
Study Progress and Safety Reports are prepared twice yearly for all ECOG-
ACRIN studies. Reports of these analyses are sent to the ECOG-ACRIN 
Principal Investigator or Senior Investigator at the participating institutions. 
Expedited reporting of certain adverse events is required, as described in Section 
5.2. 
9.5 
Gender and Ethnicity  
The anticipated accrual in subgroups defined by race, ethnicity and gender is as 
follows: 
Racial Categories 
Not Hispanic/Latino 
Hispanic/Latino 
Total 
Female 
Male 
Female 
Male 
American Indian/Alaska 
Native 
0 
0 
0 
0 
0 
Asian 
0 
0 
0 
0 
0 
Native Hawaiian or Other 
Pacific Islander 
0 
0 
0 
0 
0 
Black or African American 
1 
2 
0 
0 
3 
White 
15 
17 
0 
1 
33 
Total 
16 
19 
0 
1 
36 
The accrual targets in individual cells are not large enough for definitive subgroup 
analyses. Therefore, overall accrual to the study will not be extended to meet 
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10. 
Specimen Submissions 
Representative original diagnostic tumor, and blood specimens are to be submitted for 
use in the research studies outlined in Section 11. 
KITS: Kits are available only for US and Canadian sites for the submission of the blood 
samples to the D’Alessio Laboratory. Kit supplies are limited, therefore starter kits are 
not to be ordered. It is requested that kits be ordered after patient has consented to 
participate in the trial and has been determined to be eligible to register. To order kits 
follow the instructions outlined in Appendix X of the protocol. Kits will arrive within 3-5 
working days from when the order is placed. Institutional supplies are requested to be 
utilized if kits are not available. 
All specimens must be labeled with the ECOG-ACRIN protocol number, the patient’s 
initials and ECOG-ACRIN sequence number, the collection date, and the type of sample. 
For pathology materials, it is strongly recommended that full patient names be provided. 
All specimens must be logged and tracked via the ECOG-ACRIN Sample Tracking 
System (STS) Web Application (Section 10.3) and submitted with an STS-generated 
shipping manifest. Specimens not available for submission are to be indicated in STS as 
well. 
10.1 
Tissue Submissions to the ECOG-ACRIN Central Biopathology and Pathology 
Facility 
Submit from patients who answer “Yes” to “I agree that my samples and related 
health information may be used for the laboratory studies described above.” 
Guidelines for pathologists are provided in Appendix I. 
10.1.1 
Tissue Submission Requirements 
Formalin-fixed paraffin-embedded tumor tissue block(s) are to be 
submitted. 
a. Pre-trial diagnostic FFPE Tumor tissue: the optimal block is 70% 
tumor tissue with preferred specimen size as follows: 
• 
Surface area: 25mm2 is optimal. Minimum is 5mm2 
• 
Volume: 1mm3 optimal. Minimum volume is 0.2mm3 
NOTE: 
If blocks are not available for submission, the following 
alternative is to be submitted, in the indicated order of 
availability: 
• 
1 H&E (from the source block), 
• 
20 unstained slides. The optimal quantity of tissue 
requested should be equivalent to the amount 
indicated above. Slides and H&E must be numbered in 
the order cut. 
• 
1-2 tissue core punches 
The relevant pathology and surgical reports must accompany all 
tissue submissions: 
• 
Copy of the diagnostic or surgical Pathology Report 
• 
Other Immunologic and cytologic reports 
• 
STS generated shipping manifest for all submitted tissue. 
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10.1.2 
Shipping Procedures 
Tissue samples are to be shipped at ambient (use a cool pack in 
warm weather). Shipping manifest generated from the ECOG-ACRIN 
STS system must accompany the samples. 
Shipments to the MD Anderson Life Sciences Plaza may be done 
using the ECOG-ACRIN Central Biorepository and Pathology Facility 
(EA-CBPF) FedEx account. This account may NOT be used for 
shipment of materials to any other facility. Access to the shipping 
account for specimen shipments to the ECOG-ACRIN CBPF at MD 
Anderson can now only be obtained by logging into fedex.com with an 
account issued by the ECOG-ACRIN CBPF. For security reasons, the 
account number will no longer be given out in protocols, over the 
phone, or via email. If your site needs to have an account created, 
please contact the ECOG-ACRIN CBPF by email at 
eacbpf@mdanderson.org 
Ship to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
Life Science Plaza – Suite 910 
2130 West Holcombe Blvd, LSP9.4227 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or 
International Sites) 
Fax: 713-563-6506 
10.2 
Submissions to the D’Alessio Laboratory 
10.2.1 
Blood Submissions (MANDATORY) 
Peripheral blood samples must be shipped the day they are drawn. If 
you have any questions concerning collection and shipment please 
contact the Johns Hopkins and Asthma & Allergy Center, Attention Dr. 
D’Alessio or Andres Villabona-Rueba at email: avillab1@jhmi.edu or 
phone: 410-550-2612. 
NOTE: 
Local processing instructions are provided in Section 
10.2.1.2 below if blood is collected on Fridays or a day 
before a holiday by a US site and for all specimens 
collected by an international site. 
10.2.1.1 
Sample Preparation Guidelines 
Please completely fill all blood tubes as full as 
possible and collect the correct number and tube type 
as outlined below. 
Peripheral blood samples are to be collected: 
• 
Day 1 (+/- 5 days) 
• 
Day 14 (+/-5 days) 
• 
Day 28 (+/-5 days) 
At each time point please submit the following: 
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• 
Seven (7) FULL 10cc green top heparin tubes 
10.2.1.2 
Guidelines for Local Blood Processing 
The following instructions are for International sites and for 
sites who cannot avoid collecting samples on a Friday or 
day before a holiday. 
Local supplies are to be utilized to process, store and 
submit blood specimens that are processed locally. No 
kits, no supplies, and no additional funding support are 
available for locally processed research blood specimens. 
It is essential that all samples be labeled with the protocol 
number, patient caseID, specimen type, and timepoint/date 
of collection. 
Materials 
Abbreviation 
Name 
PBS 
Phosphate-buffered saline 
ACK 
ACK lysing buffer 
RLT buffer 
Qiagen Buffer RLT lysis buffer  
2-ME 
2-Mercaptoethanol 
Freezing media 
BAMBANKER 
Cell strainer 
Cell strainer 70um  
Processing Protocol: 
1. Read the directions and label the vials with the 
buffer/freezing medium and cell count. Provide the 
information in STS. 
2. Spin down the cells at 350g for 6 min at 4° C. 
3. Remove and SAVE all supernatant. 
a. The first 5mL should be aliquoted out in 1mL 
cryogenic vials. 
b. The remaining supernatant can be stored in 15 mL 
conical tubes (10mL per tube).  
4. Re-suspend cells in PBS according the pellet size (for 
good size pellet we use 5mL). 
a. If there is an exceptional amount of mucus present 
which does not allow to do cell count: filter the 
sample using a 70um cell strainer and wash the 
filter with 5mL PBS twice. 
b. If presence of red blood cells use ACK. The volume 
of ACK to use depends on the pellet size. (We 
usually do 3mL for 3mins in good size pellet) 
5. Do cell count. 
6. Aliquot small cell amount for Cytospin (50,000 to 
150,000 cells). 
a. Cytospin is done when having high cell counts. 
7. Spin down the cells at 350g for 6 min at 4° C. 
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8. Remove supernatant and re-suspend in freezing media 
according to cell count 
a. 2x106/tube in freezing medium for future FACS. 
b. 5x105 cell in 350uL RLT buffer and 3.3uL 2-ME. 
c. 1x105 cell/tube in freezing medium for TCR. 
9. Store the cells below -80° C. Ship on dry ice within one 
week of collection. 
Ship to:  
Johns Hopkins Asthma & Allergy Center 
Asthma and Allergy Building, Room 4A.44 
Johns Hopkins Bayview 
5501 Hopkins Bayview Circle 
Baltimore, MD, 21224 
Email: avillab1@jhmi.edu 
Phone: 410-550-2612 
10.3 
ECOG-ACRIN Sample Tracking System 
It is required (barring special circumstances) that all samples submitted on this 
trial be entered and tracked using the ECOG-ACRIN Sample Tracking System 
(STS). Samples which are not available for submission are also to be noted 
within STS. 
The software will allow the use of either 1) an ECOG-ACRIN user-name and 
password previously assigned (for those already using STS), or 2) a CTSU 
username and password. 
When you are ready to log the collection and/or shipment of the samples 
required for this study, please access the Sample Tracking System software by 
clicking https://webapps.ecog.org/Tst.  
Important: Please note that the STS software creates pop-up windows, so you 
will need to enable pop-ups within your web browser while using the software. A 
user manual and interactive demo are available by clicking this link: 
http://www.ecog.org/general/stsinfo.html. Please take a moment to familiarize 
yourself with the software prior to using the system. 
An STS generated shipping manifest must be generated and shipped with all 
sample submissions. 
Please direct your questions or comments pertaining to the STS to 
ecog.tst@jimmy.harvard.edu . 
Study Specific Notes: 
If the STS is unavailable, the Generic Specimen Submission Form (#2981) is to 
be used as a substitute for the STS shipping manifest. The completed form is to 
be faxed to the receiving laboratory the day the samples are shipped. Indicate 
the appropriate Lab on the submission form: 
• 
Johns Hopkins Asthma & Allergy Center 
• 
MDACC Life Sciences Plaza 
Retroactively enter all specimen collection and shipping information when STS is 
available. 
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10.4 
Use of Specimens in Research 
Materials will be processed and distributed to investigators for analysis for the 
research studies defined in Section 11. 
Specimens from patients who consented to allow their specimens to be used for 
undefined future ECOG-ACRIN approved research studies, including residuals 
from the mandatory diagnostic review, will be retained in an ECOG-ACRIN 
designated central repository. 
For this trial, specimens will be retained at the ECOG-ACRIN Central 
Biorepository and Pathology Facility.  
Specimens submitted will be processed to maximize their utility for current and 
future research projects. Tissue processing may include, but not limited to, 
extraction of DNA and RNA and construction of tissue microarrays (TMAs). DNA, 
RNA, serum, and plasma (if appropriate) will be isolated from the submitted 
peripheral blood specimens. 
Any residual blocks will be available for purposes of individual patient 
management on specific written request.  
If future use is denied or withdrawn by the patient, the specimens will be 
removed from consideration for use in any future research study. Pathology 
materials may be retained for documentation purposes or returned to the site. All 
other specimens will be destroyed per guidelines of the respective repository. 
10.5 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted will be tracked via the ECOG-ACRIN STS 
and receipt and\ usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized will be submitted by the laboratory to the 
ECOG-ACRIN Operations Office - Boston on a monthly basis in an electronic 
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11. 
Specimen Analyses: Diagnostic Review and Research Studies 
11.1 
Blood: MANAFEST and AUTOFEST 
With increasing appreciation that mutation-associated neoantigens (MANA) are 
an important target of anti-tumor T cell immunity and potential immune toxicity, 
simple and sensitive assays are critical to assess the broad repertoire of 
functional MANA-specific T cells in cancer patients. MANAFEST (Mutation 
Associated NeoAntigen Functional Expansion of Specific T-cells),14 integrates 
predicted MANAs identified through large-scale genomic sequencing (Section 
11.3) and computational modeling with single short term in vitro stimulation and 
deep sequencing of CDR3 regions to identify the repertoire of MANA-specific T 
cells in cancer patients based on antigen-specific clonal expansion. Each CDR3 
from expanded clones can then be used as a molecular barcode to identify and 
quantitate MANA-specific T cells in tumor sections and blood. To evaluate 
linkage between antibody (Section 11.4) and T-cell responses, the FEST assay, 
used previously in NSCLC patients with acquired resistance to anti-PD-1, to 
detect peripheral T-cell reactivity to mutation-associated neoantigens (MANAs) in 
resistant tumors, can also be used to evaluate CD-4 responses. In this study, this 
assay will also be used to evaluate CD4+ reactivity to autoantigens 
(AUTOFEST), together with MANAFEST-evaluated CD 8 responses to mutant 
peptides from patients’ tumors, and if detected, assessment for possible cross-
reactivity to wild-type peptide resulting in irAE. In this proposal, we would identify 
autoantibody hits to possible tumor mutations using pneumonitis patient sera and 
controls, and perform genomic sequencing of genes encoding identified 
autoantigens, using available tumor DNA. These assessments will be conducted 
by Kellie N. Smith, PhD and Drew M Pardoll, M.D., PhD, Department of 
Immunology at Johns Hopkins University. 
Sample Acquisition and Processing 
Blood samples will be taken as in Figure 1 (Section 11), and from patients 
enrolled in a JHU specimen collection study who did not develop irAEs, these 
patients will act as pre/post-PD-1 controls and will be matched as closely as 
possible for clinical and treatment characteristics. Blood will be shipped from 
participating study sites to JHU for processing.  
Methodology, Equipment and Reagents 
DNA will be extracted from peptide-stimulated T cells, archival tumor tissue, and 
pre- and post-treatment PBMC using a Qiagen DNA FFPE kit, DNA blood kit, or 
DNA blood mini kit (Qiagen). TCR Vb CDR3 sequencing will be performed using 
the survey (tissue and cultured cells) or deep (PBMC) resolution Immunoseq 
platforms (Adaptive Biotechnologies, Seattle, WA).46 Bioinformatic and 
biostatistical analysis of productive clones will be performed to assess the 
dynamics of peripheral T cells and to identify antigen-specific expansions. We 
will measure MANA-specific TCR expansions in stimulated cultures of 
autologous T cells. To assess T cell responses to autoantigens, candidate MHC 
class I and class II restricted epitopes respectively will be predicted from 
serologically identified autoantigens in (a) and analyzed by AUTOFEST. For 
MHCII restricted CD4+ responses, peptide epitopes (20-mers overlapping by 10 
amino acids) will be synthesized and used to stimulate autologous pre- and post-
treatment CD4+ T cells cultured for 10-days in the presence of cytokines. For 
CD8+ responses, NetMHCpan-predicted peptides matched to patient HLA-A and 
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–B alleles, will be tested. On day 10, we will isolate CD4+ T-cells and CD8+ T-
cells respectively using negative bead selection, and assess functionality. TCR 
Vβ deep sequencing will be performed on FFPE. This will allow us to match 
intratumoral TCR Vβ sequences with autoantigen specificity identified above. 
These will allow us to evaluate dynamic immunologic responses in pneumonitis. 
Quantification of Results 
We will present graphical representations of the genomic landscape pre-
treatment tumor tissue, and candidate MANAs detected in pre-treatment tumor 
tissue following after implementation of the neoantigen prediction pipeline. 
Epitope-specific expansion of each T cell clone detected in a culture will be 
compared to expansion of that clone in culture that did not undergo peptide 
stimulation and to every other peptide-stimulated culture. T-cell reactivity to a 
given epitope will be considered positive if there is at least 1 T-cell clone with 
significant expansion to the relevant peptide and every other peptide tested at a 
significance of <0.01 and an odds ratio of >5 to allow for sensitive, and specific 
antigen recognition. Autoantibodies, T-cell expansion, and cytokine levels will be 
summarized descriptively in pneumonitis vs. controls, by timepoint and treatment 
arm.  
11.2 
Blood: Autoantibody Analyses (MANDATORY) 
Autoantibody formation has been identified as a mechanism implicated in 
selected irAEs including CTLA4-mediated hypophysitis,47 and PD-1- thyroiditis.48 
These clinical observations have been made based on routine ELISA assays. 
We now have newer tools that allow us to link autoantibody to T-cell responses, 
through detection of antigen specific T-cell clones by TCR sequencing (outlines 
in Section 11.4), in both peripheral blood and tissue.25,26,27 We will leverage 
expertise in antibody discovery at JHU, as previously described in scleroderma 
patients with POL3RA-mutant cancers.6 In these cases, antibodies were 
identified using a novel immunoprecipitation (IP) assay followed by mass 
spectrometry sequencing, using patient sera pre/post event (present post, absent 
pre),32 based on molecular weights in the initial IP step and rigorous candidate 
autoantigen validation.7-12 We will also evaluate the linkage between antibody 
and T-cell responses, through AUTOFEST, as outlined above. These studies will 
be conducted by Kellie N. Smith, PhD. Department of Immunology and Livia 
Casciola-Rosen. Department of Rheumatology at Johns Hopkins University. 
Sample Acquisition and Processing 
Blood samples will be taken as in Figure 1 (Section 11), and from patients 
enrolled in a JHU specimen collection study who did not develop irAEs, these 
patients will act as pre/post-PD-1 controls and will be matched as closely as 
possible for clinical and treatment characteristics.  
11.3 
Blood: Cytokine Analyses (MANDATORY) 
It is postulated that irAEs may be an autoantibody-mediated condition, and that 
baseline and on-treatment elevations of certain cytokines may support this 
mechanism. Baseline IL17 levels have been elevated in melanoma patients who 
developed CTLA4-colitis. Cytokines such as 1L-17, IFN-γ and IL-4 are known to 
support humoral responses, via Fc region switching and increased 
immunoglobulin production.24,25 Moreover, colleagues at JHU identified that an 
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distress syndrome (ARDS), a similar diffuse alveolar damage process to PD-
1/PD-L1 pneumonitis.26 Thus, we propose that pneumonitis may be an 
autoantibody mediated process against tumor and/or self-antigens, identification 
of which could identify tumor-related biomarkers, or specific pneumonitis 
treatments (IVIG, IL17 mAb). These studies will be conducted by Kellie N. Smith, 
PhD. and Drew M. Pardoll, MD PhD. Department of Immunology at Johns 
Hopkins University. 
Sample Acquisition and Processing 
Blood samples will be taken as in Figure 1 (Section 11), and from patients 
enrolled in a JHU specimen collection study who did not develop irAEs, these 
patients will act as pre/post-PD-1 controls and will be matched as closely as 
possible for clinical and treatment characteristics.  
Methodology, Equipment and Reagents 
Positive peptides identified by AUTOFEST will be used in ELISpot and ICS 
assays to assess cytokine production at pre/post immunosuppression/PD-1, and 
in controls.  
11.4 
Sample Inventory Submission Guidelines  
Inventories of all samples submitted will be tracked via the ECOG-ACRIN STS 
and receipt and usability verified by the receiving laboratory. Inventories of 
specimens forwarded and utilized for the will be submitted by the laboratory to 
the ECOG-ACRIN Operations Office - Boston on a monthly basis in an electronic 
format defined by the ECOG-ACRIN Operations Office - Boston. 
11.5 
Lab Data Transfer Guidelines  
The data collected on the above mentioned laboratory research studies will be 
submitted electronically using a secured data transfer to the ECOG-ACRIN 
Operations Office - Boston by the investigating laboratories on a quarterly basis 
or per joint agreement between ECOG-ACRIN and the investigator. The quarterly 
cut-off dates are March 31, June 30, September 30, and December 31. Data is 
due at the ECOG-ACRIN Operations Office - Boston 1 week after these cut-off 
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12. 
Electronic Data Capture 
Please refer to the EAQ172 Forms Completion Guidelines for the forms submission 
schedule. Data collection will be performed exclusively in Medidata Rave. 
This study will be monitored by the Clinical Data Update System (CDUS) version 3.0. 
Cumulative CDUS data will be submitted quarterly from the ECOG-ACRIN Operations 
Office – Boston to CTEP by electronic means. 
13. 
Patient Consent and Peer Judgment 
Current FDA, NCI, state, federal and institutional regulations concerning informed 
consent will be followed. 
14. 
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57. Kendrick K, Baxi S, Smith R. Usefulness of the modified 0-10 Borg scale in 
assessing the degree of dyspnea in patients with COPD and asthma. Journal of 
Emergency Nursing 26:216-22, 2000 
58. Nishino M, Ramaiya NH, Awad MM, et al. PD-1 inhibitor-related pneumonitis in 
advanced cancer patients: Radiographic patterns and clinical course. Clin Cancer 
Res. 2016 Dec 15;22:6051-6060.  
59. Nishino M, Boswell EN, Hatabu H, Ghobrial IM, Ramaiya NH. Drug-Related 
Pneumonitis During Mammalian Target of Rapamycin Inhibitor Therapy: 
Radiographic Pattern-Based Approach in Waldenstrom Macroglobulinemia as a 
Paradigm. Oncologist. 2015;20: 1077-1083. 
60. Nishino M, Brais LK, Brooks NV, Hatabu H, Kulke MH, Ramaiya NH. Drug-related 
pneumonitis during mammalian target of rapamycin inhibitor therapy in patients with 
neuroendocrine tumors: a radiographic pattern-based approach. Eur J Cancer. 
2016;53: 163-170. 


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Appendix I 
 
Pathology Submission Guidelines 
The following items are included in Appendix I: 
1. Guidelines for Submission of Pathology Materials  
(instructional sheet for Clinical Research Associates [CRAs]) 
2. Instructional memo to submitting pathologists 
3. List of Required Materials for EAQ172 
4. ECOG-ACRIN Generic Specimen Submission Form (#2981) 
 


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Guidelines for Submission of Pathology Materials 
The following items should always be included when submitting pathology materials to the 
ECOG Pathology Coordinating Office: 
• 
Institutional Surgical Pathology Report 
• 
Pathology materials (see attached List of Required Material) 
• 
ECOG-ACRIN Sample Tracking System (STS)-Generated Shipping Manifest 
Instructions: 
5. Adequate patient identifying information must be included with every submission. It is 
strongly recommended that full patient names be provided. The information will be 
used only to identify patient materials, will expedite any required communications 
with the institution (including site pathologists). 
6. List required path materials for each specified timepoint separately, as per below 
b) Tumor tissue: Block. If block cannot be submit one H&E and at least 10 slides 
(number the slides in the order sectioned). Provide the Type of sample (cytology, 
core biopsy, resection specimen) and Source of tissue (e.g., lung, liver) 
7. Since blocks are being used for laboratory studies, the materials may potentially be 
exhausted. It is important that the site retains what they need for purposes of patient 
care and management. 
8. Keep a copy of the STS-manifest or Submission Form for your records. 
9. Double-check that ALL required forms, reports and pathology samples are included 
in the package. 
Pathology specimens submitted WILL NOT be processed by the Pathology 
Coordinating Office until all necessary items are received. 
Mail pathology materials to: 
MD Anderson Cancer Center CBPF 
Mike Balco 
Life Science Plaza - Suite 910 
2130 West Holcombe Boulevard, LSP9.4227 
Houston, TX 77030 
Phone: Toll Free 1-844-744-2420 (713-745-4440 Local or International Sites) 
Fax: 713-563-6506 
Email: eacbpf@mdanderson.org 
If you have any questions concerning the above instructions or if you anticipate any 
problems in meeting the pathology material submission deadline of one month, contact 
the Pathology Coordinator at the ECOG-ACRIN Central Biorepository and Pathology 
Facility. 
Rev. Add2 
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MEMORANDUM 
TO:  
__________________________________________________ 
 
(Submitting Pathologist) 
FROM: 
Edmund Lattime, PhD, Chair 
 
ECOG-ACRIN Laboratory Science and Pathology Committee 
DATE:  
____________________________________ 
SUBJECT: 
Submission of Pathology Materials for EAQ172 
 
The patient named on the attached request has been entered onto an ECOG-ACRIN 
protocol by _____________________________ (ECOG-ACRIN Investigator). This 
protocol requires the submission of pathology materials for laboratory studies. 
Keep a copy of the submission for your records and return any relevant completed 
forms, the surgical pathology report(s), the slides and/or blocks and any other required 
material (see List of Required Material) to the Clinical Research Associate (CRA). The 
CRA will forward all required pathology material to the ECOG-ACRIN Central 
Biorepository and Pathology Facility (CBPF). 
Pathology materials submitted for this study will be retained at the ECOG-ACRIN Central 
Repository for future studies per patient consent. Paraffin blocks will be returned upon 
request for purposes of patient management. 
Please note: Since blocks are being used for laboratory studies, in some cases the 
material may be depleted, and, therefore, the block may not be returned. 
If you have any questions regarding this request, please contact the Central 
Biorepository and Pathology Facility at (1-844-744-2420 (713-745-4440 Local or 
International Sites) or email: pillei1@jhmi.edu. 
The ECOG-ACRIN CRA at your institution is: 
Name: ___________________________________  
Address: _________________________________  
Phone: __________________________________  
Thank you. 
 


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ECOG-ACRIN Generic Specimen Submission Form  
Form No. 2981v3 
Page 1 of 1 
Institution Instructions: This form is to be completed and submitted with all specimens ONLY if the Sample Tracking System (STS) is not available. Use one form per 
patient, per time- point. All specimens shipped to the laboratory must be listed on this form. Enter all dates as MM/DD/YY. Keep a copy for your files. Retroactively log all 
specimens into STS once the system is available. Contact the receiving lab to inform them of shipments that will be sent with this form. 
Protocol Number    
 
Patient ID     
 
Patient Initials   Last  
 First     
 
Date Shipped    
 
Courier     
 Courier Tracking Number   
 
Shipped To (Laboratory Name)   
 
Date CRA will log into STS    
 
FORMS AND REPORTS: Include all forms and reports as directed per protocol, e.g., pathology, cytogenetics, flow cytometry, patient consult, etc. 
Required fields for all samples 
Additional fields for tissue submissions 
Completed by  
Receiving Lab 
Protocol Specified Timepoint: 
Sample Type  
(fluid or fresh tissue, 
include collection tube type) 
Quantity 
Collection  
Date and Time 24 HR 
Surgical or  
Sample ID 
Anatomic  
Site 
Disease Status  
(e.g., primary, mets, 
normal) 
Stain or 
Fixative 
Lab ID 
 
Fields to be completed if requested per protocol. Refer to the protocol-specific sample submissions for additional fields that may be required. 
Leukemia/Myeloma 
Studies: 
Diagnosis 
Intended Treatment Trial 
Peripheral WBC Count (x1000) 
Peripheral Blasts % 
Lymphocytes % 
 
 
 
 
Study Drug 
Information: 
Therapy Drug Name 
Date Drug Administered 
Start Time 24 HR 
Stop Time 24HR 
 
 
 
 
Caloric Intake: 
Date of Last Caloric Intake 
Time of Last Caloric Intake 24HR 
 
CRA Name   
 
CRA Phone   
 
CRA Email   
 
Comments 
 


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Appendix II 
 
Patient Thank You Letter 
We ask that the physician use the template contained in this appendix to prepare a letter 
thanking the patient for enrolling in this trial. The template is intended as a guide and can 
be downloaded from the web site at http://www.ecog.org. As this is a personal letter, 
physicians may elect to further tailor the text to their situation. 
This small gesture is a part of a broader program being undertaken by ECOG-ACRIN 
and the NCI to increase awareness of the importance of clinical trials and improve 
accrual and follow-through. We appreciate your help in this effort. 
 ________________________________________________________________________  
 
[PATIENT NAME] 
[DATE] 
[PATIENT ADDRESS] 
 
 
Dear [PATIENT SALUTATION], 
 
Thank you for agreeing to take part in this important research study. Many questions 
remain unanswered in cancer. With the participation of people like you in clinical trials, 
we hope to improve treatment and quality of life for those with your type of cancer. 
We believe you will receive high quality, complete care. I and my research staff will 
maintain very close contact with you. This will allow me to provide you with the best care 
while learning as much as possible to help you and other patients. 
On behalf of [INSTITUTION] and ECOG-ACRIN, we thank you again and look forward to 
helping you. 
 
 
Sincerely, 
 
 
 
 
[PHYSICIAN NAME] 
 


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Appendix III 
 
ECOG Performance Status 
PS 0 
Fully active, able to carry on all pre-disease performance without restriction 
PS 1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature e.g., light house work, office work. 
PS 2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
PS 3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
PS 4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
 


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Appendix IV  
 
Calculation of PaO2/FiO2 Ratio 
Guidelines for assessment of PaO2/FiO2 ratio 
- 
PaO2/FiO2 ratio is the ratio derived from dividing the partial pressure of arterial oxygen 
(PaO2), by the FiO2, or fraction of inspired oxygen that a study subject is receiving. 
- 
The PaO2/FiO2 is a measurement of oxygenation that is commonly used in mechanically 
ventilated patients. 
- 
A normal PaO2/FiO2 ratio is 300-500. Values that are lower than <300 are considered 
abnormal and reflect abnormal gas exchange in the lung, while values below 200 are 
associated with significant hypoxemia. 
- 
The PaO2/FiO2 will be calculated from an arterial blood gas assessment obtained after 20-
30 minutes of stable oxygen requirements/supplemental oxygen use, during which time the 
study subject can maintain Sp02 of 92-94%. 
- 
The arterial blood gas assessment will be obtained either through arterial puncture, or by 
acquisition of a sample through an indwelling arterial catheter, if the study subject already 
has one in place. 
- 
The FiO2 will be calculated depending on the fraction of inspired oxygen the study subject is 
receiving, as outlined below. 
- 
The study subject’s oxygenation by pulse oximetry, respiratory rate, and method of oxygen 
delivery at the time of the AGB assessment, will also be recorded by the study team in 
Appendix V. 
- 
An institutional pulse oximeter device will be used to record pulse oximetry. 
a) Assessment of FIO2 (fraction of inspired oxygen) 
- 
Hospitalized study subjects will lie in a supine position for 20-30 minutes before FiO2 is 
recorded. 
- 
Study subjects in the outpatient setting may be either seated or supine for 20-30 minutes 
before FiO2 is recorded. 
- 
For patients who are on room air at the time of PaO2/FiO2 calculation: 
• 
FiO2 will be 0.21 (21% of room air is estimated to contain oxygen). 
- 
For patients receiving high-flow, humidified, supplemental oxygen by facemask: 
• 
High-flow oxygen will be delivered at a rate of 50L/minute to minimize room air 
entrainment. 
• 
High-flow Oxygen will be delivered through a humidifier for patient comfort. 
• 
FiO2 setting on the high-flow machine will start at 30%, and will be titrated until the 
study subject maintains an SpO2 of 92-94% for 20-30 minutes. 
• 
Study subjects receiving supplemental oxygen by nasal cannula may be switched to 
high-flow oxygen by facemask as detailed above, to minimize room air entrainment. 
The choice to switch to facemask or mouthpiece with nasal clip (below) will be at the 
discretion of the treating investigator and the availability of equipment and resources 
at the study site. 


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- 
For patients receiving 100% supplemental oxygen through a mouthpiece with one-way 
valve and nose clip: 
• 
Study subjects receiving supplemental oxygen by nasal cannula, may be switched to 
100% supplemental oxygen through a mouthpiece with one-way valve and nose clip, 
to minimize room air entrainment. The choice to switch to facemask or mouthpiece 
with nasal clip (below) will be at the discretion of the treating investigator and the 
availability of equipment and resources at the study site. 
• 
FiO2 will be 1.0 
- 
For patients receiving supplemental oxygen through a non-invasive ventilation device 
(e.g. CPAP, BiPAP): 
• 
FiO2 settings on the non-invasive ventilation device will be titrated until the study 
subject maintains an SpO2 of 92-94% for 20-30 minutes. 
- 
For patients receiving supplemental oxygen through invasive ventilation (intubation): 
• 
FiO2 settings on invasive ventilation will be titrated until the study subject maintains 
an SpO2 of 92-94% for 20-30 minutes. 
• 
The PEEP (positive end expiratory pressure) on the ventilator will be set at  
5mmHg. 
• 
The tidal volume will be set at 6-8ml/kg of predicted body weight. 
- 
The FiO2 will be recorded by the study team as outlined in Appendix V. 
b) Assessment of PaO2: Arterial Blood Gas assessment 
- 
The ABG (arterial blood gas assessment) will be obtained after the study subject has 
received 20-30 minutes of stable oxygen requirement/use and the FiO2 has been 
recorded, as outlined above. 
- 
The ABG will be obtained by either arterial puncture, or acquisition of a sample from an 
indwelling arterial catheter. 
- 
Study subjects who are hospitalized will lie flat in a supine position while this 
assessment is completed. 
- 
Study subjects who are in the outpatient setting may be either be in a seated or supine 
position while this assessment is completed. 
- 
For study subjects undergoing an arterial puncture for ABG assessment: 
• 
The area for acquisition of the sample (skin overlying radial artery) will be cleaned 
with an alcohol wipe. 
• 
The arterial blood gas assessment will be obtained using aseptic technique. 
• 
The sample will be obtained by local study staff. 
• 
The sample will be processed through a local ABG machine immediately, to yield a 
PaO2 result. 
• 
The PaO2 result will be recorded in the study case report form. 
- 
For study subjects undergoing ABG assessment from an existing indwelling arterial 
catheter: 
• 
The tip of the arterial catheter will be cleaned with an alcohol wipe. 
• 
A sample of arterial blood will be obtained from the indwelling catheter, using aseptic 
technique. 
• 
The sample will be obtained by local study staff. 


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• 
The sample will be processed through a local ABG machine immediately, to yield a 
PaO2 result. 
• 
The PaO2 result will be recorded in the study case report form. 


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Appendix V 
 
PaO2/FiO2 Recording Form 
NOTE: 
The PF ratio will be measured without a bronchodilator. 
 
 
PaO2 
(mmHg) 
FiO2 
(fraction) 
PaO2/ 
FiO2 
 
Respiratory 
Rate 
SpO2 
Method of 
oxygen delivery 
(Please circle) 
Method of 
ABG 
assessment 
(Please 
circle) 
Day 
1 
 
 
 
 
 
1. Room air 
2. High-flow 
oxygen 
(facemask) 
3. Oxygen 
(mouthpiece 
+ nose clip) 
4. Non-invasive 
ventilation 
5. Invasive 
Ventilation 
1. Arterial 
puncture 
 
2. Arterial 
catheter 
Day 
14 
 
 
 
 
 
1. Room air 
2. High-flow 
oxygen 
3. Oxygen 
(mouthpiece 
+ nose clip) 
4. Non-invasive 
ventilation 
5. Invasive 
Ventilation 
1. Arterial 
puncture 
 
2. Arterial 
catheter 
Day 
28 
 
 
 
 
 
1. Room air 
2. High-flow 
oxygen 
3. Oxygen 
(mouthpiece 
+ nose clip) 
4. Non-invasive 
ventilation 
5. Invasive 
Ventilation 
1. Arterial 
puncture 
 
2. Arterial 
catheter 
 
 


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Appendix VI  
 
Guidelines for Infliximab Administration 
*Biosimilars and other formulations of infliximab not stated below, will not be permitted. 
1. Calculate the dose, total volume of reconstituted Infliximab solution required and the 
number of Infliximab vials needed. Each Infliximab vial contains 100 mg of the infliximab 
antibody. 
2. Reconstitute each Infliximab vial with 10 mL of Sterile Water for Injection, USP, using a 
syringe equipped with a 21-gauge or smaller needle as follows: Remove the flip-top from 
the vial and wipe the top with an alcohol swab. Insert the syringe needle into the vial 
through the center of the rubber stopper and direct the stream of Sterile Water for 
Injection, USP, to the glass wall of the vial. Gently swirl the solution by rotating the vial to 
dissolve the lyophilized powder. Avoid prolonged or vigorous agitation. DO NOT SHAKE. 
Foaming of the solution on reconstitution is not unusual. Allow the reconstituted solution 
to stand for 5 minutes. The solution should be colorless to light yellow and opalescent, 
and the solution may develop a few translucent particles as infliximab is a protein. Do 
not use if the lyophilized cake has not fully dissolved or if opaque particles, discoloration, 
or other foreign particles are present. 
3. Dilute the total volume of the reconstituted Infliximab solution dose to 250 mL with sterile 
0.9% Sodium Chloride Injection, USP, by withdrawing a volume equal to the volume of 
reconstituted Infliximab from the 0.9% Sodium Chloride Injection, USP, 250 mL bottle or 
bag. Do not dilute the reconstituted Infliximab solution with any other diluent. Slowly add 
the total volume of reconstituted Infliximab solution to the 250 mL infusion bottle or bag. 
Gently mix. The resulting infusion concentration should range between 0.4 mg/mL and 4 
mg/mL. 
4. The Infliximab infusion should begin within 3 hours of reconstitution and dilution. The 
infusion must be administered over a period of not less than 2 hours and must use an 
infusion set with an in-line, sterile, non-pyrogenic, low-protein-binding filter (pore size of 
1.2 µm or less). The vials do not contain antibacterial preservatives. Therefore, any 
unused portion of the infusion solution should not be stored for reuse. 
5. No physical biochemical compatibility studies have been conducted to evaluate the co-
administration of Infliximab with other agents. Infliximab should not be infused 
concomitantly in the same intravenous line with other agents. 
6. Parenteral drug products should be inspected visually before and after reconstitution for 
particulate matter and discoloration prior to administration, whenever solution and 
container permit. If visibly opaque particles, discoloration or other foreign particulates are 
observed, the solution should not be used. 
 


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Appendix VII 
 
Instructions for IVIG Administration 
*Biosimilars and other formulations of IVIG not stated below, will not be permitted. 
Ordering Immunoglobulin Products: 
1. Orders for immunoglobulin products must be calculated according to the patient’s 
weight. For patients with BMI greater than 30 Kg/m2, use adjusted body weight with 40% 
correction factor to determine dose. 
Dispensing Immunoglobulin Products: 
Immunoglobulin should be prepared and dispensed in accordance with the local Pharmacy 
policy and policies on drug preparation, labeling and checking. 
Assessment: 
1. Obtain patient’s baseline height and weight on every admission. 
2. For all inpatients, assess temperature, pulse, blood pressure and respiratory rate 
a. Prior to start of infusion. 
b. Every 15 minutes X 2. 
c. Then every 2 hours for the duration of the infusion. 
3. Perform a visual/verbal assessment of the patient, refer to the Infusion Reaction Form, 
with each rate change to detect symptoms of adverse effects. 
4. Maintain strict I&O (input and output) in high risk patients (e.g., pre-existing heart failure 
and renal failure). 
Administration and Monitoring of IVIG: 
1. Infuse IVIG via infusion pump or syringe pump for all areas. 
2. IVIG IS NOT COMPATIBLE WITH ANY OTHER DRUG. No other medication should be 
concurrently administered through the IV line. Flush with D5W or NS if emergency use of 
the line is necessary. Privigen, Gammagard Liquid and Gamunex-C cannot be diluted or 
mixed with NSS. If a flush or interruption of the line is needed, D5W or NS can be used 
the flush the infusion line. 
3. DO NOT AGITATE THE BOTTLE. TREAT IT GENTLY. Drug should not be turbid. Do 
not transport via the pneumatic tube. 
4. It is recommended that immunoglobulin to be administered 2 hours post blood product 
administration. 
5. Gammagard Liquid, and Gamunex-C and Privigen do not require a filter. EXCEPTION: 
Gammagard S/D® ONLY, must have a 0.22 micron in-line filter to be added to the IV 
tubing. 
6. Infusion rates are weight based. Refer to section B below: IVIG Infusion Rates for 
Privigen, Gammagard Liquid and Gamunex-C for infusion rates or refer to product-
specific prescribing information. Titrate as follows: 
a. Start infusion slowly, at a rate of 0.5 mL/kg/hr for the first 30 minutes. 
b. IVIG Infusion Rates for Privigen, Gamunex-C, and Gammagard Liquid: Advance rate 
if no adverse reaction observed. 
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i. 0.5 mL/kg/hr (0.8 mg/kg/min) for 30 minutes. 
ii. 1 mL/kg/hr (1.7 mg/kg/min) for 31-60 minutes. 
iii. 2 mL/kg/hr (3.3 mg/kg/min) for 61-90 minutes. Maximum rate for patients with 
documented renal failure, creatinine clearance less than 60ml/min 
iv. 5 mL/kg/hr 8.3 mg/kg/min) for 90 minutes to completion of infusion minutes.  
v. 5 mL/kg/hr maximum rate for remainder of infusion for all IVIG indications. 
7. For patients with documented renal failure (creatinine clearance less than 60ml/min) or 
at risk for renal failure, start at the minimum infusion rate of 0.5 mL/kg/hr for 30 minutes 
of the infusion (note: this applies to both Privigen, Gammagard, and Gamunex-C). The 
rate may then be increased according to the above protocol until a maximum rate of 
2ml/kg/hr is reached or based on patient tolerability if lower. 
8. If the patient experiences minor symptoms such as fever (temp greater than 38ºC), 
headache, chills or flu-like symptoms: 
a. Stop the infusion and notify prescriber. 
b. Obtain vital signs. 
c. Once symptoms have resolved, advanced practitioner (RN, NP, or MD) will 
determine if the infusion may be restarted. 
d. Rate should be restarted at the next lowest rate from when it was stopped. 
9. In case of hypotension, urticaria, signs/symptoms of fluid overload or other symptoms of 
anaphylaxis: 
a. Discontinue IVIG infusion and IMMEDIATELY notify the AP. 
b. With AP's order, start oxygen at 6 Liters per minute by facemask if indicated for 
adults. For pediatric patients, provide oxygen as appropriate if indicated. 
c. Obtain vital signs. 
 


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Appendix VIII 
 
Patient Pill Calendar 
This is a calendar on which you are to record the time and number of tablets of oral 
corticosteroids you take each day (these include either: prednisone or methylprednisolone). You 
should take your scheduled dose of each pill. Pills should be taken with food. Note the times 
and the number of corticosteroid tablets that you take each day. If you develop any side effects, 
please record them and anything you would like to tell the doctor in the space provided. Bring 
any unused tablets and your completed pill calendar to your doctor’s visits. Since the 
corticosteroid dose is based on a patient’s weight, the specific corticosteroid taper schedule will 
depend on patient weight. A reduction in corticosteroid dose by 20-25% per week until stop will 
yield a 4-6 week taper. You could be on the steroid for up to 56 days.* 
 
Patient Initials: _____________ Patient Study ID: ________________ 
 
DAY 
Date 
 
 
 
Month  Day Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you think 
would be of interest.) 
1 
 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 
 
Rev. Add2 


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DAY 
Date 
 
 
 
Month  Day Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you think 
would be of interest.) 
19 
 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
29 
 
 
 
 
 
 
 
 
30 
 
 
 
 
 
 
 
 
31 
 
 
 
 
 
 
 
 
32 
 
 
 
 
 
 
 
 
33 
 
 
 
 
 
 
 
 
34 
 
 
 
 
 
 
 
 
35 
 
 
 
 
 
 
 
 
36 
 
 
 
 
 
 
 
 
37 
 
 
 
 
 
 
 
 
38 
 
 
 
 
 
 
 
 
39 
 
 
 
 
 
 
 
 
40 
 
 
 
 
 
 
 
 
41 
 
 
 
 
 
 
 
 
42 
 
 
 
 
 
 
 
 
43 
 
 
 
 
 
 
 
 
44 
 
 
 
 
 
 
 
 
45 
 
 
 
 
 
 
 
 
46 
 
 
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 
48 
 
 
 
 
 
 
 
 
49 
 
 
 
 
 
 
 
 
50 
 
 
 
 
 
 
 
 


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DAY 
Date 
 
 
 
Month  Day Year 
Time pills 
taken 
 
 
AM       PM 
Number of 
pills taken 
 
 
AM      PM 
Use the space below to make notes 
about things you would like to tell the 
doctor (including unusual symptoms 
you experience, other medicine you 
have taken and anything else you think 
would be of interest.) 
51 
 
 
 
 
 
 
 
 
52 
 
 
 
 
 
 
 
 
53 
 
 
 
 
 
 
 
 
54 
 
 
 
 
 
 
 
 
55 
 
 
 
 
 
 
 
 
56 
 
 
 
 
 
 
 
 
*Prednisone 1mg/kg is the equivalent of methylprednisolone 0.8mg/kg orally or intravenously. 
Patient Signature: _______________________________________ Date: ________________ 
Reviewing Staff Signature: _______________________________ Date: ________________ 
 


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Appendix IX 
 
Patient Clinical Trial Wallet Card 
 
 
CLINICAL TRIAL WALLET CARD 
Show this card to all of your 
healthcare providers and keep it 
with you in case you go to the 
emergency room. 
Patient Name:        
Diagnosis:        
Study Doctor:       
Study Doctor Phone #:       
NCI Trial #:  EAQ172 
Study 
Drug(S): 
 
Infliximab, 
Intravenous 
immunoglobulin (IVIG) 
 
 
Version: February 2020 
For more information: 1-800-4-CANCER 
cancer.gov | clinicaltrials.gov 


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Appendix X 
 
EAQ172 Collection and Shipping Kit Order Instructions 
Specimen Collection/Shipping Kits are being provided by CENETRON CENTRAL 
LABORATORIES for US and Canadian sites only and are to be ordered ONLINE. 
Kit supplies are limited and starter kits are not to be requested. Kit requests should be made 
after patient has consented to participate in the trial. If kits are not available, sites are requested 
to utilize institutional supplies to collect and submit the blood specimens. 
Questions regarding kits can be directed to projectmanagement@cenetron.com or call the 
Cenetron Clinical Trials Group at (512) 439-2000. 
Ordering Process: 
• 
Following randomization of the patient to the trial, go to the website www.cenetron.com and 
click on the ‘Order Kits’ button at the top right. It is recommended that kits be ordered same 
day as patient randomization. 
• 
The order form is not study specific and can be used for any study. Complete the online 
form as follows: 
• 
Sponsor (REQUIRED): ECOG-ACRIN 
• 
Contact Name (REQUIRED): Name of the institution kit contact.  
• 
Protocol Number (REQUIRED): EAQ172 
• 
Phone Number (REQUIRED): Phone number of the kit contact. Please ensure that this 
is a number that can be reached from an external caller 
• 
Site Number (REQUIRED): Institution NCI Site ID 
• 
FAX Number: Fax number of the kit contact 
• 
Investigator: Last name of the kit contact is adequate 
• 
Email (REQUIRED): Email of the institution kit contact. Must be entered twice to confirm 
• 
Date Supplies Needed (REQUIRED): Add three (3) business days or more to order 
date. (Reminder that weekends and holidays must also be considered in this timeline) 
• 
KIT NAME (REQUIRED): EAQ172 Collection Kit 
• 
Quantity: 1 
• 
Comments: Provide EAQ172 Patient Case ID# and full shipping address 
• 
Patient Case ID =’ ##### 
• 
Ship Kit to’ name of the individual to whom the kit is being shipped. (May be different 
than the kit contact provided above) 
• 
Full street address, town, state and zip code 
• 
Answer the security question 
 
Please complete this form correctly, including the valid ECOG-ACRIN patient case 
number and complete shipping address. If information is missing the kit processing will 
be delayed. 
Rev. Add2