Clinical trial NCT03325166
Conditions: Lung Carcinoma Metastatic in the Brain Stage IV Lung Non-Small Cell Cancer AJCC v7
Sponsor: OHSU Knight Cancer Institute
Start date: 2017-11-03; Completion date: 2021-03-01
Enrollment: 2 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot phase II trial study evaluates the usefulness of the ferumoxytol steady state magnetic resonance imaging (MRI) technique for response assessment after pembrolizumab and radiation therapy in non-small cell lung cancer that has spread to the brain (brain metastases). The interactions of monoclonal antibodies such as pembrolizumab, and the body's immune system may result in an anti-tumor effect. However, it may also increase inflammation around the tumor which cannot be differentiated from true tumor growth on standard MRI. This study evaluates ferumoxytol as an MRI contrast agent to differentiate this treatment related inflammation from true tumor growth.

Detailed description:
PRIMARY OBJECTIVE:

I. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV) measured by steady state magnetic resonance imaging (MRI) with ferumoxytol in predicting true versus (vs) pseudoprogression after stereotactic radiosurgery (SRS) and intravenous (IV) pembrolizumab in subjects with brain metastases from non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. Evaluate the safety and tolerability of pembrolizumab when given with SRS in subjects with brain metastasis.

II. Evaluate progression free survival, overall survival, best response in brain disease, best response in systemic disease, and duration of best responses of brain and systematic diseases.

EXPLORATORY OBJECTIVES:

I. Compare the immune response as determined by the volume, pattern and intensity of delayed (24 hour \[hr\]) ferumoxytol uptake between subjects who develop true vs pseudoprogression.

II. Investigate the serum immunological parameters and correlate clinical as well as radiological response with systemic immune response to pembrolizumab as measured by immunological panel.

III. Compare the changes percentage expression in PDL-1 in the biopsy tissue before and after therapy at the time of progression.

IV. In subjects with measurable systemic lesions, investigate the feasibility of measuring vascular volume fraction (VVF), vessel size index (VSI) and vessel density index (VDI) as surrogate for response (true vs. pseudoprogression, as measured with Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1 criteria).

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years (or up to 32 cycles) in the absence of disease progression or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI at baseline, 12 weeks after radiation, at suspected radiographic progression, and 6 weeks after suspected radiographic progression.

After completion of study treatment, patients are followed up at 30 days, every 12 weeks for up to 1 year, and then every 6 months thereafter.

Arms: arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years (or up to 32 cycles) in the absence of disease progression or unacceptable toxicity. Patients also receive ferumoxytol IV and undergo MRI at baseline, 12 weeks after radiation, at suspected radiographic progression, and 6 weeks after suspected radiographic progression.
Interventions: intervention 1: Ferumoxytol intervention 2: Laboratory Biomarker Analysis intervention 3: Magnetic Resonance Imaging intervention 4: Pembrolizumab
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Undergo MRI intervention 4: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
Product:  Pembrolizumab 
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SPONSOR: Oregon Health & Science University 
OHSU eIRB #16709  
 
 
 
 NCT#:  NCT03325166 
 
TITLE: The use of perfusion MRI using ferumoxytol and small molecular weight 
gadolinium (Gd) agents to assess response to pembrolizumab in brain metastases and 
systemic lesions in NSCLC: A comparison of imaging modalities to address brain 
metastases, pseudoprogression and systemic lesion tumor flare (neuro-check pilot) 
 
 
Principal Investigator: 
 
Edward Neuwelt, MD 
Professor 
Department of Neurology 
 
 
 
 
 
Oregon Health & Science University 
 
 
 
 
 
(503) 494-5626 
 
Co-Investigators: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Guang Fang, MD, PhD 
 
 
 
 
 
Director of Clinical Flow Cytometry Laboratory 
 
 
 
 
 
Director of Hematopathology Fellowship Program 
 
 
 
 
 
Department of Pathology 
 
 
 
 
 
Oregon Health and Science University 
 
 
 
 
 
(503)-494-9439 
 
 
 
 
 
 
Biostatistician: 
 
 
Rongwei (Rochelle) Fu, PhD  
 
 
 
 
 
 
 
Professor of Biostatistics  
 
 
 
 
 
Department of Public Health and Preventive Medicine 
 
Oregon Health & Science University  
 
(503) 494-6069 
 
(503) 494-4981 (FAX) 
 
 
 
 
 
Data Management/ 


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Study Coordinators:  
Lisa Muir, MPA, CCRP 
 
 
 
Department of Neurology 
 
Oregon Health & Science University 
 
(503) 494-5626 
 
(503) 494-5627 (FAX) 
 
 
  
 
 
 
Amy Huddleston, MPA, CCRP 
 
Oregon Health & Science University 
 
(503) 494-5626 
 
(503) 494-5627 (FAX) 
 
 


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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY ............................................................................................. 8 
2.0 
TRIAL DESIGN ................................................................................................... 8 
2.1 
Trial Diagram ................................................................................................. 10 
3.0 
OBJECTIVES & Rationale ................................................................................ 10 
3.1 
Primary Objective .......................................................................................... 10 
2. 
Secondary Objectives...................................................................................... 10 
3. 
Evaluate the safety and tolerability of pembrolizumab when given with 
SRS in subjects with brain metastasis............................................................. 10 
3.2 
Exploratory Objectives ................................................................................... 11 
4.0 
BACKGROUND & RATIONALE ..................................................................... 12 
4.1 
Burden of Disease: brain metastases from non-small cell lung carcinoma..... 12 
4.2 
Immuno-therapy in the brain ......................................................................... 12 
4.3 
Challenges in Trial Design for Brain Metastases............................................ 13 
4.4 
Response Assessment in Brain Metastases...................................................... 14 
4.5 
Assessing Pseudoprogression with Ferumoxytol ............................................ 14 
4.6 
Trial Description ............................................................................................. 23 
4.7 
Pharmaceutical and Therapeutic Background ............................................... 24 
4.8 
Preclinical and Clinical Trial Data ................................................................. 26 
4.8.1 
Rationale for the Trial and Selected Subject Population ................................... 29 
4.8.2 
Rationale for Dose Selection/Regimen/Modification ....................................... 31 
4.8.3 
Rationale for Endpoints .................................................................................. 32 
4.8.4 
Biomarker Research End Points...................................................................... 32 
5.0 
METHODOLOGY ............................................................................................. 32 


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5.1 
Diagnosis/Condition for Entry into the Trial.................................................. 32 
5.1 
Subject Inclusion Criteria............................................................................... 33 
5.2 
Subject Exclusion Criteria .............................................................................. 34 
5.3 
Subject Withdrawal/Discontinuation Criteria................................................ 35 
5.3.1 
Discontinuation of Study Therapy after CR..................................................... 36 
5.3.2 
Subject Replacement Strategy ........................................................................ 36 
5.3.3 
Clinical Criteria for Early Trial Termination ................................................... 37 
6.0 
Schedule of Events .............................................................................................. 38 
7.0 
Treatment Plan and Procedures ......................................................................... 41 
7.1 
Trial Treatments ............................................................................................. 41 
7.1.1 
Timing of Dose Administration ...................................................................... 41 
7.2 
Study procedures narrative ............................................................................ 42 
7.3 
Informed Consent ........................................................................................... 43 
7.4 
Trial Procedures ............................................................................................. 44 
7.4.1 
Clinical procedures: ....................................................................................... 44 
7.4.2 
Lab tests: see Table 5 ..................................................................................... 45 
7.4.3 
Imaging: ........................................................................................................ 47 
7.4.4 
Adverse Event Monitoring ............................................................................. 47 
7.4.5 
Post-study anticancer therapy status ................................................................ 48 
7.4.6 
Safety Follow-Up Visit: 30 days post discontinuation...................................... 48 
7.4.7 
Follow-up ...................................................................................................... 48 
7.4.8 
Survival Follow-up when off study ................................................................. 48 
7.4.9 
Second Course Phase (Retreatment Period) ..................................................... 48 
7.5 
Dose Modification ........................................................................................... 49 


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7.6 
Trial Blinding/Masking................................................................................... 52 
7.7 
Randomization or Treatment Allocation ........................................................ 52 
7.8 
Stratification ................................................................................................... 52 
7.9 
Concomitant Medications/Vaccinations (allowed & prohibited) .................... 52 
7.9.1 
Acceptable Concomitant Medications ............................................................. 52 
7.9.2 
Prohibited Concomitant Medications and Therapies ........................................ 52 
7.10 
Pharmacokinetic/Pharmacodynamic Evaluations .......................................... 54 
7.11 
Blood Collection for Anti-Pembrolizumab Antibodies ................................... 54 
7.12 
Withdrawal/Discontinuation........................................................................... 54 
7.13 
Blinding/Unblinding ....................................................................................... 54 
7.14 
Diet/Activity/Other Considerations ................................................................ 54 
7.15 
Contraception ................................................................................................. 54 
7.16 
Use in Pregnancy ............................................................................................ 55 
7.17 
Use in Nursing Women ................................................................................... 55 
8.0 
Tumor Imaging, Assessment of Disease and Biomarkers................................... 55 
8.1 
Imaging Schedule............................................................................................ 55 
8.2 
Response assessment ....................................................................................... 56 
8.2.1 
Brain Lesions:................................................................................................ 56 
8.2.2 
Systemic Lesions: .......................................................................................... 57 
8.3 
Contrast agents dosing and administration .................................................... 57 
2. 
Delayed (24h) parenchymal phase ferumoxytol scan ....................................... 58 
8.4 
Image processing............................................................................................. 58 
8.4.1 
For CNS lesions: ............................................................................................ 58 
8.4.2 
For systemic lesions ....................................................................................... 59 


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8.5 
Tumor Tissue Collection and Correlative Blood Biomarker Studies ............. 60 
8.5.1 
Blood Biomarkers .......................................................................................... 60 
8.5.2 
Tissue Biomarkers ......................................................................................... 61 
9.0 
Adverse Events ................................................................................................... 61 
9.1 
Adverse Event (AE) Monitoring ..................................................................... 61 
9.2 
Sponsor Responsibility for Reporting Adverse Events ................................... 61 
9.3 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events ........ 61 
9.4 
Assessing and Recording Adverse Events....................................................... 62 
9.5 
Rescue Medications & Supportive Care ......................................................... 62 
9.5.1 
Supportive Care Guidelines ............................................................................ 62 
9.5.2 
Expected AEs due to Pembrolizumab and Guidelines for Management ............ 63 
9.5.3 
Expected AEs from Ferumoxytol and Guidelines for Management .................. 66 
9.6 
Additional 
IND 
Reporting Requirements for 
Ferumoxytol 
and 
Pembrolizumab ............................................................................................... 68 
9.7 
Definition of an Overdose for This Protocol and Reporting of Ove rdose to 
the Sponsor and to Merck............................................................................... 71 
9.8 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck ............ 71 
9.9 
Immediate Reporting of Adverse Events to the Sponsor and to Merck ......... 71 
9.9.1 
Serious Adverse Events .................................................................................. 71 
9.9.2 
Evaluating Adverse Events ............................................................................. 73 
10.0 
STATISTICAL ANALYSIS PLAN .................................................................... 73 
10.1 
Power and sample size calculation .................................................................. 73 
10.2 
Analysis plan ................................................................................................... 75 
11.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES .......................................................................................................... 76 
11.1 
Investigational Product ................................................................................... 76 


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11.2 
Packaging and Labeling Information ............................................................. 76 
11.3 
Clinical Supplies Disclosure ............................................................................ 76 
11.4 
Storage and Handling Requirements.............................................................. 76 
11.5 
Returns and Reconciliation............................................................................. 77 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS .................................... 77 
12.1 
Compliance with Trial Registration and Results Posting Requirements........ 77 
12.2 
Retention of Records....................................................................................... 77 
12.3 
Data Collection, Storage, Privacy, Confidentiality and Security .................... 77 
12.4 
OHSU Knight Cancer Institute Data and Safety Monitoring Plan ................ 78 
12.4.1 Changes to Protocol ....................................................................................... 80 
13.0 
Inclusion of Women, Minorities and Children in Clinical Trials ....................... 80 
14.0 
Supplemental Material ....................................................................................... 83 
14.1 
ECOG Performance Status............................................................................. 83 
14.2 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE).............. 83 
14.3 
Ferumoxytol Investigator’s Brochure............................................................. 83 
15.0 
Appendices.......................................................................................................... 83 
Appendix A: Ferumoxytol Adverse Events Form ...................................................... 83 
Appendix B: Pembrolizumab Adverse Events Form ................................................. 83 
16.0 
References........................................................................................................... 84 
 
 
Version # 
OHSU IRB Approval Date 
Version 1 
initial submission 01/20/2017; approved 7/27/17 
Version 2 
Submitted to IRB 12/14/17; approved 2/21/18 
Version 3 
Submitted to IRB 4/9/18; approved 5/29/18 


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Version 4 
Submitted to IRB 2/8/19; approved 3/5/19 
Version 5 
Submitted to IRB 4/15/19; approved 5/3/19 
Version 6 
Submitted to IRB 10/14/19; approved 1/7/20 
Version 7 
Submitted to IRB 3/31/22; 
1.0 TRIAL SUMMARY 
Abbreviated Title 
A comparison of imaging modalities to address brain 
metastases, pseudoprogression and systemic lesion tumor 
flare in brain metastasis after radiation and 
pembrolizumab 
Trial Phase 
Pilot study  
Clinical Indication 
Brain metastases non-small cell lung carcinoma (NSCLC) 
Trial Type 
Pilot study 
Type of control 
None 
Route of administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups  
None 
Number of trial subjects 
20 
Estimated enrollment period 3 years  
Estimated Duration of Trial 
5 years 
Duration of Participation 
5 years 
 
 
 
 
2.0 TRIAL DESIGN 
A total of twenty (20) subjects scheduled to receive stereotactic radiosurgery (SRS) for brain 
metastases will be enrolled in this single institution pilot study. Subjects with up to ten 
measurable target metastatic brain lesions secondary to non-small cell lung carcinoma 
(NSCLC), with adequate performance status, baseline hematological and metabolic parameters 
will receive pembrolizumab (200mg intravenous every 3 weeks) in addition to standard of care 
SRS, until persistent radiographic progression is confirmed. Subjects may receive standard of 
care cytotoxic chemotherapy while on trial, at the treating physician’s discretion. Subjects may 
undergo surgery to one or more of the target lesions if clinically indicated prior to enrollment. 
Subjects will be allowed to continue on pembrolizumab 200mg every 3 weeks until suspected 
radiographic progression. At suspected radiographic progression, subjects will be allowed to 
continue on Pembrolizumab for 2 more doses until follow up clinical and ferumoxytol steady 
state magnetic resonance imaging (MRI) in 6 weeks ( +/- 5 days) confirms persistent 
radiographic progression. 
 
Upon confirmation of persistent radiographic progression, subjects will be evaluated for repeat 
surgery or biopsy. After surgery, if histopathology confirms true progression, subjects will be 
taken off study; patients who are not candidates for surgery will also be taken off the study. 


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Subjects whose biopsy suggests pseudoprogression will be allowed to continue on 
pembrolizumab 200 mg Q3 weeks until further radiographic progression is confirmed.  
 
If, after initial suspected radiographic progression, persistent radiographic progression is not 
confirmed at follow up, subjects will continue on pembrolizumab until further persistent 
radiographic progression is detected and confirmed. Subjects with evidence of new lesions (not 
present at entry to the study) in the CNS or systemically that fulfil criteria for progression by 
immune related response criteria (irRC) [1]will be taken off study drug, but will be followed 
with serial clinical standard of care MRI scans until death. 
In addition, subjects that are already enrolled in the study and have measurable systemic 
disease by RECIST 1.1 Criteria [2] at screening may undergo additional MRI sequences of the 
systemic disease to evaluate the immunological response to pembrolizumab outside the CNS 
(systemic disease). Patients who are taken off study due to  persistent radiographic progression, 
who are not candidates for biopsy, refuse biopsy  or have stable brain disease but have systemic 
disease progression may be continued on pembrolizumab at the discretion of the treating 
physician, if there is evidence of clinical benefit from continuation of therapy. They will be 
followed up with clinical standard of care MRI scans and evaluated for survival, but will not 
be included in the analysis for primary end-point. 
Blood for biomarker evaluation is optional, and will be drawn as described in section 8.5. 
These markers will be correlated with imaging findings and survival. Analysis will be  
performed by the OHSU clinical flow cytometry laboratory.  
   
Any archival biopsy, fresh tissue, as well as tissue obtained at persistent radiographic 
progression will be obtained for clinical pathology review at OHSU. Tissue samples will be 
sent to QualTek Molecular Laboratories for PD-L1 biomarker assay as described in section 
8.5. 
 


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2.1 
Trial Diagram 
 
3.0 OBJECTIVES & RATIONALE 
Primary Objective  
1. Determine the sensitivity and specificity of relative cerebral blood volume (rCBV) 
measured by steady state MRI with 
ferumoxytol 
in 
predicting 
true vs 
pseudoprogression after SRS and intravenous (IV) pembrolizumab in subjects with 
brain metastases from NSCLC.  
 
Rationale: This study is not powered to test any formal hypothesis and we aim to collect 
preliminary data on the sensitivity and specificity of rCBV measurements with ferumoxytol in 
the primary objective. 
 
Secondary Objectives  
1. Evaluate the safety and tolerability of pembrolizumab when given with SRS in subjects 
with brain metastasis.  
2. Evaluate progression free survival, overall survival, best response in brain disease, best 
response in systemic disease, and duration of best responses of brain and systematic 
diseases.  
 
Rationale: Given the small sample size, we aim to collect preliminary data on survival, safety, 
tolerability and efficacy of pembrolizumab when given with SRS in subjects with brain 
metastasis. No additional toxicity profile is expected when pembrolizumab is used in 
combination with SRS and ferumoxytol. Toxicities will be evaluated using CTCAE version 


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4.0.  Subjects will have ongoing toxicity evaluation, with documentation of infusion related 
reactions (grade 3, 4), hematologic toxicities (grade 3, 4) and all other grade 3, 4 toxicities. 
Each toxicity will be attributed to pembrolizumab and ferumoxytol or neither/both.  
 
Exploratory Objectives 
1. Compare the immune response as determined by the volume, pattern and intensity of 
delayed (24hr) ferumoxytol 
uptake between subjects who develop true vs 
pseudoprogression.  
2. Investigate the serum immunological parameters and correlate clinical as well as 
radiological response with systemic immune response to pembrolizumab as measured 
by immunological panel.  
3. Compare the changes percentage expression in PDL-1 in the biopsy tissue before and 
after therapy at the time of progression.  
4. In subjects with measurable systemic lesions, investigate the feasibility of measuring 
vascular volume fraction (VVF), vessel size index (VSI) and vessel density index 
(VDI) as surrogate for response (true vs. pseudoprogression, as measured with RECIST 
1.1 criteria).  
 
Rationale for Exploratory Objectives: This study is not powered to test any formal hypothesis 
and we aim to collect preliminary data regarding the exploratory endpoints that will enable us 
to better understand the tumor biology of brain metastases and PD-1 expression and interaction 
with PD-1 inhibitors. In addition, this pilot study will enable us to collect preliminary data on 
efficacy of pembrolizumab on brain metastases.  
 
Evidence of up-regulation of the immune system is expected in the tumor micro-environment 
as well as systemically in subjects that develop pseudoprogression and respond favorably to 
pembrolizumab.  
 
1) Local immune up regulation in the tumor microenvironment will be characterized by 
increased delayed ferumoxytol uptake, the total volume of T1 intensity 24 hours after 
ferumoxytol administration will be measured and correlated with compared to response 
to therapy. Ferumoxytol is taken up by activated inflammatory cells including 
macrophages. An increased uptake on delayed scans suggests a robust inflammatory 
response. We expect greater intensity and magnitude of delayed ferumoxytol uptake 
signal in subjects who develop pseudoprogression and not in those that have true tumor 
progression. 
2) PD-L1 expression and the type of immune cells present in the tumor microenvironment 
will be compared between archival biopsy tissue and brain tumor tissue obtained before 
initiation of pembrolizumab and at the time of progression.   
3) Systemic immune up regulation will be measured by the blood immunological assay as 
described in (section 8.5). Clinical 
outcomes will 
correlate with T cell 
activation/phenotype, increases in systemic inflammatory markers will be associated 
with outcomes.  
4) In a subset of subjects with measurable systemic disease, response to therapy in the 
systemic disease will be monitored by measuring changes in tumor microvasculature 


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by MRI imaging of the lesion of interest that will precede changes in tumor response 
as measured by traditional RECIST 1.1 and immune-related response criteria (irRC).  
We expect that changes in tumor microvascular will provide a more accurate 
determination of tumor immune flare versus true progression as determined by immune 
response criteria 
  
4.0 BACKGROUND & RATIONALE 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab. 
 
4.1 
Burden of Disease: brain metastases from non-small cell lung carcinoma  
Lung cancer is the leading cause of cancer related mortality in the United States with non-
small cell lung carcinoma (NSCLC) accounting for approximately 85 % of lung cancers and 
for up to 20% of all new cases of brain metastases. The advent of newer chemotherapies and 
targeted agents have resulted in better control of systemic disease. However, management of 
metastases in the CNS continues to be a challenge. Metastatic brain tumors are known to be 
highly heterogeneous in terms of imaging characteristics, molecular markers and response to 
therapy. Current therapy for metastatic brain tumors includes surgery or radiation and has only 
shown modest improvements in survival from around 2 months to 3-6 months when compared 
to best supportive care [3, 4]. Novel immune modulatory therapies like pembrolizumab that 
can augment the body’s own immune system to respond to cancer may significantly improve 
survival outcomes in subjects with CNS disease.  
 
4.2 
Immuno-therapy in the brain 
Until recently, brain was believed to an immune privileged region devoid of lymphatic tissue 
and immune cells necessary to aid immune-surveillance and antitumor activity. Our 
understanding of the CNS immune microenvironment has drastically changed in the last few 
years. The presence of tumor infiltrating lymphocytes around primary and metastatic brain 
tumors and improved survival in patients with dense infiltrates of tumor infiltrating 
lymphocytes suggest that the immune system plays an antitumor  important role [5]. More 
recent evidence indicates the presence of previously unidentified central nervous system 
lymphatic system that plays an important role in trafficking immune cells and antibodies in 
and out of the CNS [6]. Cancer cells evade this immune surveillance by various mechanisms 
including high expression of the immune checkpoints. Immune checkpoints are a group of 
inhibitory pathways that help maintain self-tolerance and minimize collateral tissue damage 
from an inflammatory response. However, this pathway is a major mechanism by which cancer 
cells evade immune-surveillance by T cells that are specific for tumor antigens. It is now 
believed that inhibiting the immune checkpoints is one of the most promising approaches to 
activating and maintaining therapeutic antitumor immunity [7].   
 
Pembrolizumab is a checkpoint inhibitor that targets the programmed death 1 Protein (PD-1), 
a receptor on T lymphocytes. Pembrolizumab augments the anti-tumor immune response by 
blocking the interaction of PD-1 with tumor cells. Pembrolizumab received FDA approval for 
advanced metastatic melanoma based on Phase I and II clinical studies in subjects who had 
previously progressed on ipilimumab [8]. These studies indicate an overall response rate of 


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around 26%, a majority of which were durable responses, some over 6 months. Similar studies 
comparing efficacy in advanced NSCLC are currently underway. The FDA recently granted 
pembrolizumab breakthrough therapy designation for advanced NSCLC based on the Phase 
1b KEYNOTE -001 study [9]. There are two other ongoing Phase 2 and 3 studies in advanced 
lung cancer (KEYNOTE-010 and KEYNOTE-024). In contrast to similar drugs that work on 
the PD-1 ligand inhibitors present on tumor cells, pembrolizumab acts on the peripheral T-
cells and is hence expected to activate antitumor immunity even if it does not cross the blood 
brain and blood tumor barrier (neuro-vascular bundle), which is a major hurdle for any drug 
targeting the CNS.  
 
Early studies with PD-1 inhibitors evaluating systemic tumors excluded patients with brain 
metastases. Although promising early data is emerging in brain metastases from various tumor 
types, very limited mature prospective data is available regarding their efficacy in brain tumors, 
specifically in brain metastases from NSCLC [10-15]. There are several ongoing clinical trials 
but the results are not available yet. Recently reported data from an open-label phase II trial 
evaluating the safety and activity of pembrolizumab monotherapy in brain metastases in 36 
untreated brain metastases(n=36, 18 melanoma, 18 NSCLC) showed a brain response rate of 
33% and was tolerated [16]. Similarly, 
initial reports on the safety of combining 
pembrolizumab with radiation suggest that it is well tolerated with no reported grade 3 or 
greater acute toxicities [17, 18]. Our study will thus be vital in gathering additional vital data 
in a homogeneous group of patients with NSCLC brain metastases that will be helpful in 
designing future studies.  
 
4.3 
Challenges in Trial Design for Brain Metastases 
A major challenge in managing and designing trials for brain metastases is correctly 
determining tumor response to therapy, especially differentiating true progression from 
pseudoprogression or treatment-related changes. After radiation, a large percentage of brain 
tumors can paradoxically increase in size due to an inflammatory 
response called 
‘pseudoprogression’. The term ‘pseudoprogression’ describes the phenomenon of subacute 
radiochemotherapy treatment-related sequelae in the CNS in subjects with brain metastases 
that presents as increasing or new contrast enhancement on MRI [19, 20]. These subjects 
stabilize or recover spontaneously, usually without any change in treatment. Although the 
exact pathophysiology of pseudoprogression is yet to be understood, it is widely believed to 
be mediated by an inflammatory response. The incidence of pseudoprogression is increasing 
and a becoming major challenge in clinical trials with immune modulatory agents [21]. 
  
Radiation alone can cause a spectrum of injury to the CNS and range from reversible edema 
to radiation necrosis. Pseudoprogression is believed to fall in this spectrum and is better 
characterized in high grade glioma [22]. Our data suggests that the true incidence of 
pseudoprogression and radiation injury may have been significantly underestimated [23, 24]. 
The risk for radiation necrosis increases with high dose fractions, hyperfractionation or 
stereotactic radiosurgery (SRS), all of which are frequently used in the treatment of brain 
metastases [25, 26]. We expect a higher incidence of pseudoprogression in this study due to 
the combination of radiation with immunotherapy.  
 


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4.4 
Response Assessment in Brain Metastases 
Radiological assessment guidelines such as RECIST 1.1 and WHO criteria for response 
assessment in systemic solid tumors have consistently proven inadequate in the CNS due to 
the unique anatomy of brain vasculature including the blood-brain barrier (BBB) and the 
neurovascular unit (NVU), as well as the inherent heterogeneity of brain metastases [2, 27-29]. 
It is now well recognized that enhancement seen on MRI represents just the area with disrupted 
BBB and does not show micrometastatic or infiltrative tumor, or lesions with a relatively 
normal BBB. The lack of reliable imaging biomarkers for response assessment is a major 
limiting factor in the development of new and effective therapies for brain tumors [29]. 
Currently the consensus-based updated Response Assessment in Neuro-Oncology Working 
Group (RANO) criteria is used for evaluation of brain metastases [30]. Among other 
drawbacks, all radiographic progression after the 12 week window following radiation is 
attributed to active tumor growth and considered progressive disease by RANO criteria. 
Another major problem with response assessment is the use of vascular endothelial growth 
factor (VEGF) inhibitors like bevacizumab or corticosteroids. These agents can alter the NVU 
around the tumor and decrease contrast enhancement (pseudo-response) when measured by 
conventional response criteria. Bevacizumab has failed to show significant survival benefits 
but is frequently used as an anti-edema measure [31-33]. 
 
Inaccurate attribution of progression, pseudoprogression, or radiation necrosis at enrollment or 
at the time of response assessment may significantly bias clinical trial outcomes. In addition, 
incorrect response assessment may lead to premature changes in therapy, potentially negating 
the benefits of a particular therapy. Radiographic false-positive changes are expected to 
increase after immune-modulatory therapy like PD-L1 inhibitors such as pembrolizumab.  A 
subject on a potentially beneficial immune-modulatory therapy could be taken off a clinical 
trial because the subject may falsely fulfill RANO or RECIST criteria for progression even 
though in reality, the radiographic progression could be due to pseudoprogression or response 
to immunotherapy. This is especially true in trials with immunotherapies where response may 
be slow or delayed. A novel guideline for evaluation of immune therapy activity called 
Immune-Related Response Criteria (irRC) [34] in systemic solid tumors proposed to assess 
immune responses in systemic malignancies. The apparent increase in tumor burden 
sometimes precedes eventual response and this is believed to be mediated by a transient 
immune response and local immune cell infiltration with or without edema. Similar results are 
expected in brain tumor therapies with immune modulatory agents such as pembrolizumab. 
However, irRC is also not expected to be suitable for response assessment in brain tumors due 
to its inability to differentiate true progression from pseudoprogression and effects of radiation. 
 
4.5 
Assessing Pseudoprogression with Ferumoxytol 
We have developed a novel functional imaging technique that may help us differentiate 
radiation necrosis, immune response and pseudoprogression from true disease progression in 
brain tumors. Ferumoxytol(Feraheme)[35] iron oxide nanoparticles, an FDA-approved iron 
supplement, is a blood-pool contrast agent at early time points after infusion (minutes to hours). 
Dynamic susceptibility contrast (DSC) ferumoxytol perfusion MRI (feMRI) provides 
consistent measurement of rCBV, which has been used as a marker of actively growing tumor 
in glioblastoma multiforme (GBM). At later time points (over hours to days) ferumoxytol is 


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phagocytosed by macrophages and activated glial cells in and around the CNS lesion, 
providing a marker of neuroinflammation. We hypothesize that early feMRI measurement of 
rCBV and delayed ferumoxytol uptake can help us differentiate brain tumor response and 
progression. Ferumoxytol is being used in this study off-label and under a physician’s IND.   
 
Preliminary results: Imaging response and inflammation in CNS malignancies. 
We have used DSC feMRI to evaluate outcomes in high grade glioma [36]. Prior studies have 
demonstrated 
elevated 
rCBV 
(rCBV>1.75) 
in 
actively 
growing 
tumor, 
while 
pseudoprogression shows low rCBV in primary brain tumors. [19, 20, 36-41]. We have also 
validated the relevance of the 1.75 rCBV cut-off for survival in high grade gliomas [42]. Our 
retrospective neuroimaging study in 68 subjects with high grade gliomas treated with 
chemoradiation (CRT) suggests that pseudoprogression significantly increases overall survival 
(OS) from around 13 months to over 34 months [36, 43] (Figure 1). Around 30% of all 
pseudoprogression occurred beyond the 12-week RANO cut-off, including 2 cases occurring 
over 6 months after CRT [41]. Figure 2 shows a representative case in high grade glioma, 
where the subject fulfilled criteria for progressive disease (PD) by RANO criteria over 3 
months after radiation, but was shown to have pseudoprogression by the demonstration of low 
blood volume in the area of interest on feMRI. The rate of pseudoprogression in high grade 
gliomas diagnosed at any time after CRT range from 9.3 -31% in large studies [19, 44]. Our 
studies using DSC feMRI as well as similar rCBV measurements using small molecular weight 
gadolinium (Gd) agents with mathematical leakage correction suggest that pseudoprogression 
can occur at extended time frames [41].  
 
A representative case showing pseudoprogression in a GBM on immune-modulatory therapy 
with EGFRv3 based vaccine, is shown in Figure 3. Figure 4 shows an example of the use of 
feMRI to evaluate treatment efficacy in brain metastasis. 
 
  
 


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Recently, Varallyay and colleagues have further improved rCBV measurement by measuring 
steady-state perfusion using high resolution imaging with ferumoxytol in brain tumors [42]. 
We can now obtain high-resolution steady state-CBV images that differentiate regions of high 
vascularity and active tumor growth [36, 42].  Figure 5 shows a comparison of the DSC and 


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steady-state feMRI techniques. Steady-state MRI with ferumoxytol is particularly helpful in 
imaging cortical lesions with very high resolution. 
 
 
            
 
 
Ferumoxytol and other iron oxide nanoparticles can be taken up by phagocytic cells of the 
reticuloendothelial system as well as tumor-associated macrophages [45-47] and brain 
microglia [48]. We are actively investigating the utility of ferumoxytol for imaging 
inflammation, and assessing nanoparticle uptake into tumor-associated macrophages/microglia 
in inflammatory lesions in a rat model (Figure 6). We have demonstrated that ferumoxytol 
nanoparticles are taken up by phagocytic cells in the brain over hours to days after IV infusion 
(Figure 6). Similar patterns of ferumoxytol uptake are seen in a rat neuroinflammation model 
compared to a subject with GBM (Figure 7). Figure 8 shows typical early and delayed imaging 
in a subject with GBM. 
 


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For the past three decades the OHSU Blood-Brain Barrier Program has developed significant 
laboratory and clinical expertise in imaging the CNS [49, 50]. We have shown that ferumoxytol 
is a safe and effective contrast agent that is not inferior to GBCA for brain tumor imaging, and 
can provide significantly better information regarding the tumor vasculature (Figure 9) [51]. 
We have developed multiple clinical trials to assess ferumoxytol as a MRI contrast agent for 
anatomic and dynamic MRI of intracerebral tumors. Based on our studies, ferumoxytol has 
been granted orphan drug status for the imaging of brain tumors and we are working with the 
FDA to move towards market approval of ferumoxytol for brain tumor MRI. We have clarified 
with the FDA that ferumoxytol can be used as diagnostic imaging agent in addition to 
pembrolizumab which is the therapeutic agent being evaluated, both under separate 
investigational new drug applications (IND).   
 
 
 
 
 
Although our work concentrates on CNS metastases, similar imaging modalities may be useful 
for the assessment of therapeutic efficacy and immune response in systemic metastases. The 


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phenomenon 
of immune 
flare in solid 
non-CNS tumors may be equivalent 
to 
pseudoprogression in CNS malignancies. Steady-state feMRI has been used to assess tumor 
vasculature in cancers of the breast, pancreas and prostate [52-54]. A subset of subjects 
enrolled in this study may also have systemic metastases. This imaging technique uses 
ferumoxytol to assess tumor vascularity, and is analogous to our work in the CNS. This will 
allow direct comparison of these metastatic sites, to determine if we can delineate immune 
flare from therapeutic response and the immune component of flare. In both CNS and systemic 
metastases, we hypothesize that perfusion MRI using steady-state ferumoxytol imaging will 
provide a measure of rCBV indicative of active tumor growth, while delayed imaging of 
ferumoxytol may provide an important biomarker of inflammation and immune response. We 
hypothesize that feMRI techniques will provide a better modality than immune response 
criteria for evaluating the response to pembrolizumab in NSCLC metastases. 
 
4.6 
Trial Description 
This study will focus on NSCLC subjects with brain metastases that have failed or refused first 
line therapy with standard platinum doublet therapy and have 10 or less brain metastases. A 
significant survival benefit has been shown with radiation in this population, and surgery or 
SRS is the standard of care for subjects with fewer than 10 brain lesions. The JLGK0901 Study 
evaluated the role of SRS for brain metastasis patients[55-57]. This prospective observational 
study, including 1194 brain metastasis patients, clearly showed the non-inferiority of SRS 
without WBRT as the initial treatment for those with 5–10 lesions versus patients with 2–4 in 
terms of overall survival (OS). Their results are considered the highest level of evidence which 
would allow SRS without whole brain radiation to be advocated for patients with up to 10 
metastatic brain lesions. This clinical trial will study will evaluate the sensitivity and specificity 
of ferumoxytol steady state images to detect true tumor progression from pseudo progression 
in subjects receiving SRS with a PD-1 inhibitor, pembrolizumab[58]. 
 
A total of twenty (20) subjects scheduled to receive stereotactic radiosurgery (SRS) for brain 
metastases will be enrolled in this single institution pilot study. Subjects with up to ten 
measurable target metastatic brain lesions secondary to non-small cell lung carcinoma 
(NSCLC), with adequate performance status, baseline hematological and metabolic parameters 
will receive pembrolizumab (200mg intravenous every 3 weeks) in addition to standard of care 
SRS, until persistent radiographic progression is confirmed. Subjects may undergo surgery to 
one or more of the target lesions if clinically indicated prior to enrollment. Subjects will be 
allowed to continue on pembrolizumab 200mg every 3 weeks until suspected radiographic 
progression on clinical standard of care MRI. At suspected radiographic progression, subjects 
will be allowed to continue on Pembrolizumab for 2 more doses until follow up clinical and 
feMRI within 6 weeks ( +/- 5 days) confirms persistent radiographic progression. 
 
Upon confirmation of persistent radiographic progression, subjects will be evaluated for repeat 
surgery. After surgery, if histopathology confirms true progression, subjects will be taken off 
study; patients who are not candidates for surgery will also be taken off the study. Subjects 
whose biopsy suggests pseudoprogression will be allowed to continue on pembrolizumab 200 
mg Q weekly until further radiographic progression is confirmed.  
 


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If, after initial suspected radiographic progression, persistent radiographic progression is not 
confirmed at follow up, subjects will continue on pembrolizumab until further persistent 
radiographic progression is detected and confirmed. Subjects with evidence of new lesions (not 
present at entry to the study) in the CNS or systemically that fulfil criteria for progression by 
immune related response criteria (irRC) [1] will be taken off study drug, but will be followed 
with serial clinical MRI scans until death. 
 
In addition, subjects that are already enrolled in the study and have measurable systemic 
disease by RECIST 1.1 Criteria [2] at screening may undergo additional MRI sequences of the 
systemic disease to evaluate the immunological response to pembrolizumab outside the CNS 
(systemic disease). Patients who are taken off study due to  persistent radiographic 
progression , who are not candidates for biopsy, refuse biopsy  or have stable brain disease but 
have systemic disease progression may be continued on pembrolizumab at the discretion of the 
treating physician, if there is evidence of clinical benefit from continuation of therapy. They 
will be followed up with clinical MRI scans and evaluated for survival, but will not be included 
in the analysis for primary end-points 
 
Blood for biomarker evaluation will be drawn as described in section 8.5. These markers will 
be correlated with imaging findings and survival.  
   
If available, any archival biopsy, fresh tissue obtained up to 2 months prior to enrollment as 
well as tissue obtained at persistent radiographic progression will be obtained for clinical 
pathology review at OHSU. Brain Tissue samples will also be sent to QualTek Molecular 
Laboratories for PD-1 biomarker assay as described in section 8.5. 
 
The trial population will correspond to those subjects within protocol MK-3475-PN010 that 
would otherwise be excluded due to brain metastases. We feel this data would be adjunct to 
what Merck will obtain from protocol 10 and help strengthen the assessment of PD1 activity 
in both brain metastases and systemic disease. OHSU/Portland VA is a MK-3475-PN010 
clinical trial site. A separate but similar study design may be considered for evaluating subjects 
with advanced malignant melanoma with brain metastases in the future.  
 
OHSU, along with the Veterans Administration Medical center, Portland, Oregon is the largest 
academic medical center and cancer center in the state with a large referral base from adjacent 
states. The high volume of subjects with lung cancer ensures attainment of anticipated accrual 
targets for this trial. 
 
4.7 
Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
 


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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily 
member related to CD28 and CTLA-4 which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of 
murine PD-1 has been resolved.  PD-1 and family members are type I transmembrane 
glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding 
and a cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif 
(ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and 
SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade.  The mechanism by which PD-1 down modulates T-cell responses is similar 
to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells.  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells.  The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors.  Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and contain 
short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 ligand to 
PD-1 inhibits T-cell activation triggered through the T-cell receptor.   
 
PD-L1 is expressed at low levels on various non-hematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues.  Although healthy organs express 
little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this 
T-cell inhibitor.  PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2.  Pembrolizumab has recently been approved in the United Stated for the 
treatment of subjects with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
Our preliminary data suggests that use of bevacizumab may alter rCBV measurements in high 
grade gliomas. For the purpose of this study, a short course of up to 3 doses of bevacizumab 


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may be allowed, when clinically indicated, as an anti-edema measure and will not be criteria 
for exclusion. Bevacizumab is preferred over steroids when studying immune-modulatory 
therapies, since use of steroids can potentially dampen the immune response and outcomes. 
Study MRI will be performed prior to the start of bevacizumab therapy whenever possible. 
Imaging data from subjects who require more than 3 doses of bevacizumab will be stratified 
and analyzed separately. A separate analysis of subjects based on their avastin and steroid dose 
will be performed as part of the final analysis. Currently, the differences in the pathophysiology 
or response to bevacizumab in pseudoprogression resulting radiation or PD-1 inhibitors is not 
clear. This study will provide critical data that can provide insight to the use of bevacizumab 
as a steroid sparing agent to control the edema and mass effect. There are several ongoing 
studies in several tumor types (including brain metastases) evaluating the efficacy of the 
pembrolizumab and bevacizumab combination, however no study has a completed dataset. 
However, none of the studies are investigating the role of bevacizumab in pseudoprogression. 
 
4.8 
Clinical Safety Data with Ferumoxytol 
Investigator’s Brochure Released on February 15, 2018: 
Since approval, AMAG has conducted two post-marketing clinical trials (Protocol Number 
FER-CKD-201 and AMAG-FER-CKD-401). FER-CKD-201 was a randomized, open-label 
trial that compared the safety and efficacy of ferumoxytol to iron sucrose for the treatment of 
IDA in CKD subjects either on or not on dialysis. In this trial, 162 patients were randomized 
in a 1:1 ratio to either ferumoxytol or iron sucrose. Ferumoxytol was administered as a 1.02 g 
course given as a regimen of 2 x 510 mg within 2 to 8 (5±3) days. The most common AEs 
among ferumoxytol treated subjects were nausea (7.5%) and muscle spasms (5.0%). Adverse 
events occurring in ≥2.0% of subjects treated with ferumoxytol included: nasopharyngitis, 
URI, headache, hyperkalemia, and cough (3.8%); peripheral edema, constipation, diarrhea, 
hypotension, hypoglycemia, and anemia (2.5%). There was only one ferumoxytol related 
SAE in the FER-CKD-201 study, 1 event of anaphylactic reaction in 1 subject occurred on 
the same day as the subject’s first dose of ferumoxytol.   
The AMAG-FER-CKD-401 study was an international Phase IV, randomized, open-label, 
active controlled multicenter trial of the safety and efficacy of ferumoxytol (2x510 mg) 
compared with IV iron sucrose (10x100 mg) in the treatment of iron deficiency anemia in 
293 patients with CKD on hemodialysis. Overall related AEs, related SAEs and protocol-
defined AEs of special interest were reported 4.4%, 0% and 17.4%.  
 
Imaging Program: 
The potential use of ferumoxytol as an MRI contrast agent was evaluated in open-label 
feasibility studies, including one Phase I study (Protocol Number 7228-01) in healthy 
volunteers and two Phase II studies (Protocol Numbers 58,254-2 and 58,254-5) in subjects 
undergoing a diagnostic imaging procedure. In the combined studies, 70 imaging subjects 
were exposed to a single administration of ≤4 mg Fe/kg ferumoxytol. Results from these 
studies demonstrated that ferumoxytol was useful in visualizing the arterial circulation. 
Ferumoxytol has a long blood half-life, unlike the majority of other MRI contrast agents, 
enabling arterial and venous imaging for a period of several hours following injection. 
 
March of 2015 FDA Black Box Warning: 


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In March of 2015 the FDA placed a black box warning on ferumoxytol stating: 
WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS 
Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients 
receiving Feraheme. Initial symptoms may include hypotension, syncope, unresponsiveness, 
cardiac/cardiorespiratory arrest.  
 
• Only administer Feraheme when personnel and therapies are immediately 
available for the treatment of anaphylaxis and other hypersensitivity reactions. 
 
• Observe for signs or symptoms of hypersensitivity reactions during and for at 
least 30 minutes following Feraheme infusion including monitoring of blood 
pressure and pulse during and after Feraheme administration. 
 
• Hypersensitivity reactions have occurred in patients in whom a previous 
Feraheme dose was tolerated. 
 
In the black box warning the FDA updated their recommendations of how ferumoxytol 
should be given.  The option to give ferumoxytol (510mg) as a fast undiluted injection in 
approximately 1 minute has been removed.  It was recommended that ferumoxytol (510mg) 
be given over at least 15 minutes. To accommodate for this, the dose of ferumoxytol in this 
study will be given in a minimum of two separate, fractionated doses. The rate of 
administration of the second dose will be slowed down to no faster than .1 mL/s.  
 
Post-Marketing Safety 
AMAG’s pharmacovigilance system proactively reviews spontaneous reports. Routine 
surveillance of events is performed daily and monthly signal detection and evaluation 
processes monitor and update the safety profile. To date the information received from the 
post-marketing setting is consistent with the known safety profile of ferumoxytol. 
As shown in Table 1, cumulative postmarketing reporting rates for serious AESIs (adverse 
events of special interest) with ferumoxytol since product approval (30 June 2009) have 
remained low. These event reporting rates are rare and very rare using CIOMS standardized 
assessment, and no new safety trends or signals have been identified. The reporting rates for 
all AEs remained low and declined over time. In addition, the reporting rates for all serious 
events including HSRs have declined following the change in the prescribing information to 
administration with infusion instead of rapid injection (March 2015). Overall, there is no new 
safety signal arising from the review of the anaphylactic reactions/shock and hypersensitivity 
reaction events. The risk of anaphylaxis/hypersensitivity linked to iron agents is well 
recognized and the need for special caution when administrating ferumoxytol is adequately 
addressed in the US Prescribing Information. The available information from these events 
does not change the safety profile of ferumoxytol. 
 
Table 1 
Reporting Rates of Serious AESIs by Ferumoxytol Administration 


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AESI 
Rapid Injection                
(2009-31 Mar 2015)            
Estimated Exposure: 1,216,518 
Rapid Injection                
(2009-31 Mar 2015)            
Estimated Exposure: 556,177 
No of Cases 
Reporting Rate 
(Estimated) 
No of Cases 
Reporting Rate 
(Estimated) 
Anaphylaxis 
95 
0.0078 
16 
0.0029 
Hypersensitivity 
(severe) 
73 
0.0060 
5 
0.00089 
Cardiac 
disorders 
371 
0.0030 
4 
0.00071 
Hypotension 
(serious) 
72 
0.0059 
2 
0.00035 
Syncope, loss of 
consciousness, 
unresponsive 
44 
0.0036 
42 
0.00071 
Fatal 
481 
0.0040 
43 
0.00071 
 1Includes cases received in April 2015 with event onset in March 2015 (AMAG201500330). 
2Follow-up received on AEOI reported in Q2, per HCP due to underlying disease (epilepsy) and not ferumoxytol 
(AMAG201600940). 
3Case AMAG201602875: As per the treating physician, the death is not related to ferumoxytol; Case 
AMAG201601453: Death due to metastasis of neoplasm after 6 months of discontinuation of ferumoxytol 
therapy. 
 
 
Based on communication with AMAG Pharmaceuticals, manufacturer of ferumoxytol, all 
recommendations apply to iron replacement therapy where infusion rate and dilution do not 
impact efficacy. However, for an imaging indication certain infusion parameters are required 
to gain information, such as dynamic imaging. Increased infusion rate will only affect the 
first injection of 1 mg/kg, which is a small fraction of the full therapeutic dose, and therefore 
may minimally increase the risk of adverse reactions. The next two injections are given at a 
slower rate. The recommended 15 minutes has no scientific basis, it has been chosen 
arbitrarily. For MR imaging stopping the scanner for 15 minutes would be disadvantageous. 
Applying multiple injections, which is not the case with iron replacement therapy, may 
increase safety, compared to continuous injection. This may contribute to the fact that in our 
patient population only minor adverse reactions have been reported.  


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OHSU Toxicity Data 
As of December 31st, 2015, a total of 671 infusions of ferumoxytol had been completed on 
331 study subjects as part of OHSU’s Blood Brain Barrier sponsored IRB approved protocols. 
The dose has ranged from 75 to 510 mg of ferumoxytol (0.5 to 11 mg/kg). In all these cases, 
ferumoxytol was given during MRI, using multiple IV bolus injections (1:1 diluted 
ferumoxytol, 3ml/s flow rate, with 20ml saline flush at the same flow rate.) In most studies the 
first 1mg/kg (or 75mg) was used for dynamic perfusion imaging; the remaining dose was 
injected in one or two subsequent bolus injections. The full 510mg was never given as a single 
injection. Within 42 days after ferumoxytol administration, there were 85 adverse events 
possibly, probably or definitely related to ferumoxytol. Among the 85 events, 43 patients had 
1 event, 12 had 2 events, 3 had three events, one had 4 events and one had five events. 80% of 
the toxicity events occurred within 48 hours post ferumoxytol administration. There were no 
severe, grade 4 or 5 toxicities (CTCAE version 3 and 4) that were attributed to ferumoxytol. 
Table 2 shows the toxicities up to and beyond 48 hours. (Data has been submitted for 
publication in December of 2016) 
 
Table 
2. Toxicities possibly, probably or definitely related to ferumoxytol administration for MR 
imaging. Data includes 671 administrations at OHSU between 2004 and Dec 31st 2015. 
 
4.8.1 Rationale for the Trial and Selected Subject Population 
Subjects with metastatic brain tumors are frequently excluded from Clinical trials of systemic 
disease. Systemic therapy has consistently failed to show benefit in brain metastases due to the 
presence of the blood brain barrier, among other things [59]. Pembrolizumab acts on the T-
cells in the periphery to augment systemic immune response and thus does not have to cross 
the blood brain barrier and. A synergetic effect of combined immunotherapy and stereotactic 
Toxicity Category 
Attribute
# of 
events
Freq of 
events
# of 
events
Freq of 
events
# of 
events
Freq of 
events
Gastrointestinal
31
4.62%
23
3.43%
8
1.19%
Cardiac General
17
2.53%
17
2.53%
0
0.00%
Pain
17
2.53%
17
2.53%
0
0.00%
Dermatology/Skin
7
1.04%
5
0.75%
2
0.30%
Metabolic/Lab
5
0.75%
0
0.00%
5
0.75%
Occular/Visual
2
0.30%
1
0.15%
1
0.15%
Allergy/Immunology
1
0.15%
1
0.15%
0
0.00%
Constitutional
1
0.15%
1
0.15%
0
0.00%
Hemorrhage/Bleeding
1
0.15%
0
0.00%
1
0.15%
Other
1
0.15%
1
0.15%
0
0.00%
Pulmonary/Upper Resp
1
0.15%
1
0.15%
0
0.00%
Vascular
1
0.15%
1
0.15%
0
0.00%
Total
85
12.67%
68
10.13%
17
2.53%
Overall (<42 days) Within 48 hours
>48 hours


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radiation is expected to promote the release of tumor specific antigens that can then direct 
antigen- presenting cells to induce a T cell mediated immune response [60-63]. Prior studies 
have demonstrated the safety and efficacy of pembrolizumab for systemic non–small-cell lung 
cancer [9]. Since pembrolizumab acts at the level of T–cells, it does not have to cross the blood 
brain barrier and hence is expected to be efficacious in our cohort with brain metastases as 
well.     
 
Half of all patients with NSCLC develop brain metastases during the course of their disease. 
Approximately 10% of US patients with NSCLC have an activating mutation with in the 
epidermal growth factor receptor (EGFR) while 3-5% will have chromosomal translocation 
involving the gene coding for the protein anaplastic lymphoma kinase (ALK).[64, 65] Patients 
with oncogenic driver mutations within the EGFR or ALK are currently treated with individual TKI 
with specific activity against such mutations. The ability of these TKIs to penetrate the BBB and control 
CNS metastatic disease vary significantly between different TKIs with 3rd generation EGFR-TKI (e.g. 
osimertinib) and 2nd and 3rd generation ALK-TKI (alectinib, ceritinib, brigatinib and lorlatinib) 
achieving therapeutic CSF levels while earlier generation TKIs (e.g. erlotinib, gefitinib, afatinib and 
crizotinib) failing to reach therapeutic CNS levels. Pharmacologic difference in CNS penetrance among 
various TKIs accounts for the wide variations in incidence and control rate of CNS metastases among 
EGFR and ALK-mutated NSCLC patients treated with different TKIs, as well as the intra-patient 
discrepancy observed between visceral and CNS disease control rate.  For enrollment in this study, 
Subjects with EGFR or ALK driver mutations should have disease progression on FDA-
approved therapy for these driver mutations. Subjects who develop brain metastases (while on 
FDA-approved therapies for EGFR or ALK aberrations) may be included at the discretion of 
the treating oncologist, depending on whether an EGFR or ALK- specific TKI with proven 
CNS activity is available or not and whether visceral disease outside the CNS is controlled or 
progressing on the current treatment.  
 
Patients for whom an FDA-approved TKI with adequate CNS penetration is available will be excluded. 
Our accrual goal is a total of 20 patients over 3 years and excluding these patients will not affect the 
study accrual.  
 
Significance:  
With immunotherapy, a transient increase in size of lesion on imaging called flair response is 
frequently seen before a response is noted [34]. A similar increase in size of the lesion is noted 
after radiation therapy in primary brain tumors [19, 43, 66]. Currently, subjects who have 
imaging changes within the first 12 weeks after chemo-radiation are followed up with serial 
scans to confirm true vs pseudoprogression and may sometimes be excluded from clinical trials 
due to the lack of validated noninvasive methods to distinguish true progression from 
pseudoprogression [30, 67].  
 
Our group has demonstrated that rCBV measured by ferumoxytol steady state imaging is very 
helpful in distinguishing pseudoprogression from true disease progression in brain tumors. 
[43]. Accurate diagnosis of pseudoprogression will prevent subjects being taken off a 
potentially beneficial clinical trial when there is an anatomical increase in tumor burden after 
radiation or immunotherapy. This study will validate and determine the sensitivity and 
specificity of ferumoxytol steady state imaging in distinguishing the two entities. This study 


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will also provide information that will be invaluable in designing future trials for metastatic as 
well as primary brain tumors and help improve the practice of neuro-oncology. 
 
4.8.2 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested 
in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to 
test for initial tumor activity.  Recent data from other clinical studies within the MK-3475 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-
2 release assay) suggested that peripheral target engagement is durable (>21 days).  This early 
PK and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W 
dosing schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time 
data from 476 subjects. Within the resulting population PK model, clearance and volume 
parameters of MK-3475 were found to be dependent on body weight. The relationship between 
clearance and body weight, with an allometric exponent of 0.59, is within the range observed 
for other antibodies and would support both body weight normalized dosing or a fixed dose 
across all body weights.  MK-3475 has been found to have a wide therapeutic range based on 
the melanoma indication.  The differences in exposure for a 200 mg fixed dose regimen relative 
to a 2 mg/kg Q3W body weight based regimen are anticipated to remain well within the 
established exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The 
exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 
mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of 
tumor burden on exposure. In addition, exposure was similar between the NSCLC and 
melanoma indications. Therefore, there are no anticipated changes in exposure between 
different indication settings. 
 
The choice of the 200 mg every 3 weeks is an appropriate dose based on simulations performed 
using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 
3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 
mg/kg dose every 3 weeks, 2) will maintain individual subject exposures in the exposure range 
established in melanoma as associated with maximal efficacy response and 3) will maintain 
individual subjects exposure in the exposure range established in melanoma that are well 
tolerated and safe.  


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This fixed FDA approved dose regimen (200 mg, intravenously every 3 weeks) will simplify 
the dosing regimen to be more convenient for physicians and to reduce potential for dosing 
errors.  A fixed dosing scheme will also reduce complexity in the logistical chain at treatment 
facilities and reduce wastage. 
 
4.8.3 Rationale for Endpoints 
4.8.3.1 Efficacy Endpoints 
This pilot study is designed to determine the sensitivity and specificity of ferumoxytol steady 
state imaging in distinguishing true progression in subjects who will receive SRS with 
Immunotherapy (pembrolizumab) for brain metastases. This information will be used to 
validate this novel imaging biomarker and help design future brain tumor studies that 
incorporate immunotherapy. We will use radiographic progression to determine a subject’s 
suitability to continue on treatment. Furthermore, since the benefits of immunotherapy can take 
months to become apparent, we will not make treatment decisions within the first 12 weeks 
and at the time of suspected progression, no change in therapy will be made until persistent 
radiographic progression is noted on a follow up scan at least 6 weeks later.  
 
The secondary endpoints will provide preliminary data on safety, toxicity, and efficacy 
(progression free survival, overall survival, best response and duration of best response 
survival) in brain metastasis from NSCLC receiving pembrolizumab in addition to standard of 
care treatments. Data from this pilot study will be used to power a larger study. 
 
4.8.4 Biomarker Research End Points 
Blood Biomarker  
The number and type of T cell can suggest response to immunotherapy in various cancers [68]. 
This exploratory study will look at serum immune cell subtypes at various time points and 
correlate them with radiographic and clinical outcomes. This is further elaborated in section 
8.5.  
 
Tissue Biomarker  
The type and number of tumor infiltrating immune cells including lymphocytes and 
macrophages correlate with prognosis [69]. Data in melanoma and breast cancer suggest a 
correlation between the immunophenotype to treatment response [70, 71]. This study will 
explore the changes in the PDL-1 expression (before and after therapy with pembrolizuma b) 
and types of tumor infiltrating immune cells with radiographic and clinical outcomes. This is 
further elaborated on in section 8.5. 
 
5.0 METHODOLOGY 
5.1 
Diagnosis/Condition for Entry into the Trial 
Subjects with up to ten measurable target metastatic brain lesions secondary to non-small cell 
lung carcinoma (NSCLC) to include adenocarcinoma and squamous cell carcinoma by 
histology 
 


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5.1 
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Be willing and able to provide written informed consent/assent for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Have a histologically confirmed diagnosis of NSCLC   
4. Have up to ten measurable (by RANO) brain metastasis planned for stereotactic 
radiosurgery. 
5. Have PD-L1 expression of greater than 1%.  
6. Subjects may already be receiving PD-1/L1 inhibitors (including pembrolizumab or 
other PD-(L)1 inhibitors such as nivolumab, atezolizumab, avelumab, durvalumab) for 
the treatment of systemic disease. A washout period of at least 3 weeks is required from 
the last dose of PD-(L)1 inhibitor. 
7. Subjects with EGFR or ALK genomic tumor aberrations should have documented 
disease progression on FDA-approved therapy for these aberrations. Subjects with 
EGFR or ALK genomic tumor aberrations who develop new brain metastases may be 
included at the discretion of the treating physician.  
8. Have a performance status of 0-2 on the ECOG Performance Scale. 
9. Demonstrate adequate organ function as defined in Table 3. 
10. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be performed or confirmed as negative, a serum 
pregnancy test will be required.   
11. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication.  Subjects of 
childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > 1 year. Male subjects should agree to use an adequate 
method of contraception starting with the first dose of study therapy through 120 days 
after the last dose of study therapy. (Section 7.16).   
 
Table 3  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 


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Protocol/Amendment No.:  #7  Date: 3/31/2022 
 
 
 
Albumin 
>2.5 mg/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
5.2 
Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Has evidence of leptomeningeal disease on MRI or in CSF. 
2. If tumor demonstrates EGFR or ALK genomic tumor aberrations, subject should have 
documented disease progression on FDA-approved therapy for these aberrations. 
3. Has a diagnosis of immunodeficiency and is not on continuous daily 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
(Subjects may receive steroids before or after SRS to prevent or manage cerebral 
edema; inhalational steroids are permitted) 
4. Has previously progressed on a PD-1 or PD-L1 checkpoint inhibitor for systemic 
disease. 
5. Has a known history of active TB (Bacillus Tuberculosis) 
6. Has hypersensitivity to pembrolizumab, or ferumoxytol or any of their excipients.  
7. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events 
due to agents administered more than 4 weeks earlier. 
a. Note: The use of Denosumab is an exception to this criterion.  
8. Subject who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to a previously administered agent. 
a. Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion 
and may qualify for the study. 
b. Note: Subjects with ≤ Grade 2 hematologic toxicities are an exception to this 
criterion and may qualify for the study. 
c. Note: Subjects with ≤ Grade 2 fatigue are an exception to this criterion and 
may qualify for the study. 
9. Has a known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of 
the skin that has undergone potentially curative therapy or in situ cervical cancer. 
10. Has active autoimmune disease that has required systemic treatment in the past 2 
years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment.  
11. Has known history of, or any evidence of active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation 


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Protocol/Amendment No.:  #7  Date: 3/31/2022 
 
 
 
for the full duration of the trial, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.   
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
15. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine within 30 days of planned start of study therapy. 
a. Note:  Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-
Mist®) are live attenuated vaccines, and are not allowed. 
19. Subjects with clinically significant signs of uncal herniation, such as acute pupillary 
enlargement, rapidly developing motor changes (over hours), or rapidly decreasing 
level of consciousness, are not eligible. 
20. Subjects with known allergic or hypersensitivity reactions to parenteral iron, 
parenteral dextran, parenteral iron-dextran, or parenteral iron-polysaccharide 
preparations (Ferumoxytol Investigator’s Drug Brochure, 2009). Subjects with 
significant drug or other allergies or autoimmune diseases may be enrolled at the 
investigator’s discretion. 
21. Subjects who have a contraindication for 3T MRI: metal in their bodies (a cardiac 
pacemaker or other incompatible device), are severely agitated, or have an allergy to 
gadolinium containing contrast material. 
22. Subjects with known iron overload (genetic hemochromatosis).  In subjects with a 
family history of hemochromatosis, hemochromatosis must be ruled out prior to study 
entry with normal values of the following blood tests: Transferrin saturation (TS) test 
and Serum ferritin (SF) test. All associated costs will be paid by the study.  
23. Subject who have received ferumoxytol within 3 weeks of study entry. 
24. Subjects with three or more drug allergies from separate drug classes. 
 
5.3 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.   
 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Persistent radiographic progression confirmed by tissue biopsy.  
• Persistent radiographic progression if subject is not a candidate for repeat surgery or 
subject refuses a repeat biopsy to pathological confirmed of disease progression    


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Protocol/Amendment No.:  #7  Date: 3/31/2022 
 
 
 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, at the discretion of 
the treating physician. Please see Section 7.4.9 
• Unacceptable adverse experiences as described in Section 9.0 
• Miss two consecutive treatments for any reason other than surgery 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum or urine pregnancy test. If the urine test is 
positive, cannot be performed or cannot be confirmed as negative, a serum pregnancy 
test will be required.  Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab 
or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 5.4.1 
• Administrative reasons 
 
The End of Treatment and Follow-up visit procedures are listed in the Schedule of Events 
(Section 6).  After the end of treatment, each subject will be followed for 30 days for adverse 
event monitoring (serious adverse events will be collected for 90 days after the end of treatment 
as described in Section 9).  Subjects who discontinue for reasons other than progressive disease 
will have post-treatment follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent or becoming lost to follow-up.  After documented 
disease progression each subject will be followed by telephone for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first. 
 
5.3.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR in the brain and have been treated for at least 24 months with pembrolizumab.   
 
At the discretion of the investigator, subjects who have had CR in the brain but develop 
progressive systemic disease may be eligible for up to one year of additional treatment with 
pembrolizumab via the Second Course Phase, if no additional cancer treatment was 
administered since the last dose of pembrolizumab, the subject meets the safety parameters 
listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at 
the same dose and schedule at the time of initial discontinuation.  Additional details are 
provided in Section 7.4.9. 
 
5.3.2 Subject Replacement Strategy 
Subjects that are unevaluable will be replaced. Subjects that are unevaluable are those who do 
not reach the first follow-up imaging time point (12 weeks after first pembroluzimab infusion). 
 


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Protocol/Amendment No.:  #7  Date: 3/31/2022 
 
 
 
5.3.3 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 
 


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6.0 SCHEDULE OF EVENTS 
 
Screening visit: 
within 30 days 
of first 
treatment 
Treatment: every 3 
weeks (+15 days) for 
up to 2 years or 32 
cycles 
At suspected 
radiographic 
progression 
(+15 days) 
 
At persistent 
radiographic 
progression 
(+15 days) 
 
At discontinuation of 
treatment (+15 days) 
(unless testing has been 
done within 1 month) 
Safety follow-up: 30 
days (+15 days) post 
discontinuation of 
pembro  
Follow-up: for 
subjects who 
complete 2 years 
of treatment or 32 
cycles 
Survival: 
follow-up once 
off study8 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
Archival Tissue Collection 
(if available) 
X 
 
 
 
 
 
 
 
Biopsy or Resection of  
Metastatic Brain Lesion and 
biomarkers1 
X1 
 
 
X1 
 
 
 
 
Demographics and Medical 
History 
X 
 
 
 
 
 
 
 
Medication, herbal or dietary 
supplement review 
X 
X 
 
 
X 
X 
X 
 
Trial Treatment 
Administration 
(Pembrolizumab)  
 
X11 
 
 
 
 
 
 
Review Adverse Events, 
include Events of Clinical 
Interest10 
 
X 
 
 
 
X 
 
 
Physical Examination2 
X 
X 
 
 
X 
X 
X 
 
Vital Signs and Weight 
X 
X 
 
 
X 
X 
X 
 
ECOG Performance Status 
X 
X 
 
 
X 
X 
X 
 
CBC with Differential3 
X 
X 
 
 
X 
X 
 
 
Comprehensive Serum 
Chemistry Panel3 
X 
X 
 
 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
FT4 and TSH4 
X 
X 
 
 
 
X 
 
 
PT/INR, aPTT 
X 
 
 
 
 
X 
 
 
Pregnancy Test (urine or 
serum, females only) 
X 
 
 
 
 
 
 
 
Clinical Tumor Imaging  
X 
X5 
 
 
 
 
X7 
 
Ferumoxytol imaging 
 
X6 
 
 
 
 
 
 
Biomarker Collection 
(serum) - optional 
 
X6 
 
 
 
 
 
 
PET scan abd, chest, pelvis 
X9 
 
 
 
 
 
 
 
Post-study anticancer therapy 
status 
 
 
 
 
 
 
X 
 
Survival Status 
 
 
 
 
 
 
X 
X 
Telephone contact 
 
 
 
 
 
 
 
X8 


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Protocol/Amendment No.:  #7  Date: 3/31/2022 
 
 
 
1Brain surgery is not necessary before enrollment. However, a brain surgery may be done prior to enrollment or at the time of persistent radiographic progression if 
clinically indicated. Pembrolizumab needs to be stopped for 4 weeks prior to and will not be restarted for at least 4 weeks after surgery (section 7.2).  All tissue 
will be sent for biomarkers. 
 
2Physical exam only required with every pembrolizumab infusion.  
 
3CBC and CMP to be done with every cycle while on pembrolizumab – labs must be done within 30 days before first pembrolizumab infusion, and within 72 hours 
before subsequent infusions. 
 
4 FT4 and TSH with every cycle while on pembrolizumab 
 
5Clinical standard of care MRIs (gadolinium with perfusion) are done at baseline, 12 weeks post radiation, then every 9 weeks, and 6 weeks after suspected 
radiographic progression (see special instructions below for evaluating persistent radiographic progression). All timepoints are +15 days. Clinical scans may be done 
more frequently, at physician’s discretion. Each MRI scan will be evaluated for progression. 
 
6Ferumoxytol steady state MRIs (within 10 days of clinical standard of care MRIs) are done baseline, 12 weeks post radiation, anytime there is suspected 
radiographic progression and 6 weeks after suspected radiographic progression. All timepoints are +15 days. Serum biomarkers will be obtained +15 days of 
ferumoxytol MRI scan. 
 
7 Follow-up after completing 2 years of treatment or 32 cycles (whichever comes later): clinical standard of care MRI and clinical visit every 12 weeks (+30 days) 
for up to 1 year, and every 6 months (+30 days) until death. 
 
8 Survival follow-up once off study: Telephone contact every 12 weeks (+30 days) to assess for survival status until death, withdrawal of consent, the end of the 
study, or loss to follow-up, whichever occurs first. 
 
9Evaluation of systemic disease burden: A standard of care PET /CT or CT abdomen, chest and pelvis with contrast will be obtained within 3 months of enrollment 
and every 6 months while on study thereafter.  
 
10Adverse event review will be recorded in Epic continuously while on study. A separate Epic note will be done with each course. All AEs are assessed for attribution 
to pembrolizumab, ferumoxytol, and standard of care therapy.  
 
11 First dose of pembrolizumab will be given on the first day of radiation (+15 days), and every 3 weeks thereafter (+15 days). 
 
Imaging instructions for evaluating persistent radiographic progression: if there is suspected progression, subjects undergo a ferumoxytol steady state MRI and 
continue on pembrolizumab for two more cycles (total of 6 weeks). At the 6 week point, clinical standard of care and ferumoxytol MRIs will be repeated to 
confirm persistent radiographic progression. If the 6 week scan confirms progression, then pembrolizumab is discontinued and subject is evaluated for surgery. If 
histopathology confirms pseudoprogression or is inconclusive, the subject will continue on pembrolizumab every 3 weeks until further radiographic progression is 


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Protocol/Amendment No.:  #7  Date: 3/31/2022 
 
 
 
suspected. If histopathology confirms progression, the subject will be removed from the study. If the subject is not a surgical candidate, they will be taken off study 
and move into the survival follow up stage.  
 


 
41 
 
7.0 TREATMENT PLAN AND PROCEDURES 
The Schedule of Events - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
 
7.1 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 4 
Table 4 Trial Treatment 
Drug 
Dose/Poten
cy 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Therapeutic Agent 
Pembrolizumab 
200 mg  
Every 3 
weeks (+15 
days) 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
Imaging Agent 
Ferumoxytol 
 
Baseline, 12 
weeks post 
radiation, 
anytime 
there is 
suspected 
radiographic 
progression 
and 6 weeks 
after 
suspected 
radiographic 
progression 
(+15 days).  
 
IV infusion 
Baseline, 12 weeks 
post radiation, 
anytime there is 
suspected 
radiographic 
progression and 6 
weeks after 
suspected 
radiographic 
progression 
(+15days).  
 
 
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
 
7.1.1   Timing of Dose Administration 
Pembrolizumab: Trial drug treatment should be administered on Day 1(+15 days) of each cycle 
after all procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0).  Pembrolizumab will not be administered less than 14 days after any major 
surgeries including brain biopsy. 
 
All trial treatments will be administered on an outpatient basis. 
 


 
42 
 
Pembrolizumab 200mg will be administered as IV infusion every 3 weeks as per institutiona l 
guidelines.  The expiration of the reconstituted pembrolizumab is 6 hours at room temperature 
and 20 hours refrigerated. The total cumulative storage time at room temperature and 
refrigeration should not exceed 24 hours. The Pharmacy Manual contains specific instructions 
for the preparation of the Pembrolizumab infusion fluid and administration of infusion 
solution.  
Ferumoxytol (only for study MRIs): The total dose of ferumoxytol will be 7mg/kg (not 
exceeding 510mg total).  The ferumoxytol will be mixed with normal saline 1:1 solution to 
dilute to 15mg/ml.  1 mg/Kg IV will be  injected at the start of the 7th dynamic cycle during 
the DSC acquisition at a flow rate of 3ml/s followed by 20ml saline flush. The rest of the 
ferumoxytol will be given as IV injections at a low flow rate (.1ml/s) followed by 20 mL saline 
flush. The flow rates may be adjusted at the physician’s discretion.  
 
Vitals monitoring for ferumoxytol MRIs: Blood pressure and pulse will be taken at the start of 
MRI (+ 5 minutes), after each ferumoxytol injection (+ 5 minutes), and again 30 minutes (+ 5 
minutes) after the first injection of ferumoxytol. 
 
7.2 
Study procedures narrative 
Enrolled subjects will receive pembrolizumab (200 mg I.V. every 3 weeks) starting on the first 
day of radiation (+15 days) until persistent radiographic progression is confirmed. Subjects 
may receive standard of care cytotoxic chemotherapy (carboplatin and pemetrexed) while on 
trial, at the treating physician’s discretion. [72, 73] MRI scans will be performed to assess 
response to therapy. Clinical standard of care MRIs are done at baseline, 12 weeks post 
radiation and then every 9 weeks thereafter until suspected radiographic progression. An early 
follow up clinical standard of care MRI will be performed 6 weeks (+15 days) from the date 
of MRI showing suspected radiographic progression to confirm persistent radiographic 
progression. Clinical scans may be done more frequently, based on physician’s discretion. 
Each MRI scan will be evaluated for progression.  
 
Additional ferumoxytol steady state MRIs will be done at baseline, 12 weeks after radiation, 
at suspected radiographic progression and within 6 weeks (+15 days) from suspected 
radiographic progression to confirm persistent radiographic progression.  
 
When persistent radiographic progression is confirmed, subjects will be evaluated for a 
craniotomy with intent to complete resection and /or biopsy of the enhancing lesion, if this is 
thought to be the clinical standard of care.  
 
Biopsy tissue obtained from surgery at persistent radiographic progression will be evaluated 
by the pathologists at OHSU. The pathologist will determine if the tissue is consistent with 
progression or pseudoprogression, where progression is defined as presence of viable 
metastatic carcinoma in the biopsy tissue and absence of tumor cell is assumed to reflect 
pseudoprogression. If histopathology confirms pseudoprogression the subject will continue on 
pembrolizumab every 3 weeks until further radiographic progression is suspected. If 
histopathology confirms progression, the subject will be removed from the study, followed 
clinically with serial clinical stand of care MRIs every 3 months for up to a year and then every 
6 months until death or lost to follow-up. 


 
43 
 
 
The decision regarding surgery will be consensus based and will be made after each individua l 
case has been presented at the OHSU interdisciplinary brain tumor board. If a subject is not a 
surgical candidate, or is unwilling to undergo surgery, they will be taken off study. They will, 
however, be eligible for continuation of pembrolizumab, at the physician’s discretion, at the 
same dose and frequency, if clinical benefit is noted. They will be followed clinically with 
serial clinical standard of care MRI scans every 3 months for up to a year and then every 6 
months until death or until lost to follow up. These subjects will not be included in the analysis 
the primary end-points but will be included in the survival analysis.  
 
In subjects where the lesion remains unchanged or regresses in volume at 6 weeks) after the 
date of suspected radiographic progression, pembrolizumab will be continued until further 
persistent radiographic progression is confirmed.   
 
All subjects will be followed with clinical examination and clinical standard of care MRI scans 
until death or lost to follow up. Subjects will be treated for up to 2 years, toxicity, or 
progression whichever comes first.  Dose reductions/discontinuations for pembrolizumab will 
be as per Merck guidelines.   
 
Pembrolizumab may be stopped for up to 3 months in the context of a craniotomy to confirm 
persistent radiographic progression or unrelated major surgery. Dosing delays of up to 7 days 
are permitted at physician discretion for medical / surgical events or logistical reasons. Dosing 
interruptions (missing a dose) are permitted in the case of medical / surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, medical events, subject vacation, 
and/or holidays), not to exceed two consecutive doses or a maximum of 9 weeks. The reason 
for interruption will be documented in the subject’s study record. Pembrolizumab will not be 
administered less than 14 days after any major surgeries including brain biopsy. 
7.3 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information 
provided 
to the subject 
must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 


 
44 
 
 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
 
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.4 
Trial Procedures 
See the Schedule of Events for when tests should be completed. 
 
7.4.1 Clinical procedures: 
• Demographics  
• Medical history 
• Prior medication review 
o The investigator or qualified designee will review prior medication and herbal and 
dietary supplement use, including any protocol-specified washout requirement, and 
record prior medication taken by the subject within 28 days before starting the trial.  
Treatment for the disease for which the subject has enrolled in this study will be 
recorded separately and not listed as a prior medication.  
o The investigator or qualified designee will record medication, if any, taken by the 
subject during the trial.  All medications related to reportable SAEs and ECIs 
should be recorded as defined in Section 7.2. 
o Subjects will be asked to stop all nonprescription herbal supplements and over the 
counter medication.  
• Full physical examination 
• Vital signs  
o temperature, pulse, respiratory rate, height, weight and blood pressure.  Height 
will be measured at screening only. 
• ECOG performance status (Appendix) 
• Archival tissue collection: 
o If available, any tumor biopsy tissue (lung, mediastinal, or brain) that was 
obtained prior to screening for the study will be requested and sent to the 
Merck-designated Contract Research Organization (CRO) QualTek Molecular 
Laboratories for PD-1 biomarker assay.  
• Biopsy or resection of metastatic brain lesion 
o When clinically indicated, a biopsy or resection will be done of the brain 
lesion(s) 1) prior to enrollment and SRS, and 2) at the time of persistent 
radiographic progression. Any tumor biopsy tissue will be sent to the Merck-
designated Contract Research Organization 
(CRO) QualTek Molecular 
Laboratories for PD-1 biomarker assay.  
• Radiation therapy: 
o All patients will receive standard of care stereotactic radiosurgery in 1-5 
fractions, at the discretion of the treating radiation oncologist. If all lesions 
cannot be treated on the same day, all lesions MUST be treated ≤14 days of 
treatment of the first lesion. Gamma knife or X-rays with nominal energy of 4 
megavoltage (MV) or greater for accelerator-based treatments, including 


 
45 
 
isocentric conical collimators, mini-multi-leaf (5 mm or less) technology or 
linear accelerators mounted on robotic arms will be used to deliver the target 
dose.  
o Target Volume: The volumes shall be defined by a planning MRI brain scan, 
with the patient in the treatment position.  The target volume should include 
the enhancement seen on planning MRI with 0-1 mm margin.  The maximal 
cross-sectional diameter must be < 3.0 cm for a lesion treated with a single 
fraction.  
o Target Dose: The dose should be prescribed to the highest isodose line 
encompassing the 90-95% target volume.  General dose guidelines are as 
follows 
• Lesion diameter < 1cm – 20-22 Gy in 1 fraction  
• Lesion diameter 1-2 cm – 18-20 Gy in 1 fraction  
• Lesion diameter 2-3 cm – 18 Gy in 1 fraction, or 27 Gy in 3 fraction or 
30-35 Gy in 5 fractions 
• Lesion diameter 3-5cm – 30 – 35 Gy in 5 fractions 
o Up to 8 of dexamethasone can be administered on the day of single fraction 
SRS, at the discretion of the treating physician.  
o Radiation therapy to an additional symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion at any time during the study if :  
• they fulfill other criteria to remain in the study and  
• this lesion has remained stable or shows radiographic response 
compared to baseline. 
• this additional lesion was not in the initial radiation field.  
 
• Subjects may receive standard of care cytotoxic chemotherapy (carboplatin and 
pemetrexed) while on trial, at the treating physician’s discretion. Chemotherapy to be 
administered per package insert. 
• Subject may also provide consent/assent for future correlative research (optional).  
Subjects may participate in the main trial without participating in future correlative 
research. 
 
7.4.2 Lab tests: see Table 5 
• CBC with differential 
• Comprehensive serum chemistry panel 
• Urinalysis  
• FT4, TSH 
• PT/INR 
• aPTT 
• Pregnancy test (urine or serum) (women). If the urine test is positive, cannot be 
performed or cannot be confirmed as negative, a serum pregnancy test will be required.   
• Serum biomarker assay (see Section 8.5.1) 
 


 
46 
 
Table 5 Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Carbon Dioxide ‡ 
Microscopic exam (If abnormal)  
Free tyroxine (T4) 
Absolute Neutrophil Count 
  (CO2 or biocarbonate) 
results are noted 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
Calcium 
Urine pregnancy test † 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
 
 
Potassium 
 
    
 
Sodium   
 
    
 
Total Bilirubin 
 
    
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
    
 
Total protein 
 
   
 
 
 
 
 
 
 


 
47 
 
Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
 
7.4.3 Imaging  
Standard of care clinical brain MRI: Clinical MRIs are done at baseline, 12 weeks post 
radiation and then every 9 weeks (see special instructions below for evaluating persistent 
radiographic progression). Gadolinium is the preferred contrast agent, when subject qualifies 
(per institutional policy) for gadolinium infusion, but it is not required. Clinical scans may be 
done more frequently, at physician’s discretion. Each MRI scan will be evaluated for 
progression. 
 
Ferumoxtyol MR: ferumoxytol steady state MRIs of the brain are done baseline, 12 weeks 
post radiation, anytime there is suspected radiographic progression and 6 weeks after suspected 
radiographic progression. Additional MR imaging of systemic lesions may be performed in 
the same setting and time points as the brain imaging. Details are explained in section 8.4.2. 
Blood pressure and pulse will be taken at the start of MRI (+ 5 minutes), after each ferumoxytol 
injection (+ 5 minutes), and again 30 minutes (+ 5 minutes) after the first injection of 
ferumoxytol. 
 
Evaluation of systemic disease burden: A standard of care PET/CT or CT abdomen, chest 
and pelvis with contrast will be obtained within 3 months of enrollment and at least every 6 
months thereafter. This is considered standard of care for patients with NSCLC. Stable 
systemic disease burden should be demonstrated at enrollment and for continuation of study 
drug.  
 
7.4.3.1 Imaging instructions for evaluating persistent radiographic progression:  
If there is suspected progression, subjects undergo a ferumoxytol steady state MRI and 
continue on pembrolizumab for two more cycles (total of 6 weeks). At the 6 week point, 
clinical standard of care and ferumoxytol MRIs will be repeated to confirm persistent 
radiographic progression. If the 6 week scan confirms progression, then pembrolizumab is 
discontinued 
and subject 
is 
evaluated 
for surgery. 
If histopathology 
confirms 
pseudoprogression, the subject will continue on pembrolizumab every 3 weeks until further 
radiographic progression is suspected. If histopathology confirms progression, the subject will 
be removed from the study. 
 
7.4.4 Adverse Event Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Events and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0.  Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. All AEs will be attributed to pembrolizumab or ferumoxytol separately.  
 


 
48 
 
For subjects receiving treatment with pembrolizumab all AEs of unknown etiology associated 
with pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs) 
 
Please refer to Section 9 for detailed information regarding the assessment and recording of 
AEs.   
 
7.4.5 Post-study anticancer therapy status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy.  Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
 
7.4.6 Safety Follow-Up Visit: 30 days post discontinuation 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizuma b 
(as described in Section 7.4.9) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
 
7.4.7 Follow-up 
Subjects who complete 2 years of treatment or 32 cycles (whichever comes later) will move 
into the Follow-Up Phase and should be assessed every 12 weeks (±30 days) by clinical 
standard of care MRI scans and clinical assessment to monitor disease status for up to 1 year 
or until they progress or death.  After 1 year, the imaging and clinical assessment time point 
will occur every 6 months (± 30 days) until death. Follow-up may be done more frequently, at 
physician’s discretion. 
 
7.4.8 Survival Follow-up when off study 
Once a subject is taken of study for any reason, the subject moves into the survival follow-up 
phase. Survival data will be collected from the medical record when available. When possible, 
the patient will be contacted by telephone approximately every 12 weeks to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first.  
 
7.4.9 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with CR in the brain may be eligible for up to one year of 
additional pembrolizumab therapy if they progress systemically.  This retreatment is termed 
the Second Course Phase of this study and is only available if the study remains open and the 
subject meets the following conditions: 
Either  


 
49 
 
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR, and 
▪ Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
▪ Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 
OR 
o Had CR in the brain and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.2 
Female subject of childbearing potential should have a negative serum or urine pregnancy 
test within 72 hours prior to receiving retreatment with study medication. If the urine 
test is positive, cannot be performed or cannot be confirmed as negative, a serum 
pregnancy test will be required.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication. Subjects of child 
bearing potential are those who have not been surgically sterilized or have been free 
from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
 
Visit requirements are outlined in Section 6.0 – Schedule of Events. 
 
7.5 
Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per Table 6 below.  
 


 
50 
 
Table 6 Dose Modification and Toxicity Management Guidelines for Immune -related AEs 
Associated with Pembrolizumab  
General instructions: 
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 
and corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of 
last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive 
treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs 
and symptoms of pneumonitis 
• 
Evaluate participants with 
suspected pneumonitis with 
radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus). 
• 
Participants with ≥ Grade 2 
diarrhea suspecting colitis 
should consider GI consultation 
and performing endoscopy to 
rule out colitis.  
• 
Participants with 
diarrhea/colitis should be 
advised to drink liberal 
quantities of clear fluids.  If 
sufficient oral fluid intake is not 
feasible, fluid and electrolytes 
should be substituted via IV 
infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function 
tests (consider weekly or more 
frequently until liver enzyme 
value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 


 
51 
 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for 
hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and 
symptoms of hypophysitis 
(including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and 
symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and 
symptoms of thyroid disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal 
function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 or 4 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to 
confirm etiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may 
be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in cas e 
of T1DM).   
 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 


 
52 
 
and/or holidays), not to exceed two cycles. Subjects should be placed back on study therapy 
within 3 weeks of the scheduled interruption in all cases other than when pembrolizumab is 
stopped for craniotomy to confirm progression or unless otherwise discussed with the Sponsor. 
The reason for interruption should be documented in the subject’s study record. 
 
There is limited data regarding optimal therapy for refractory and/or persistent side effects 
from pembrolizumab (after discontinuation of pembrolizumab and initiation of steroids). 
These subjects will be managed according to best available practice and guidelines/treatment 
algorithms provided by the drug manufacturer Merck & Co. This may include but not limited 
to the use of drugs such as infliximab (5 mg/kg). If symptoms persist after the first inflixima b 
dose, a second dose of infliximab (5 mg/kg) may be repeated two weeks after the initial dose. 
7.6 
Trial Blinding/Masking 
This is an open-label pilot trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
7.7 
Randomization or Treatment Allocation 
N/A 
 
7.8 
Stratification 
N/A 
 
7.9 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
 
7.9.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded in Epic including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids.   
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
 
7.9.2 Prohibited Concomitant Medications and Therapies 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol 


 
53 
 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• All herbal and natural supplement that are being used will be recorded at all clinic 
visits. Natural therapies and herbal supplements may stimulant or suppress subjects 
immune system. Immune suppressants may reduce the efficacy of pembrolizumab and 
their concomitant use may potentially increase the risk of infections. Concomitant use 
of immune stimulants may potentially increase the risk of adverse auto-immune 
responses. Concomitant use of the natural therapies and herbal supplements in Table 7 
below are prohibited  
• Emerging data suggests that marijuana can affect response rates. The use of marijuana 
and marijuana derived produces are allowed in this study. Subjects will be made aware 
(in the consent form) of the potential risks of using marijuana while on the study. 
 
Table 7 Prohibited Concomitant Natural Therapies and Herbal Supplements 
Name  of herbal supplement 
Immune stimulating agents  
1. 
Coriolus MushroomDHEA 
 
2. 
7-keto-DHEA 
 
3. 
Echinacea*  
4. 
European mandrake  
5. 
European mistletoe 
6. 
Fo-Ti Root 
7. 
Ginseng, panax and siberian 
8. 
Glossy Privet (ligustrum) 
9. 
Greater Celandine 
10. Jiaogulan 
11. Larch Arabinogalactan 
12. Lycium 
13. Melatonin 
14. MGN-3 
15. Podophyllum 
16. Pokeweed  
17. Pycnogenol 
18. Coriolus Mushroom 
19. DHEA 
 
 
20. 7-keto-DHEA 
 
21. Echinacea*  
 
22. European mandrake  
 
 
23. European mistletoe 
24. Fo-Ti Root 
25. Ginseng, panax and siberian 
26. Glossy Privet (ligustrum) 
27. Greater Celandine 
28. Jiaogulan 
29. Larch Arabinogalactan 
30. Lycium 
31. Melatonin 
32. MGN-3 
33. Podophyllum 
34. Pokeweed  
35. Pycnogenol 
36. Quillaia 
37. Reishi Mushroom (gandoderma) 
38. Shitake Mushroom 
39. Sweet Annie 
40. Terminalia chebula  
41. Thunder god vine 
42. Wild indigo 
43.  Zinc  
Note:*Can be immune suppressing also 
 
Immune suppressing agents 
1. 
Bitter Melon  
2. 
Caramel Color  
8. Fish Oils  
9. Licorice 


 
54 
 
3. 
Carrageenan(intravenous only) 
4. 
Echinacea** 
5. 
Indole-3-carbinol  
6. 
Ipriflavone 
7. 
Hydrazine  
 
10. Periwinkle(vinca) 
11. Poria Mushroom  
Note : ** Can be immune stimulating also 
 
 
 
 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
   
7.10 Pharmacokinetic/Pharmacodynamic Evaluations 
NA 
 
7.11 Blood Collection for Anti-Pembrolizumab Antibodies  
NA 
7.12 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 9 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.4.9.  After discontinuing treatment following assessment of 
CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.4.6) and then proceed to the Follow-Up Period of the study (described in Section 7.4.7). 
 
7.13 Blinding/Unblinding 
N/A 
7.14 Diet/Activity/Other Considerations 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
 
7.15 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  Non-pregnant, non-
breast-feeding women may be enrolled if they are willing to use 2 methods of birth control or 
are considered highly unlikely to conceive.  Highly unlikely to conceive is defined as 1) 
surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had 
menses for greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study.  The two birth control methods can be either two barrier 
methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should 


 
55 
 
start using birth control from study Visit 1 throughout the study period up to 120 days after the 
last dose of study therapy.  
 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
 
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period. If there is any question that a subject will not 
reliably comply with the requirements for contraception, that subject should not be entered into 
the study. 
 
7.16 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the Sponsor and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).  
  
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner, the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck. 
 
7.17 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
8.0 TUMOR IMAGING, ASSESSMENT OF DISEASE AND 
BIOMARKERS 
8.1 
Imaging Schedule  
• Clinical standard of care MRIs are done at baseline, 12 weeks post radiation and then 
every 9 weeks (see special instructions below for evaluating persistent radiographic 
progression).  
• Ferumoxytol steady state MRIs and serum for biomarkers are done baseline, 12 weeks 
post radiation, anytime there is suspected radiographic progression and 6 weeks after 
suspected radiographic progression.  
 


 
56 
 
Imaging instructions for evaluating persistent radiographic progression: if there is 
suspected progression, subjects undergo a ferumoxytol steady state MRI and continue on 
pembrolizumab for two more cycles (total of 6 weeks). At the 6 week point, clinical standard 
of care and ferumoxytol MRIs will be repeated to confirm persistent radiographic 
progression. If the 6 week scan confirms progression, then pembrolizumab is discontinued 
and subject is evaluated for surgery. If histopathology confirms pseudoprogression or is 
inconclusive, the subject will continue on pembrolizumab every 3 weeks until further 
radiographic progression is suspected. If histopathology confirms progression, the subject 
will be removed from the study. 
 
8.2 
Response assessment 
8.2.1 Brain Lesions:  
 
Complete response (CR): Complete disappearance of all enhancing abnormalities on clinical 
enhanced MRI scan (in the absence of gadolinium, ferumoxytol enhancement will be used).  
Some subjects will have a small but persistent enhancing abnormality on MRI related to biopsy 
or focal hemorrhage.  It is often difficult to ascertain whether this represents a residual nidus 
of tumor or scar tissue.  Adjunctive radiologic studies such as SPECT or PET as clinically 
indicated may be helpful, but often the nature of these abnormalities may only be determined 
by following the subject with serial scans.  If this type of abnormality does not change or slowly 
involutes over time off therapy and corticosteroids, it is reasonable to categorize it as a CR. 
 
Partial Response (PR): At least 50% decrease in the contrast enhancing lesion seen on MRI 
as compared to baseline imaging.  In the event of multiple lesions, the determination of partial 
response will be based on the sum of the bi-dimensional measurements (greatest diameter x 
greatest perpendicular) across lesions AND no new sites of disease 
 
Stable disease (SD): less than a PR but is not progressive disease. 
 
Progressive disease (PD): 
• Suspected Radiographic Progression: progression will be defined by a 20% increase 
in volume of enhancement compared to the best response on clinical standard of care 
MRI. At any time point if progression is suspected on the clinical scan, additional 
steady state ferumoxytol MRI will be performed within 7 days of the clinical scan. 
Progression will then be confirmed with a follow up scan in 4 weeks +/-5 days with a 
clinical standard of care MRI scan and additional ferumoxytol scan. 
 
• Persistent Radiographic Progression: sustained and evident progression greater than  
increase in volume of enhancement compared to best response on a follow up scan at 
least 4 weeks after the scan where progression was suspected as per RANO BM form 
arm 1 or RANO criteria for subjects in arm 2. In cases with persistent radiographic 
progression the date of initial scan when progression was suspected will be considered 
to be the date of progression. 
 
• Appearance of any new lesion or site of disease in the brain during or at the end of 
therapy. 


 
57 
 
 
• Confirmation of true progression: For the purpose of this study, Histopathologic 
evidence of viable tumor cells in patients with persistent radiographic progression will 
be define to have confirmed true progression. True progression is confirmed by 
histopathology, Pembrolizumab will be stopped and patient swill be taken off-study.. 
Patients who refuse biopsy or biopsy is not deemed clinically necessary will be taken 
off study at persistent radiographic progression. However, they will be continued to be 
monitored with clinical MRI scan and until death. 
 
• Pseudoprogression (PsP): for the purpose of this pilot study, PsP may be confirmed 
by imaging or by pathology. 
o PsP Imaging: stable or decrease in volume of enhancement at 4 weeks (+5 days) 
after suspected radiographic progression. 
o PsP pathology: No viable tumor tissue is seen by histopathology evaluation on 
tissue obtained after confirmed radiographic progression by imaging. 
 
• Clinical progression: Subjects may be removed from study if they experience 
symptomatic deterioration without radiographic evidence of disease progression. 
 
Not evaluable (NE): Only relevant if any of the target lesions had additional interventions for 
clinical managements, patient is unable to get follow up scans or images are of poor quality. 
 
Duration of Best Response: The duration of best response is measured from the time 
measurement criteria are met for SD, CR or PR (whichever is first recorded) until the first date 
that recurrent or PD is objectively documented (taking as reference for PD the smallest 
measurements recorded since the treatment started). 
 
Progression free survival and overall survival will be calculated from the date of diagnosis to 
the date of confirmed progression or death, respectively. The date of diagnosis was used 
because the time between the date of diagnosis and the start of treatment or date of enrollment 
may vary due to subject variables or logistical issues based on radiation planning.  
 
8.2.2 Systemic Lesions: 
Measurements based on RECIST version 1.1 will be used to make a diagnosis of suspected 
systemic progression; it will be confirmed using irRC at follow-up.  
 
8.3 
Contrast agents dosing and administration 
Clinical Standard of Care MRI:  
Gadolinium is the preferred contrast agent, when subject qualifies (per institutional policy, see 
section 8.4.2) for gadolinium infusion, but is not required. In subjects that are already enrolled 
and have underwent at least one gadolinium enhanced MRI, but do not qualify to get 
Gadolinium at subsequent imaging time points, non-contrast enhanced MRI can be used as 
clinical MRI. 
 
Dosing of Gadoteridol:  After acquiring precontrast images, gadoteridol (Prohance®, Bracco 
Pharm) will be injected using a power injector. An IV bolus of 0.1 mmol/kg at a flow rate of 


 
58 
 
up to 3 mL/s will be administered, followed by a saline flush during the first DSC sequence. 
The appropriate volume of gadoteridol is based on the subject’s weight (0.2 ml/kg gadoteridol 
= 0.1 mmol/Kg) followed by a 20ml saline flush.  
 
 
Ferumoxytol Imaging 
Ferumoxytol imaging consists of two consecutive days of imaging (early and delayed) and will 
be performed only at time points described in the Schedule of Events (Section 6). 
 
1. Early intravascular phase scan ferumoxytol imaging   
Dosing of ferumoxytol: The total dose of ferumoxytol (AMAG Pharmaceuticals, Inc., 
Cambridge MA) will be 7mg/kg (not exceeding 510mg total).  The ferumoxytol will 
be mixed with normal saline 1:1 solution to dilute to 15mg/ml.  1 mg/Kg IV will be  
injected at the start of the 7th dynamic cycle during the DSC acquisition at a flow rate 
of 3ml/s followed by 20ml saline flush. The rest of the ferumoxytol will be given as IV 
injections at a low flow rate (.1ml/s) followed by 20mg saline flush. The flow rates may 
be adjusted at the physician’s discretion.  
 
2. Delayed (24h) parenchymal phase ferumoxytol scan (optional) 
No contrast agent will be given during this MRI.  
 
8.4 
Image processing 
Image processing will be done at OHSU.  
 
8.4.1 For CNS lesions:  
SS-CBV maps will be created using the high resolution T2*w scans before and after contrast 
agent and ΔR2* maps will be created using the formula ΔR2*=ln(SIpre/SIpost)/TE, in which 
SIpre and SIpost indicate the signal intensities pre- and post ferumoxytol, and TE is the echo 
time. DSC-CBV maps from gadoteridol DSC will be created using a mathematical leakage 
correction method in NordicICE (Nordic Neurolab, Bergen, Norway) an FDA approved 
perfusion MRI software (if gadoteridol could not be given per institutional protocol in section 
8.4.2, only ferumoxytol maps will be used). The coregistration and overlay of CBV maps on 
T1-w MPRAGE will be done using NordicICE as well [36, 42]. The clinical MR sequences, 
such as T1 weighted scans with and without gadoteridol, and T2 weighted pre contrast scans 
will also be read. Images will be read by 2 radiologists. The radiologists will be blinded to the 
type of CBV maps (SS and DSC) and subject information.  
 
8.4.2 Oregon Health & Science University policy on assessment of lab results prior to 
gadolinium based contrast media 
For patients with the following risk factors, a serum creatinine level will be obtained with 
calculation of eGFR according to the following guidelines:   
  
1) Creatinine/eGFR NOT required:  
• Dialysis patients – No eGFR required 
• Dialysis patients are excluded from the requirements in numbers 2 and 3 below.  


 
5 9  
 
  
2)  Cre atinine/e G F R re q uire d wit hin 2 4 h o urs of M RI s c a n:  
•  All in patie nts (inclu des D a y patie nts a n d E R patie nts)  
•  O ut patie nts w h os e m ost re c e nt e G F R < 6 0    
  
3) Cre atinine/e G F R re q uire d wit hin 3 0 da ys of M RI s c a n:    
•  P atie nts > 6 0 ye ars of a ge  
•  O ut patie nts wit h a hist or y of h y perte nsio n re q uirin g me dic atio n  
•  O ut patie nts wit h dia betes mellit us  
•  O ut patie nts 
wit h kid ne y dis e as e: kid ne y tra ns pla nt, sin gle kid ne y, kid n e y 
c a nc er, kid ne y s ur ger y   
•  O ut patie nt c hildre n < 1 ye ar of a ge  
 
T he te c h n olo gist or R N will n otif y t he ra diolo gist f or t he f ollo win g:  
 
1) P atie nt has a hist or y of N S F ( N e p hr o ge nic S yste mic Fibr osis  
2) P atie nt is o n dialysis  
3) P atie nts wit h e G F R < 3 0 m L/ min/ 1. 7 3 m 2  
4) P atie nt re c eive d ga d olini u m bas e d c o ntras t me dia wit hin t he past 2 4 h o urs  
5) F or q uestio ns relate d t o kid ne y f u nctio n or patie nt hist or y  
  
I nf or me d C o ns e nt: T he ra diolo gist will o btain inf or me d c o ns e nt a n d d oc u me nt ris k/ be nefit of 
pr oc e d ure in t he patie nt’s me dic al re c or d f or a n y of t he f ollo wi n g patie nts w h o will be 
re c eivin g I V ga d olini u m-bas e d c o ntrast:  
  
1)  P atie nts wit h e G F R < 3 0  
2)  ) P atie nts o n dialysis 
 
 
 
8. 4.3  F o r s yste mic le si o ns  
Wit h i m m u n ot hera p y tre at me nt, a n incre as e in t otal t u m or b ur de n of pre vio usly sta ble 
s yste mic lesio ns (t u m or flare re a c tio n) has be e n des cribe d [1 ]. Bas e d o n t he loc atio n of t he 
s yste mic lesio ns, a n d t he fe asibilit y of M R i ma gin g, s u bje cts will be offere d o ptio nal 
M R 
i ma gin g of s yste mic lesio ns, t o e valuate res p o ns e as part of t he e x plorat or y e n d p oints. O nly 
s u bje cts wit h me as ure a ble, b ut sta ble, s yste mic in v olve me nt at t he ti me of e nr oll me nt, will be 
c o nsidere d f or t his i ma gin g. S u bje cts m ust pr o vide a d ditio nal c o ns e nt f or t his o ptio nal 
p ortio n of t he st u d y.  
 
Fra ctio nal Blo o d V olu me  (f B V), V ess el Size I n de x ( V SI), a n d V ess el D e nsit y I n de x ( V DI)  values 
will be o btaine d b y definin g a re gio n of interest o ver t he e ntire t u m or are a.  T his pr oc ess will be 
re pe ate d f or 3 c e ntral slic es of t he t u m or f or e ver y lesio n, a n d t he me a n value wit hin t he re gio n of 
interest ( R OI) will be c alc ulate d. T 2 a n d T 2 * values will be o btaine d, usin g G R E a n d S E data 
res pe ctively, b y plottin g 
me a n R OI value at e a c h e c h o, a n d c alc ulatin g t he best-fit e x p o ne ntial 
de c a y f u nctio n. R 2 a n d R 2 * will be define d as t he in vers e of T 2 or T 2 * values; 
, 
 will be 
c alc ulate d as t he ratio of values bef ore a n d after ir o n c o ntrast inje ctio n.  
D R 2
D R 2
*


 
6 0  
 
Fra ctio nal Blo o d V olu me of t he t u m or w as derive d fr o m t he relatio ns hip of 
, fra ctio nal blo o d 
v olu me (f B V) a n d ma g netic field c o nsta nts (
,
) t o c ha n ges in ma g netic s us c e ptibilit y, 
.  
                 
 
 
     
 
   
 
               
 
w here f B V m us cl e  is ass u me d t o be a c o nsta nt of 3 %.  
V ess el Size I n de x will be c o m p ute d usin g t he f ollo win g e q uatio n:  
 
F or n or malize d value c alc ulatio ns, t he first t w o ter ms will be c o nsidere d t o be c o nsta nt f or all 
i ma ges a n d will be t heref ore disre gar de d.  
V ess el D e nsit y I n de x w as c o m p ute d as f ollo ws:  
 
As f or t he V SI c alc ulatio ns, t he first ter m in t he V DI e q uatio n 
will  be disre gar de d d uri n g 
c alc ulatio n of n or malize d values.  
 
P ara ma g netic ma ps will als o ge nerate d b y c alc ulatin g V SI, V DI a n d f B V values o n a v o xel -b y -
v o xel basis. Hist o gra ms will be o btaine d b y plottin g vess el in dic es wit hin a t u m or re gio n -of -
interest a gainst t he fre q ue nc y of oc c urre nc e.  
 
D ata will be re p orte d as f B V, V SI a n d V DI +/ - sta n dar d err or of t he me a n. 
 
8. 5  
T u m o r Tis s ue C olle cti o n a n d C o rrel ati v e  Bl o o d Bi o m ar k e r  St u die s  
8. 5.1  Bl o o d Bi o m ar k e rs  ( o pti o n al) 
•  C orrelate clinic al a n d ra diolo gic al res p o ns e wit h s yste mic i m m u ne res p o ns es usi n g 
m ultic olor flo w c yt o metr y, me as urin g t otal T -c ells ( C D 3 +) wit h C D 4/ C D 8 ratio,  
•  T -Re g ( C D 4 +/ C D 1 2 7 -/ brig ht C D 2 5 +) , D N T ( C D 3 +/ C D 4-/ C D 8-), N aïve T 
( C D 3 +/ C D 4 5 R A +), me m or y T ( C D 3 +/ C D 4 5 R O +), T-c ell a ctivatio n ( C D 3 +/ varia ble 
C D 6 9 +/ varia ble C D 2 5 +/ varia ble H L A -D R),  N K a n d N K -a ctivatio n ( C D 3-
/ C D 5 6 +/ varible C D 1 6 +), t otal B-c ells ( C D 1 9 +), naïve B -c ells ( C D 1 9 +/I g D +/ C D 2 7-), 
me m or y B -c ells ( C D 1 9 +/I g D -/ C D 2 7 +). 
•  Blo o d will be c olle cte d jus t prior t o first d os e of pe m br oliz u ma b, at 1 2 w e e ks after 
ra dios ur ger y, at s us picio n of ra dio gra p hic pr o gressio n, a n d 6 w e e ks after s us pe cte d 
ra dio gra p hic pr o gressio n.  
•  Blo o d s a m ples will be c olle cte d at O H S U a n d pr oc ess e d at t he O H S U res e arc h 
la b orat or y.  
D R 2
*
g B 0
D c
D c =
3
4 p
D R 2, m uscle
*
f B Vm uscle g B 0
=
3
4 p
D R 2, t u m or
*
f B Vt u m org B 0
3
4 p
D R 2, m uscle
*
f B Vm uscle g B 0
=
3
4 p
D R 2, t u m or
*
f B Vt u m org B 0
f B Vt u m or = f B Vm uscle
D R 2, t u m or
*
D R 2, m uscle
*
V SI = 0. 4 2 4( A D C
gD c B 0
)1/ 2 D R 2
*
D R 2
V DI = 3 2 9 D R 2
D R 2
*


 
61 
 
 
8.5.2 Tissue Biomarkers 
PD-L1 testing will be performed by the CRO QualTek Molecular Laboratories.  Any archived 
tissue samples or tissue obtained from brain biopsy prior to enrollment (archival tissue) and 
those obtained at suspected radiographic progression will be sent to the CRO for PD-L1 
expression assay.  We will correlate outcomes and imaging findings with PD-L1 expression in 
archival systemic tumor tissue, brain biopsy prior to enrollment, and tissue obtained at 
persistent radiographic progression. Frozen tissue and fixed tissue blocks from initial lung 
biopsies will be used. In a subset frozen sections and fixed tissue blocks from subjects who 
undergo resection of brain metastases for clinical indications will also be utilized.  
 
9.0 ADVERSE EVENTS 
9.1 
Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Events and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0.  Toxicities will be attributed and 
graded, and action taken with regard to trial treatment will be recorded.  
 
AEs will be attributed as unrelated, related or possibly related to:  
1) pembrolizumab 
2) ferumoxytol 
3) standard of care stereotactic radiosurgery 
 
For subjects receiving treatment with pembrolizumab, all AEs of unknown etiology associated 
with Pembrolizumab exposure should be evaluated to determine if it is possibly an event of 
clinical interest (ECI) of a potentially immunologic etiology (termed immune-related adverse 
events, or irAEs). 
 
9.2 
Sponsor Responsibility for Reporting Adverse Events 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations. 
  
9.3 
OHSU IRB Reporting of Unanticipated Problems and Adverse Events 
Unanticipated Problems (UP) and Adverse Events (AE) will be reported to OHSU IRB 
according to the policies, procedures and guidelines posted on the OHSU IRB web site 
 
http://www.ohsu.edu/research/rda/irb/policies.shtml. 
 
Fatal and life-threatening events must be reported to OHSU IRB within 5 working days after 
the PI learns of the event. If any of these require a change (as determined by the PI or the IRB) 
to the protocol or consent form, the PI will make those changes promptly and submit the 
revised documents to the OHSU IRB. 
 
All other UP reports will be submitted to OHSU IRB no later than 15 calendar days of 
notification of the event.  If the event requires changes as determined by the PI or the IRB) to 
the protocol or consent form, the PI will make the changes promptly and submit the revised 


 
62 
 
documents to the IRB.  UP and AE reports are submitted through OHSU e-IRB and will be 
reviewed by OHSU IRB.   
 
9.4 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
 
Adverse events may occur during the course of the use of Merck product in clinical trials or 
within the follow-up period specified by the protocol, or prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure. 
 
Progression of the cancer under study is not considered an adverse event unless it is considered 
to be drug related by the investigator. 
 
All adverse events will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the Adverse Event case report 
forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is 
described in Section 9.6.3.1. 
 
9.5 
Rescue Medications & Supportive Care 
9.5.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 


 
63 
 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  
 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to follow the treatment 
guidance.. Refer to Section 7.5 for dose modification.  
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
 
9.5.2 Expected AEs due to Pembrolizumab and Guidelines for Management 
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
▪ Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  


 
64 
 
▪ Evaluate subjects with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor subjects for changes 
in thyroid function (labs every 3 months) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
▪ In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
▪ In hypothyroidism, 
thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
▪ Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
▪ Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
 
• Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN):  
o One fatal case of SJS in a clinical trial and one fatal case of TEN in the post-
marketing setting have been reported in patients treated with pembrolizumab. 


 
65 
 
Including these cases, there have been 8 cases of SJS (6 in clinical trials, and 2 
post-marketing) and 2 cases of TEN (both post-marketing) all of which were 
serious. 
o The risk of SJS and TEN is reported at approximately 0.4 - 7 cases per million 
patient years in the general adult population. 
o Independent risk factors include certain medications such as anticonvulsants, 
sulfonamides, aminopenicillins, allopurinol, and NSAIDs. Non-medication 
triggers include infection, contrast media, and vaccinations. 
o Malignancy is associated with an increased mortality rate in patients with SJS 
and TEN. 
 
For signs or symptoms of SJS or TEN, withhold Pembrolizumab and refer the 
patient for specialized care for assessment and treatment. If SJS or TEN is 
confirmed, permanently discontinue Pembrolizumab.  
 
• Immune-mediated myocarditis  
A total of 6 cases of myocarditis have been reported in patients treated with 
pembrolizumab in clinical trials or in an expanded access program. There were was 1 
fatal case reported in a clinical trial. 
 
A search of the literature identified neither background incidence rates nor prevalence 
of myocarditis specifically among cancer patients. Immune-mediated myocarditis 
should be suspected if other causes of myocarditis, such as infection or prior radiation 
therapy, have been excluded. Risk factors include certain medications and treatment 
modalities such as radiation, anthracycline, alkylating agents and most recently 
checkpoint inhibitors. For suspected immune-mediated myocarditis, ensure adequate 
evaluation to exclude other etiologies, and administer corticosteroids.  
 
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
 
 
Table 8 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Table 8 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
Pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 


 
66 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
prophylactic medications indicated for 
< =24 hrs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 50% 
of the original infusion rate (e.g., from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate 
premedication 
should 
be 
permanently discontinued from further trial 
treatment administration. 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
9.5.3 Expected AEs from Ferumoxytol and Guidelines for Management 
Possible risks and side effects of the study agent ferumoxytol from the Ferumoxytol 
Investigator’s brochure 2012 are below. 
 
In Phase III clinical studies in subjects with iron deficiency anemia and chronic kidney disease, 
the most commonly reported side effects (≥2% of subjects) following treatment with 
ferumoxytol were diarrhea, nausea, dizziness, hypotension, constipation, and peripheral 
edema. 
 
Pharmacological class effects commonly associated with marketed IV iron products include 
hypotension and hypersensitivity reactions. In clinical studies of ferumoxytol, hypotension was 
reported in 1.9% (33/1726) of subjects. Three of these subjects (0.2%) had related serious 
hypotensive events, one of which was characterized as an anaphylactoid reaction. All of the 
events resolved on the same day of occurrence without sequelae. Serious hypersensitivity 
reactions have been observed in 0.2% (3/1726) of subjects following administration of 
ferumoxytol. Other adverse reactions potentially associated with hypersensitivity, including 
pruritus, rash, urticaria, or wheezing were reported in 3.7% (63/1726) of subjects; each of these 
reactions occurred in <1% of subjects exposured to ferumoxytol. 
 


 
67 
 
The overall incidence of AEs in a post-marketing study irrespective of relationship to study 
medication was lower in subjects administered ferumoxytol (48%) than in those treated with 
iron sucrose (65%). The incidence of SAEs was higher in ferumoxytol-treated subjects than in 
iron sucrose-treated subjects (9% vs 7%). The incidence of related SAEs was similar between 
the two treatment groups (1% in both groups). The most common AEs among ferumoxytol-
treated subjects were nausea (7.5%) and muscle spasms (5.0%). 
 
In the Phase II imaging study where ferumoxytol was used as an imaging agent (doses 1.0, 2.5 
and 4.0 mg/kg) in subjects with peripheral arterial disease (PAD), there was a possible dose 
dependent increase in overall TEAEs reported in this study. Only 3.5% of the subject 
population experienced TEAEs that were related to ferumoxytol. The majority of the 
treatment-related AEs were mild in severity and were resolved. 6.1% of the subject population 
experienced SAEs that were eventually resolved; none were treatment related. There were 3 
AESIs reported in 3 subjects (2.6%); 1 subject in each dose group experienced 1 AESI. In the 
1.0 mg/kg dose group 1 subject experienced acute hypotension. In the 2.5 mg/kg dose group 1 
subject experienced a hypersensitivity reaction of rash, and in the 4.0 mg/kg dose group 1 
subject experienced a drug hypersensitivity reaction (acute hypersensitivity reaction to 
ferumoxytol). 
 
Given the potential for hypersensitivity and other adverse reactions observed with other IV 
anemia therapies, subjects should be monitored for signs and symptoms of hypotension and 
hypersensitivity following administration of ferumoxytol as outlined in study protocols. 
Ferumoxytol should only be administered when personnel and therapies are immediately 
available for the treatment of anaphylaxis and other hypersensitivity reactions. In the event of 
a ferumoxytol-related adverse reaction, the infusion will be stopped and additional medical 
treatment will be considered depending on the severity of the reaction.    
 
With certain IV iron preparations, mild 
to severe low blood phosphorus 
levels 
(hypophosphatemia) have also frequently been reported following administration, particularly 
in women with heavy AUB. Mild to moderate, asymptomatic reductions in blood phosphorus 
levels have been infrequently observed following ferumoxytol administration. 
 
Elemental iron is essential for normal cell and tissue development, as well as for tumor cell 
growth. There are no clinical data to suggest that therapeutic IV iron supplementation, given 
to correct anemia, stimulates tumor development, despite the theoretical risk. While free iron 
has been implicated in increased oxidative stress, which is potentially associated with cellular 
damage and carcinogenesis, there are no clinical studies to support that transient increases in 
oxidative stress resulting from iron supplementation result in increased tumor growth. 
 
Other potential risks to subjects receiving ferumoxytol include the temporary discomfort at the 
site of injection, as well as the potential for bruising, local infection, and pigmentation 
following IV administration. 
 
There are no studies of ferumoxytol in pregnant women, and the risk to a pregnant mother and 
unborn baby is unknown. In animal studies, ferumoxytol caused fetal malformations and 
decreased fetal weights at maternally toxic doses of 6 times the human daily dose. Thus 


 
68 
 
ferumoxytol should only be used during pregnancy if the potential benefit justifies the potential 
risk to the fetus. 
 
It is also unknown whether ferumoxytol is present in human milk. Animal studies showed that 
when administered daily to pregnant and lactating females, a small amount of ferumoxytol was 
excreted into breast milk. Because many drugs are excreted in human milk and because of the 
potential for adverse reactions in nursing infants, a decision should be made whether to 
discontinue nursing or to avoid ferumoxytol, taking into account the importance of 
ferumoxytol to the mother and the known benefits of nursing. 
 
No data from clinical trials are available regarding overdose of ferumoxytol in humans. During 
the post-marketing phase, several subjects received an overdose of ferumoxytol ranging from 
1 g in 1 day to 2.5 g over 14 days. Only one case of minor rash was observed. 
 
Although this section provides general guidance regarding the risks and side effects associated 
with administration of ferumoxytol, investigators should refer to the protocol for study-specific 
follow-up and the monitoring procedures. 
 
9.6 
Additional IND Reporting Requirements for Ferumoxytol and Pembrolizumab 
Sponsor-investigator of this IND is responsible for compliance with the FDCA (21 U.S.C. §§ 
301 et. seq.) as well as the implementing regulations [Title 21 of the Code of Federal 
Regulations (CFR)]. Responsibilities include: 
• Reporting any unexpected fatal or life-threatening suspected adverse reactions to this 
Division no later than 7 calendar days after initial receipt of the information [21 CFR 
312.32(c)(2)]. If IND is in eCTD format, submit 7-day reports electronically in eCTD 
format. If IND is not in eCTD format, submit 7-day reports by telephone or fax; 
• Reporting any (1) serious, unexpected suspected adverse reactions, (2) findings from 
other clinical, animal, or in-vitro studies that suggest significant human risk, and (3) a 
clinically important increase in the rate of a serious suspected adverse reaction to this 
Division and to all investigators no later than 15 calendar days after determining that 
the information qualifies for reporting [21 CFR 312.32(c)(1)].  If IND is in eCTD 
format, submit 15- day reports to FDA electronically in eCTD format. If IND is not in 
eCTD format, submit 15-day reports in paper format; and 
• Submitting annual progress reports within 60 days of the anniversary of the date that 
the IND went into effect (the date clinical studies were permitted to begin) [21 CFR 
312.33]. 


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Table 9 Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 
CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units 
Action taken  
Did the adverse event cause the Merck product to be discontinued? 
Relationship to 
test drug  
Did the Merck product cause the adverse event? The determination of the likelihood that the Merck product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.  
The following components are to be used to assess the relationship between the Merck product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to the Merck product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of the Merck product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors 
 
 
 


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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
product 
(continued)  
Dechallenge 
Was the Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Merck product; or (3) the trial is a single-dose drug trial); or (4) Merck product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to the Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Merck product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE MERCK PRODUCT, OR IF REEXPOSURE TO THE MERCK PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Merck product or drug class pharmacology 
or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to the Merck product.  The temporal sequence of the AE onset relative to the administration of the Merck product 
is reasonable.  The AE is more likely explained by the Merck product than by another cause. 
No, there is not a reasonable 
possibility Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of the Merck product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.) 


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9.7 
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 
if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentiona l 
overdose without adverse effect.” 
 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety (Attn: Worldwide 
Product Safety;  FAX 215 993-1220). 
 
9.8 
Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously 
reported to them), including the pregnancy of a male subject's female partner that occurs during 
the trial or within 120 days of completing the trial completing the trial, or 30 days following 
cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  All 
subjects and female partners of male subjects who become pregnant must be followed to the 
completion/termination of the pregnancy.  Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events).  If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 993-1220). 
 
9.9 
Immediate Reporting of Adverse Events to the Sponsor and to Merck 
9.9.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 


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• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event  
 
Refer to Table 8 for additional details regarding each of the above criteria. 
 
Any serious adverse event, or follow up to a serious adverse event, including death due to any 
cause other than progression of the cancer under study that occurs to any subject from the time 
the consent is signed through 90 days following cessation of treatment, or the initiation of new 
anti-cancer therapy, whichever is earlier, whether or not related to Merck product, must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety.  
 
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be 
handled in the same manner as SAEs.  
 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time outside of the time period specified in the previous paragraph also must be reported 
immediately to the Sponsor and to Merck. 
 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
 
All subjects with serious adverse events must be followed up for outcome. 
 
9.9.1.1 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning 
when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specifie d 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 


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For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
9.9.2 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
 
10.0  STATISTICAL ANALYSIS PLAN 
Given the exploratory nature of this study, the statistical analyses will be descriptive in nature. 
For the primary and secondary objectives, sensitivity, specificity, rate of adverse event and 
distribution of best responses will be analyzed using proportions and exact 95% confidence 
intervals. Progression free survival and overall survival will be assessed using the Kaplan-
Meier product limit estimates. Outcomes in the exploratory objectives will be summarized 
using descriptive statistics as appropriate and associations between immunological parameters, 
clinical responses, radiological responses and other variables will be explored using two 
sample tests or correlation measures, as appropriate.    
 
10.1 Power and sample size calculation 
This pilot study will enroll 20 subjects. Here we roughly estimate the precision of sensitivity 
and specificity in the primary objective based on 20 subjects.  
 
Assuming that on average, we have n = 2 lesions/subject. Further, we assume that these lesions 
are totally independent based on their biologically and physiologically features (i.e., two 


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lesions grown in the same subject are not more similar or different compared to two lesions 
grown in two subjects). Further, we assume that all subjects will eventually have disease 
progression and due to dropout and inoperable cases, a total of n = 15 subjects will undergo 
surgery. 
 
For sensitivity, assume that we will have data from 12 subjects with true progression who also 
undergo surgery.  (Typically subjects will only be operated on one lesion; some subjects may 
not undergo surgery due to increased volume in more than one lesion; subjects may die due to 
systematic disease etc.).  Then based on n = 12, if we observe 10 subjects (lesions) for whom 
the true progression is correctly identified by Ferumoxytol MRI, then the sensitivity will be 
83% with a 95% CI between 52% and 98% (Table 10).  
 
Table 10: Estimated sensitivity and 95% CI based on 12 subjects (lesions).  
Number of subjects 
(lesions) with true 
progression 
Number of subjects 
(lesions) whose true 
progression was 
detected by 
ferumoxytol MRI 
Sensitivity 
Exact 95% CI of 
sensitivity 
12 
12 
100% 
74% to 100% 
12 
11 
92% 
62% to 99.8% 
12 
10 
83% 
52% to 98% 
12 
9 
75% 
43% to 95% 
12 
8 
67% 
35% to 90% 
 
 
For specificity, we assume that we will observe 8 subjects (about ~40%) who have pseudo-
progression based on followup scan or surgery. Further, assume that among the 8 patients, 50% 
will have pseudo-progression in two lesions and 50% will have pseudo-progression in one 
lesion. Then we will have 12 lesions with pseudo-progression. If we observe 10 lesions for 
whom the pseudo-progression status is correctly identified by Ferumoxytol MRI, then the 
specificity will be 83% with a 95% CI between 52% and 98% (Table 11).  
 
 Table 11: Estimated specificity and 95% CI based on 12 lesions.  
Number of lesions 
with pseudo-
progression 
Number of lesions with 
pseudo-progression 
detected by 
ferumoxytol MRI 
Specificity 
Exact 95% CI of 
specificity 
12 
12 
100% 
74% to 100% 
12 
11 
92% 
62% to 99.8% 
12 
10 
83% 
52% to 98% 
12 
9 
75% 
43% to 95% 
12 
8 
67% 
35% to 90% 
 
 


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10.2 Analysis plan 
For sensitivity and specificity, the unit of the analysis is lesion since lesions within the same 
patients are biologically and physiologically independent based on the opinions of clinical 
experts.  For sensitivity, since each subject only contributes one lesion so the number of 
subjects equal to the number of lesions.  Given this is a pilot study for a rare disease, we aim 
to maximize the use of available data and plan such analysis a-priori. 
 
For the primary and secondary endpoints, sensitivity, specificity, rate of adverse events for 
tolerability and safety, including any potential toxicities involving SOC chemotherapy, and the 
distribution of best responses will be analyzed using proportions and exact 95% confidence 
intervals. In the primary analysis of sensitivity and specificity, the cutoff for rCBV will be 
specified as 1.75,  sensitivity analysis will be based on subjects (lesions) with surgical results, 
and specificity analysis will be based on lesions with pseudo-progression determined based on 
surgical results or follow-up scan, as detailed in the power and sample size calculation section. 
In secondary analysis, we will try other cutoff points for rCBV, and include all subjects that 
will be confirmed with true progression through surgery or follow up imaging.  Progression 
free survival and overall survival will be assessed using the Kaplan-Meier product limit 
estimates for all patients, taking censoring into account.  
 
For exploratory objectives, continuous variables will be summarized using mean and standard 
deviation, or median and range based on the distribution of data. The categorical variables will 
be summarized using frequencies and proportions, with exact 95% CI as appropriate.  
 
Immune responses will be determined by the volume, pattern and intensity of delayed (24hr) 
ferumoxytol uptake and compared between subjects who develop true vs pseudoprogression 
and provide data using Wilcoxon Rank Sum test (volume and intensity) or Fisher’s exact test 
(pattern). ECD8, CD19, CD25, CD27, CD45, CD56, CD45R0, CD45RA, titers of IgD, T 
and T) and correlated with clinical responses (complete response, disease progression, 
pseudoprogression etc.) using Wilcoxon Rank Sum test, and with radiological response (size 
of tumor) using Pearson’s correlation coefficient or Spearman’s correlation coefficient.  
 
Among the 20 subjects, 5 to 10 subjects are expected to have data on PD-1 receptor expression 
(Yes vs. No) and immune cells (T cells, CD4+, CD8+, macrophages, M1, M2 etc) before 
initiation of Pembrolizumab and at the time of progression. If data allow, we will compare the 
PD-1 receptor expression and immune cells data before initiation of pembrolizumab and at the 
time of progression using exact McNemar’s test or Wilcoxon signed test to accommodate the 
paired nature of the data.  
 
Lastly, in subjects with measurable systemic lesions, vascular volume fraction (VVF), vessel 
size index (VSI) and vessel density index (VDI) will be measured and compared between 
subjects with true vs. pseudoprogression, if data allow.  
 
In summary, all these proposed analyses will be conducted on an exploratory basis. A two-
sample t-test may be used if the data show adequate normality. We will only provide 
descriptive statistics if the comparison mentioned above will not yield clinical meaningful 


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results. The purpose of these exploratory analyses is to see whether some preliminary signals 
in the data could be detected.  
 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES 
11.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, 
distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
 
Clinical Supplies will be provided by Merck and AMAG Pharmaceuticals as summarized in 
Table 12. 
 
Table 12 Investigational Product Descriptions 
Product Name & Potency 
Dosage Form 
Investigational Drug - Merck 
1. Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
2. Pembrolizumab 100 mg/4mL 
Solution for Injection 
Investigational Contrast Agent – AMAG Pharmaceuticals 
1. Ferumoxytol 510mg/17mL 
Single Dose Vial 
 
11.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
 
11.3 Clinical Supplies Disclosure 
Pembrolizumab 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
 
Ferumoxytol 
Ferumoxytol is a commercially available agent and is supplied to investigators by purchasing 
through the OHSU research pharmacy. It is FDA approved for iron replacement therapy.  It is 
supplied in single dose vials containing 510 mg per 17 ml.  It is being used in this study off-
label and under a physicians IND.   
 
11.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Receipt and dispensing of both agents will be recorded by 
the OHSU Research Pharmacy. Clinical supplies may not be used for any purpose other than 
that stated in the protocol. 
 


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11.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
 
Upon completion or termination of the study, all unused and/or partially used investigationa l 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to a rra nge  for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
 
12.0  ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
 
12.2 
Retention of Records 
U.S. FDA regulations (21 CFR §312.62[c]) and the ICH Guideline for GCP (see Section 4.9 
of the guideline) require that records and documents pertaining to the conduct of clinical trials 
and the distribution of investigational drug, subject records, consent forms, laboratory test 
results, and medication inventory records, must be retained for 2 years after the last marketing 
application approval in an ICH region or after at least 2 years have elapsed since formal 
discontinuation of clinical development of the investigational product.  All state and local laws 
for retention of records also apply.  
 
For studies conducted outside the U.S. under a U.S. IND, the Principal Investigator must 
comply with the record retention requirements set forth in the U.S. FDA IND regulations and 
the relevant national and local health authorities, whichever is longer. 
 
12.3 Data Collection, Storage, Privacy, Confidentiality and Security 
Research charts will be maintained for each subject and housed in the offices of the PI; only 
the study staff has access to the research charts and these offices are secure, non-public spaces 
that are locked after hours, ensuring that all records will remain confidential and secure. All 
study staff is trained on the subject privacy and confidentiality policies and is up to date on all 
required research staff training. This ensures subject privacy during recruitment, consent and 
all study procedures.  
 


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Data will not be released to any entity other than Merck, the IRB and the Knight Cancer 
Institute, and study personnel. No information that would reveal the identity of the subject such 
as name, social security number, address, or phone number will be disclosed.    
 
Data Storage and disposition: the study team will maintain a password protected database 
(REDCap) for subject enrollment and all data collection. The database (REDCap) will be 
maintained on an OHSU secured, password protected network, and only the study team will 
have access to the spreadsheet, ensuring confidentiality and security of the data. Data will be 
kept indefinitely. 
 
If the investigator relocates or for any reason withdraws from the study, the study records must 
be transferred to an agreed upon designee, such as another institution, another investigator, or 
to OHSU Knight Cancer Institute (KCI) Clinical Trials Office. Records must be maintained 
according to sponsor or FDA requirements. 
 
12.4 OHSU IRB Reporting of Reportable New Information and Adverse Events (only if 
applicable) 
Reportable New Information (RNI) and Adverse Events (AE) will be reported to IRB 
according to the policies, procedures and guidelines posted on the OHSU IRB web site: 
• Fatal and life-threatening RNI will be reported to OHSU IRB within 5 days of 
notification of the event. All other reports will also be submitted to OHSU IRB no later 
than 5 days of occurrence or notification of the event. Copies of the report documents 
will be kept in the study regulatory binder. 
• Reportable New Information is submitted through OHSU eIRB and will be reviewed 
by OHSU Knight Cancer Institute and IRB. 
 
 
12.5 OHSU Knight Cancer Institute Data and Safety Monitoring Plan 
In addition to complete study and pharmacy files, complete records must be maintained on 
each subject treated on this protocol.  OHSU Knight Cancer Institute, through the auditing 
function of the Knight Clinical Trials Office, is responsible for ensuring that all member 
investigators and affiliate investigators conduct clinical research studies in compliance with 
local IRB standards, FDA regulations and NIH policies and in accordance with the Data and 
Safety Monitoring Plan policies and procedures. 
 
The study will be audited by an OHSU KCI Auditor. Newly approved studies may be audited 
any time after enrollment has been initiated. Each OHSU Knight approved treatment protocol 
will be audited on an annual basis in accordance with the Knight Data and Safety Monitoring 
Plan. 
 
The Knight DSMC will review and monitor study progress, toxicity, safety and other data from 
this study. Information that raises any questions about participant safety or protocol 
performance will be addressed by the Investigator, statistician and study team. Should any 
major concerns arise, the Knight DSMC may recommend corrective action and determine 


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whether or not to suspend the study. 
 
The Knight DSMC will review each protocol every 6 months, but may occur more often, if 
required, to review toxicity and accrual data (please refer to Knight DSMP for additional 
details on audit frequency). The Knight DSMC will review accrual, toxicity, response and 
reporting information. Information to be provided to the DSMC may include: participant 
accrual; treatment regimen information; AEs and SAEs reported by category; summary of any 
deaths on study; audit results; and a summary provided by the study team. Other information 
(e.g. scans, laboratory values) will be provided upon request.  
 
Clinical Data & Safety Monitoring 
Monitoring visits will be performed during the study to ensure that the rights and well-being 
of human participants are protected, that the reported trial data are accurate, and that the 
conduct of the trial is in compliance with the protocol, GCP, and applicable regulatory 
requirements.  
 
Details of monitoring activities, including designation of assigned monitoring entities, scope 
of monitoring visits, timing, frequency, duration of visits, and visit reporting, will be included 
in a separate trial-specific monitoring plan (TSMP). 
 
The Investigator agrees that the monitor will be permitted to conduct monitoring visits at 
appropriate intervals. The Investigator agrees to provide all relevant information and 
documentation as requested by the monitor, including access to all original study documents 
and source data, including access to electronic medical records and/or source documents if 
necessary. 
 
The monitor will conduct source data review and verification as outlined in the TSMP, and 
following each visit will generate a report summarizing the visit findings. 
 
Regardless of monitoring entity, the OHSU Sponsor-investigator is ultimately, singularly 
responsible for overseeing every aspect of the design, conduct, and final analysis of his/her 
investigation. 
 
If at any time Investigator noncompliance is discovered at OHSU, the Sponsor-investigator 
shall promptly either secure compliance or end the Investigator’s participation in the study. 
 
Independent audits may be conducted by the Knight DSMC to verify that the rights and well-
being of human participants are protected, that the reported trial data are accurate, that the 
conduct of the trial is in compliance with the protocol and applicable regulatory requirements, 
that monitoring practices are adequate and in compliance with the monitoring plan, and that 
evidence of ongoing investigator oversight is present. 
 
Quality Assurance & Quality Control 
The investigational site will provide direct access to all trial related source data/documents, 
and reports for the purpose of monitoring by the monitor and/or sponsor, and auditing by the 


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Knight DSMC and/or regulatory authorities.  
 
Quality assurance (QA) auditing activities will occur as detailed in the Knight DSMP. All 
discrepancies, queries, deviations, observations, and findings will be compiled into a final audit 
report along with a Corrective and Preventative Action Plan. 
 
The Sponsor-investigator, or study monitor, will verify that the clinical trial is conducted and 
data are generated, documented (recorded), and reported in compliance with the protocol, 
GCP, and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), 
Good Manufacturing Practices (GMP)). 
 
 
12.5.1 
Changes to Protocol 
Any modification of this protocol must be documented in the form of a protocol revision or 
amendment signed by the PI and approved by the KCI and IRB, before the revision or 
amendment may be implemented. The only circumstance in which the amendment may be 
initiated without regulatory approval is for a change necessary to eliminate an apparent and 
immediate hazard to the subject. In that event, the investigator must notify the KCI and IRB in 
writing within 10 working days after the implementation. Investigators holding the IND must 
notify FDA of substantive changes to the protocol. 
 
13.0 INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN 
CLINICAL TRIALS 
The following protocol attachment is required by the OHSU Knight Cancer Institute, Clinical 
Research Review Committee in order to meet NIH guidelines on the inclusion of women, 
minorities and children as subjects in clinical research. This policy conforms to section 492B of 
the Public Health Service Act, NIH Revitalization Act of 1993, and Public Law 103-43. 
No OHSU Knight Cancer Institute study will focus on any particular gender, racial or ethnic 
subset. No subject will be excluded from the study on the basis of gender, racial or ethnic origin. 
Male, female and minority volunteers will be recruited for this study from the general population 
and approximately 50% men and 50% women will be studied.  
 
The projected gender, racial, and ethnic composition of the study will represent that of the state  
of Oregon.  
 
Table 13 Population Demographics - Oregon (%)              
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
 
 
11.7 
Not Hispanic or Latino 
 
 
88.3 
Ethnic Category: Total of all 
subjects* 
 
 
100* 


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Source:   U.S. Census Bureau, 2010    *Totals may not equal 100 due to rounding. 
 
Table 14 Projected Accrual              
Ethnic Category 
Sex/Gender 
Females 
Males 
Unknown 
Total 
Hispanic or Latino 
1 
1 
 
2 
Not Hispanic or Latino 
9 
9 
 
18 
Unknown 
 
 
 
Ethnic Category: Total of all 
subjects* 
10 
10 
 
20 
Racial Category 
 
American Indian or Alaskan Native  
 
 
Asian 
1 
 
1 
Black or African American 
 
 
 
Native Hawaiian or other Pacific 
Islander 
 
 
 
White 
9 
8 
 
17 
More than one race 
 
1 
 
1 
Unknown 
 
1 
 
1 
Racial Category: Total of all 
subjects* 
10 
10 
 
20 
Source:   Adapted from U.S. Census Bureau, 2010    *Totals may not equal 100 due to 
rounding. 
                  
Racial Category 
 
American Indian or Alaskan Native 
 
 
1.4 
Asian 
 
 
3.7 
Black or African American 
 
 
1.8 
Native Hawaiian or other Pacific 
Islander 
 
 
0.3 
White 
 
 
83.6 
More than one race 
 
 
3.8 
Unknown/Other 
 
 
5.3 
Racial Category: Total of all 
subjects* 
 
 
100* 
TOTALS 
50.4 
49.6 
100* 


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Inclusion of Children 
In accordance with NIH guidelines on the inclusion of children as participants in research 
involving human subjects, children under the age of 18 years must be included in all human 
subjects’ research, conducted or supported by the NIH, unless there are clear and compelling 
reasons not to include them. Therefore, proposals for research involving human subjects must 
include a description of plans for the inclusion of children. 
 
This protocol does not include children for the following reason: No dosing or adverse event 
data are currently available on the use of this Study Agent in this way in subjects <18 years of 
age, therefore, children are excluded from this study but will be eligible for future pediatric 
trials with this Study Agent. 
 
 
 


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14.0 SUPPLEMENTAL MATERIAL 
14.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically 
strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* 
As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, 
T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert 
Comis M.D., Group Chair. 
 
14.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
14.3 Ferumoxytol Investigator’s Brochure 
15.0 APPENDICES 
Appendix A: Ferumoxytol Adverse Events Form 
Appendix B: Pembrolizumab Adverse Events Form 
 
 
 


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