Clinical trial NCT03091478
Conditions: Patients With Leptomeningeal Disease
Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Start date: 2017-04-12; Completion date: 2019-12-14
Enrollment: 13 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label phase II study of pembrolizumab in patients with advanced solid tumors with leptomeningeal carcinomatosis (LMD). Approximately 18 subjects in this study will receive pembrolizumab at a dose of 200mg intravenously (IV) every 3 weeks (Q3W) for 4 doses.

Detailed description:
This is an open-label phase II study of pembrolizumab in patients with advanced solid tumors with leptomeningeal carcinomatosis (LMD). Patients may have received any number of prior therapies for their respective solid tumors, but must not have received prior anti-PD-1 therapy and developed progressive disease. Approximately 18 subjects in this study will receive pembrolizumab at a dose of 200mg intravenously (IV) every 3 weeks (Q3W) for 4 doses. In patients who derive clinical benefit from therapy, pembrolizumab may be continued until documented disease progression, unacceptable adverse event(s), intercurrent illness that prevents further administration of treatment, investigator's decision to withdraw the subject, subject withdrawal of consent, noncompliance with trial treatment or procedure requirements, or for administrative reasons.

Arms: arm 1: Pembrolizumab 200 mg every 3 weeks
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: 200mg every 3 weeks

Protocol documents:
Prot_SAP_000.pdf: 
 
 
TITLE: Pembrolizumab in Patients with Leptomeningeal Disease  
Principal Investigator: 
Jarushka Naidoo, MB BCH 
 
Supporter: 
 
 
Merck Sharp & Dohme Corp. 
2000 Galloping Hill Road  
Kenilworth, NJ 07033 U.S.A. 
Phone: 908-740-4000 
 
Lead Institution: 
Sidney Kimmel Comprehensive Cancer Center 
Johns Hopkins University 
401 N. Broadway 
Baltimore, MD 21231 
United States of America 
 
Participating Site: 
Johns Hopkins Bayview Medical Center 
4940 Eastern Avenue 
Baltimore, MD 21224 
 
IND 131065 Sponsor, Julie Brahmer, MD. 
 
Supplied Agent: 
Pembrolizumab  
 
Version: Protocol Version 2.0 
 
Date: December 4, 2018 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
2 
 
1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab in Leptomeningeal Disease 
Trial Phase 
II 
Clinical Indication 
All solid tumors 
Trial Type 
Interventional 
Type of control 
No Treatment Control 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W) 
Number of trial subjects 
18 subjects 
Estimated enrollment period 
The sponsor estimates that the trial will require approximately 18 months 
from the time the first subject signs the informed consent until the last 
subject signs the informed consent. 
Estimated duration of trial 
The sponsor estimates that the trial will require approximately 24 months 
from the time the first subject signs the informed consent until the last 
subject’s last visit. 
Duration of Participation
6 months 
Estimated average length of 
treatment per patient 
3 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is an open-label phase II study of pembrolizumab in patients with advanced solid tumors 
with leptomeningeal carcinomatosis (LMD). Patients may have received any number of prior 
therapies for their respective solid tumors, but must not have received prior anti-PD-1 therapy 
and developed progressive disease. Approximately 18 subjects in this study will receive 
pembrolizumab at a dose of 200mg intravenously (IV) every 3 weeks (Q3W) for 4 doses. In 
patients who derive clinical benefit from therapy, pembrolizumab may be continued until 
documented disease progression, unacceptable adverse event(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the subject, 
subject withdrawal of consent, noncompliance with trial treatment or procedure requirements, 
or for administrative reasons.  
This study aims to determine if pembrolizumab can cause a radiologic, cytologic or clinical 
response in the CNS in patients with advanced solid tumors with LMD. The primary 
endpoint is thus central nervous system (CNS) response, defined either as radiologic 
response (reduction in size of LMD on gadolinium-enhanced MRI imaging of the brain and 
total spine including T1- weighted, T2-weighted, fluid attenuated inversion recovery and 
post-gadolinium sequences) 
and/or cytologic response (conversion of positive to negative CSF cytology on 2 consecutive 
samples) and/or clinical response (Table 8), as detailed in the section 4.1.5.1.1 and 6.1.2.7. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
3 
 
Secondary endpoints will include progression-free survival (PFS), overall survival (OS), and 
safety.  
Patients will undergo routine screening investigations including CBC, CMP, urine, pregnancy 
test, standard radiologic imaging of the body (CT), cerebrospinal fluid (CSF) sampling for 
cytology, and a pre-treatment gadolinium-enhanced MRI scan of the brain and total-spine. 
During the trial, patients will be monitored with a clinical visit, adverse event assessment and 
routine laboratory tests at the time of each dose of pembrolizumab. Patients will have a CSF 
sample taken, blood draws, radiologic imaging of the body (CT), and a contrast-enhanced MRI 
scan of the brain and total-spine after 2 and 4 cycles of therapy for response assessment and 
correlative studies. In patients with a CSF sample that demonstrates negative cytology, an 
additional confirmatory CSF sample will be obtained 3 weeks after the first negative CSF 
cytology sample.  
After completion of 4 cycles of therapy, subjects will be evaluated every 6-9 weeks with 
radiologic imaging of the body (CT) and CNS (MRI) to assess response to treatment both 
inside and outside of the CNS. Response assessments will be completed by a radiologist at the 
treating site, findings will be confirmed by an independent radiologist, and evaluated by 
RECIST 1.1 criteria and immune-related criteria (irRC) for systemic disease, and MRI criteria 
for CNS disease. Following the first radiologic assessment of the body that demonstrates 
radiologic progressive disease (PD), RECIST 1.1 will be adapted as described in section 
6.1.2.7.5 (Table 9) to accommodate for the tumor response patterns seen with pembrolizumab 
treatment (e.g., tumor flare) using immune-related RECIST criteria. Contrast-enhanced MRI 
Brain scans will be used to assess for measurable disease in the CNS at the time of screening, 
and to determine CNS radiologic response during the study. CNS radiologic response by MRI 
will be defined as a reduction in size of a measurable lesion throughout the neuro-axis, where 
a measurable lesion will be defined as one that is greater than or equal to 3mm in size, as 
detailed in section 6.1.2.7. CNS cytologic response will be assessed by two serial CSF cytology 
samples, as detailed in the section 6.1.2.8.3. Clinical response will be evaluated by the treating 
investigator, detailed in section 6.1.2.7 (Table 8). 
After completion of 4 cycles of therapy or the patient’s last dose of therapy, each subject will 
be followed for 90 days after the end of treatment for adverse event monitoring, or 30 days 
after the end of treatment if the subject initiates new anti-cancer therapy. Subjects who 
discontinue treatment for reasons other than PD will have post-treatment follow-up for disease 
status until PD, initiation of a new cancer therapy, withdrawal of consent, or becoming lost to 
follow-up. All subjects will be followed by telephone contact for overall survival (OS) until 
death, withdrawal of consent or the Investigator is notified by the Sponsor to discontinue 
follow-up, whichever comes first. 
This trial will be conducted in conformance with Good Clinical Practices.  
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart – Section 5.0 Details of each 
procedure are provided in Trial Procedures- Section 6.0. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
4 
 
2.2 
Trial Diagram 
 
3.0 OBJECTIVE(S) & HYPOTHESES 
3.1 
Primary Objective 
(1) To determine whether pembrolizumab 200mg Q3W induces a radiologic, cytologic or 
clinical response in the CNS, in patients with LMD from solid tumors, as defined in section 
4.1.5.1. 
Hypothesis: Pembrolizumab may lead to a CNS response in patients with LMD from solid 
tumors. 
3.2 
Secondary Objectives 
(1) To determine whether pembrolizumab administered in patients with LMD from solid 
tumors improves CNS progression-free survival (PFS) as defined in section 4.1.5.1 
(2) To determine whether pembrolizumab administered in patients with LMD from solid 
tumors improves overall survival (OS), as defined in section 4.1.5.1 
(3) To determine whether pembrolizumab administered in patients with LMD from solid 
tumors, is safe and tolerable, as defined in section 4.1.5.1. 
Hypothesis: Pembrolizumab will improve CNS-PFS and OS in patients with solid tumors 
and LMD. 
Hypothesis: Pembrolizumab will be safe and tolerable in patients with LMD from solid 
tumors. 
3.3 
Exploratory Objectives 
(1) 
To determine whether genomic markers can be detected in the CSF of patients with LMD 
from solid tumors, as detailed in section 4.1.5.2. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
5 
 
(2) 
To investigate potential associations between genomic markers in the CSF and 
CNS/systemic tumor burden, clinical outcomes, and genomic markers in the serum, 
before and after pembrolizumab therapy, as detailed in section 4.1.5.2. 
(3) 
To determine whether immune cells can be detected in the CSF of patients with LMD, 
before and after pembrolizumab, as detailed in section 4.1.5.2. 
(4) 
To investigate potential associations between markers of immune activation on cells in 
the CSF, and clinical outcomes or response to pembrolizumab, as detailed in section 
4.1.5.2. 
Hypothesis: CSF t-DNA will be detectable in the CSF of patients with LMD. CSF t-DNA 
levels may correlate with tumor burden, clinical outcomes, or response to pembrolizumab 
therapy. 
Hypothesis: Immune cells will be detectable in the CSF of patients with LMD, before and 
after pembrolizumab. 
Hypothesis: Markers of immune activation on tumor or immune cells in the CSF will predict 
for improved clinical outcomes or response to pembrolizumab. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background 
information on pembrolizumab (MK-3475). 
 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors. 
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 


J16156 / Protocol version 2.0/ December 4, 2018 
 
6 
 
(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.  KeytrudaTM (pembrolizumab) has recently been approved in the United 
Stated for the treatment of patients with unresectable or metastatic melanoma and disease 
progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
4.1.2 Preclinical and Clinical Trial Data 
Therapeutic studies in mouse models show that administration of antibodies blocking PD-
1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities. Anti–mouse PD-1 and anti–mouse PD-L1 have demonstrated antitumor responses 
as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, melanoma, 
and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-cell 
infiltration into the tumor and the presence of IFN-γ, granzyme B, and perforin, indicating 
that the mechanism of action involved local infiltration and activation of effector T-cell 
function in vivo1-5. In addition, the combination of gemcitabine and anti–PD-L1 mAb 
demonstrated synergy in the rejection of pancreatic mouse tumors1. In-house experiments 
have confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as well as in 
combination with chemotherapy in syngeneic mouse tumor models.  
Immuno-modulatory agents recently showed promising efficacy in multiple cancer types. 
Two recent Phase III studies of IPI, an anti-CTL4 mAb, showed significant prolongation of 


J16156 / Protocol version 2.0/ December 4, 2018 
 
7 
 
overall survival in subjects with melanoma6,7. Recent data with anti–PD-1 antibodies have 
validated PD-1 as an attractive target for clinical intervention8,9. Importantly, responses have 
been of long duration and pembrolizumab is generally well tolerated9. Based on these data 
and considerations, the anti–PD-1 antibody, pembrolizumab, appears to be an attractive 
candidate for continued clinical development in cancer.  
4.1.3 Ongoing Clinical Trials 
Ongoing clinical trials of pembrolizumab are being conducted in advanced melanoma, non-
small cell lung cancer (NSCLC), a number of advanced solid tumor indications and 
hematologic malignancies. For study details please refer to the IB. 
 
In addition, there are published and ongoing clinical studies of immune checkpoint blockade 
in patients with brain metastases, as detailed in section 4.1.4.2 
 
Rationale 
4.1.4 Rationale for the Trial and Selected Subject Population 
4.1.4.1 Anti-PD-1 and Anti-PD-L1 Therapy in Solid Tumors 
Immune checkpoint blockade with anti-PD-1 therapy is a promising treatment option for 
patients with multiple solid tumors. Anti-PD-1 agents nivolumab and pembrolizumab are 
FDA-approved for patients with metastatic melanoma10,11 and second-line NSCLC12,13,14, 
nivolumab monotherapy is approved for renal cell carcinoma15 and Hodjkin’s lymphoma16, 
atezolizumab for bladder carcinoma17, as well as the nivolumab/ipilimumab combination for 
metastatic melanoma18. There are ongoing studies of single agent anti-PD-1 therapy in a 
number of solid tumor indications that have demonstrated promising results19-21, as well as the 
anti-PD-1/PD-L1 plus anti-CTLA-4 combination in NSCLC22,23. Ongoing clinical trials of 
pembrolizumab and other anti-PD-1/PD-L1 agents are being conducted in a number of 
advanced solid tumors and hematologic malignancies. For study details please refer to the IB. 
  
Studies are needed to try to utilize these clinically effective agents in disease settings where 
they have not been previously tested, to advance progress in challenging patient populations 
with limited treatment options.  
 
4.1.4.2 Rationale for Anti-PD-1 therapy in patients with CNS metastatic disease 
CNS metastasis from solid tumors can occur as parenchymal brain metastasis (BM), or 
leptomeningeal metastasis (LMD) or both (BM)24. Parenchymal disease is more common and 
accounts for approximately 80% of CNS metastasis, while LMD is less commonly seen and 
carries a worse prognosis. Immunotherapeutic agents were previously thought to be 
ineffective in patients with CNS metastases, as they would not have the ability to penetrate 
the blood–brain barrier. However, published studies have demonstrated that activated T-cells 
have the ability to pass through the blood-brain barrier25,26. Therefore, immunotherapies that 
reinvigorate T-cell responses might be effective in achieving anti-tumor activity in patients 
with both parenchymal BM and LMD. While patients with stable or treated BM have been 


J16156 / Protocol version 2.0/ December 4, 2018 
 
8 
 
included in many studies utilizing immune checkpoint antibodies to date, patients with LMD 
have been excluded from all of these studies thus far. Patients with LMD thus constitute a 
group of patients with a substantial unmet clinical need. 
 
4.1.4.3 Clinical Studies of Anti-PD-1 therapy in patients with CNS metastatic disease 
 
Immune checkpoint blockade has been investigated for therapeutic efficacy in patients with 
BM. The first immune checkpoint antibody to be clinically investigated in patients with BM 
was the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab. This agent was administered 
at a dose of 3mg/kg Q3W for 4 doses in patients with stage III (unresectable) or IV metastatic 
melanoma with asymptomatic BM, in the context of an expanded access program (EAP). Of 
855 patients participating in the EAP in Italy, 146 had asymptomatic BM. In these patients, the 
median PFS and OS with ipilimumab was 2.8 and 4.3 months, respectively, and nearly one-
fifth of patients were alive 1 year after commencement of ipilimumab. Thus, ipilimumab 
demonstrated durable benefit in selected patients with advanced melanoma metastatic to the 
brain27. In addition, safety data from this study were similar to that of published clinical studies 
in patients with metastatic melanoma without BM. In a subsequent phase II study, the potential 
benefit of ipilimumab in patients with BM from melanoma who were both asymptomatic 
(n=51/72) and symptomatic (n=21/72), was investigated. Patients with asymptomatic BM had 
a 27% rate of CNS disease control (n=12/51) and those with symptomatic BM had a 10% rate 
of CNS disease control (n=2/21). In this study, patients with BM demonstrated similar anti-
tumor activity, 2-year survival, and safety as patients treated with ipilimumab without BM in 
reported studies28.   
The potential clinical benefit of anti-PD-1 therapy with pembrolizumab 10mg/kg Q2W is 
currently being investigated in a phase II study of patients with BM from metastatic melanoma 
or NSCLC, with at least 1 asymptomatic 5-20mm BM not requiring immediate local therapy 
or systemic steroids, and at least 1 BM amenable to biopsy or resection. Seventeen melanoma 
patients have been treated thus far on this clinical study, of which 12 patients were evaluable 
for response, and 42% exhibited either a partial response (PR) or  stable disease (SD) in the 
brain (n=5/12)29. Similarly, 15 patients with NSCLC and BM were treated in this study, and 
10 were evaluable for response. Fifty percent of these patients (n=5/10) demonstrated a 
response in the brain with pembrolizumab (PR=4, CR=1)30. The duration of response in the 
brain was at least 12 weeks in 4 of the 5 responders in the NSCLC patients, and 7+, 6+ and 3+ 
months in the 3 melanoma responders. Taken together, these data indicate that immune 
checkpoint blockade with pembrolizumab may confer clinical benefit in patients with 
metastatic disease in the CNS. 
While immune checkpoint blockade has demonstrated early reports of efficacy in patients with 
parenchymal BM, the potential efficacy of these agents in patients with CNS metastatic disease 
that takes the form of LMD, has not been studied. This group of patients have been excluded 
from therapeutic studies with these agents thus far, and are an underserved group of patients 
with limited or no treatment options.  
4.1.4.4 Current Therapies for Leptomeningeal Disease 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
9 
 
There are no standard therapies for patients with LMD from solid tumors. In patients with 
breast cancer and LMD, intrathecal (IT) chemotherapy with or without radiation to bulky 
disease 31,32 is supported by current NCCN guidelines (Figure 1) based on a small number of 
randomized studies that mainly include patients with breast cancer, and utilize a number of 
response assessment systems (Table 1). These approaches were limited by reduced efficacy 
in the setting of altered CSF flow dynamics (IT therapy), inability to target the entire neuro-
axis (i.e. radiation therapy), and the need for additional treatment to manage systemic or 
parenchymal CNS disease, which is present in the majority of these patients 33,34. In addition, 
IT therapy has been associated with both short and long-term neurotoxicity, and device-
related complications from administration using Ommaya reservoirs. In patients with breast 
cancer, LMD may also be treated with high dose systemic chemotherapy with methotrexate 
(HD-MTX). This is based on two retrospective studies with substantial methodological 
limitations, one which included only one case of breast cancer35, and the second that includes 
patients with both BM alone and BM with LMD36.  
 
There are no recommended treatment strategies for patients with lung cancer or patients with 
any other solid tumor and LMD. Retrospective studies have investigated the role of WBRT37, 
and selected retrospective studies indicate that WBRT may confer a survival benefit in 
patients with LMD from NSCLC38,39. The use of IT chemotherapy with MTX and cytarabine 
has been investigated in patients with NSCLC, small cell lung carcinoma (SCLC) and LMD, 
and demonstrated no OS benefit, cytologic response and some neurologic 
stability/improvement was seen, but SCLC patients were excluded from the analysis40,41. A 
phase I study of high-dose gefinitib in patients with EGFR-mutant NSCLC and LMD 
accrued 7 patients, and did not identify an MTD. In this study, 4 patients had improvement in 
neurological symptoms, 1 patient cleared their CSF of NSCLC cells, and 2 patients 
demonstrated a decrease in CSF tumor cells42. There are reported case series and single cases 
of patients with both EGFR-mutant and ALK-rearranged NSCLC with LMD, who have 
sustained both clinical and radiologic responses to LMD with the use of targeted agents. In 
EGFR-mutant NSCLC, patients with LMD who received erlotinib demonstrated clearance of 
CSF cytology in 64% of cases (n=9/14) as opposed to those who received gefitinib (n=1/11, 
9%)43. In addition, pulsatile high-dose erlotinib has been shown to achieve higher CSF 
concentrations in patients with CNS metastases, and resulted in responses in 2 patients of a 9 
patient series of patients with LMD44, and in 3 of a separate 10-patient series45. In ALK-
rearranged NSCLC, strategies that have yielded CNS responses have included: crizotinib and 
IT-MTX methotrexate (MTX) in 2 crizotinib-naïve patients46, treatment with second-
generation ALK inhibitor ceritinib47, and high dose second-generation inhibition with 
alectinib48. Other strategies that have been used to treat BM in patients with ALK-rearranged 
NSCLC, such as crizotinib and high-dose systemic chemotherapy49, one daily dosing50 or 
high-dose cirizotinib51, have not been studied in patients with LMD. Similarly, case reports 
of melanoma patients detail prolonged survival in BRAF-mutant melanoma treated with 
either vemurafenib52 or dabrafenib53, respectively. This is despite reports that detail variable 
CSF concentrations of vemurafenib compared to systemic concentrations54. 
 
A limited number of prospective studies have been completed in patients with solid tumors 
and LMD. Most recently a phase II study of single agent temozolamide demonstrated a 


J16156 / Protocol version 2.0/ December 4, 2018 
 
10 
 
response rate of 15.8% (n=3/19)55, and single agent pemetrexed, 4% (n=1/21), in all solid 
tumors56 (Table 1). 
 
Patients with areas of bulky LMD that cause obstruction of CSF flow or are thought to be 
causing neurologic deficit, may be treated with local radiation therapy (RT) or WBRT for 
palliation (Figure 1). There are no prospective clinical studies evaluating the use of local RT 
or WBRT alone, however the Southwest Oncology Group (SWOG) investigated the 
combination of WBRT and IT-MTX in solid tumors in 198857 (Table 1). 
 
Interpretation of clinical studies in patients with LMD are complicated by a lack of 
randomized data, and a variety of response assessments used in reported studies. In the 
studies detailed in Table 1 below, response may have been captured as clinical response, 
radiologic response, or cytologic response, or a combination of two or three of these response 
assessments, defined in different ways. Definitions for clinical response on these studies 
included: improvement or stability in neurologic symptoms34,58, improvement in neurologic 
function and KPS at 1 month35, or improvement in neurologic function with cessation of 
steroid use55. Definitions for radiologic response in these studies included: reduction in size 
of measurable lesions on brain MRI36,55, CT brain or myelogram31; and definitions for 
cytologic response may have referred to clearance of previously positive CSF cytology at 1 
month35, or on 2 or more consecutive CSF samples34. In one study, response was defined by 
clinical, radiologic and cytologic parameters, such that a complete responder would 
demonstrate a normal neurologic examination, negative CSF cytology, normal CSF protein 
and glucose, and no measurable disease on CT or myelogram31. In a second study, response 
was defined by clinical and cytologic parameters, with the combination of a negative CSF 
cytology assessment and stable/improved neurologic function as response32. Additionally, 
selected studies included patients with both LMD and parenchymal brain metastases, which 
may confound the interpretation of some response data36,56. Therefore, historical data of 
response rates in patients with LMD are subject to wide variability and interpretation. 
 
Figure 1: NCCN Guideline for the Management of Leptomeningeal Metastasis 
 
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
11 
 
Table 1: Reported Responses for Standard Therapies for Leptomeningeal Disease 
 
 
Study Type 
Treatment 
No. 
Assessable 
Patients 
Disease 
Response 
Rate 
Response 
Criteria 
OS 
Intrathecal chemotherapy 
Grossman et 
al JCO199331 
Prospective 
IT-MTX 
vs. IT-
thiotepa 
52 
Solid 
tumors& 
0% (0/26) 
vs. 0% 
(0/26)  
Clinical+ 
Radiologi
c + 
Cytologic 
response 
15.9 
vs.  
14.1  
weeks 
Glantz et al 
Clin Can Res 
199932 
Prospective 
IT 
cytarabine 
vs. IT-
MTX 
61 
Solid 
tumors@ 
26% (8/31, 
cyt) vs. 
20% (6/30, 
MTX) 
Clnical + 
Cytologic 
11.1 
weeks  
Boogerd et al 
et al 200458 
Prospective 
IT-MTX 
vs. No IT-
MTX 
35 
Breast 
Cancer 
41% (7/17) 
vs. 39% 
(7/18) 
Clinical 
1.8 vs. 
30.3 
weeks 
High-dose chemotherapy 
Glantz et al 
JCO 199835 
Retrospective 
8mg/m2 IV 
HD-MTX 
16 
Solid 
tumors* 
12.5% 
(2/16)* 
Clinical or 
Cytologic 
55.2 
weeks 
Lassman et al 
J Neuro-
Oncol 200636 
Retrospective 
3.5 g/m2 
IV HD-
MTX 
32 
Solid 
tumors# 
28% (9/32)
# 
Radiologi
c or 
Cytologic 
 
12.6 
weeks 
Scott et al J 
Neuro-Oncol 
2014 
Retrospective 
IT MTX + 
liposomal 
cytarabine 
29 
Solid 
tumors$ 
38% 
(11/29) $ 
Clnical + 
Cytologic 
30.2 
weeks 
Standard Chemotherapy 
Segura et al J 
Neuro-oncol 
201255 
Prospective 
Temozolo
mide 
19 
Solid 
tumors” 
10%  
(2/19) 
Clinical+ 
Cytologic 
or 
Radiologi
c 
6.1 
weeks 
Kumthekar et 
al J 
Neurooncol 
201356 
Prospective 
Pemetrexed 
 
21 
Solid 
tumors** 
4% (1/21) 
Clinical + 
Cytologic 
7.3 
months 
Whole Brain Radiation 
 
Sause et al J 
Neuro-oncol 
198857 
Prospective  
WBRT + 
IT-MTX 
26 
Solid 
tumors+ 
31% (8/26) 
 
3.1 
months 
Ozdemir et al 
J Neuro-
Oncol 201637 
Retrospective 
20-30 Gy 
in divided 
doses 
51 
NSCLC 
7% (4/51) 
 
3.9 
months 
*breast cancer (n=1), lymphoma (n=8), SCLC (n=1), NSCLC (n=1), malignant astrocytoma 
(n=4), anaplastic astrocytoma (n=1), clinical response reported here. 
#breast cancer (n=29), cancer of unknown primary (n=1), head and neck carcinoma (n=1), 
NSCLC (n=1) 
$breast cancer (n=15), GBM (n=6), NSCLC (n=5), Other (n=4) 
&breast (n=25), NSCLC (n=12), lymphoma (n=10), Other/Unknown (n=5) 


J16156 / Protocol version 2.0/ December 4, 2018 
 
12 
 
@ breast (n=22), SCLC (n=4), NDCLC (n=6), melanoma (n=14), primary brain (n=14), 
other (n=10) 
+breast cancer (n=17), melanoma (n=3), lung cancer (n=4), bladder cancer (n=1), ovarian 
cancer (n=1) 
^breast cancer (n=13), lung cancer (n=33), stomach cancer (n=5), other (n=4) 
“breast cancer (n=10) NSCLC (n=7), melanoma (n=1), breast and NSCLC (n=1) 
**breast (n=13), lung (n=4), colorectal (n=1), endometrial (n=1), esophageal (n=1) and 
pinealoblastoma (n=1). 
 
4.1.4.5 Rationale for Anti-PD-1 Therapy in Patients with Leptomeningeal Disease 
The most common solid tumors to metastasize to the leptomeninges include: NSCLC 
(25.8%), breast cancer (17.7%), small cell lung cancer (16.9%) and melanoma (8.9%) 59. The 
incidence of LMD by disease-specific tumor type in the era of MRI scans, is estimated at: 
3.8-5% of NSCLC patients60,61, 5% of breast cancer patients62, 2-3% of patients with 
metastatic melanoma63, 2-10% of SCLC patients64, and 0.03% of patients with genitourinary 
carcinomas65. The incidence of LMD is also projected to be higher in patients with 
oncogene-addicted cancers such as NSCLCs that harbor an activating mutation in the 
epidermal growth factor receptor (EGFR), or a chromosomal rearrangement such as EML4-
ALK, or in patients with breast cancer that harbors a HER-2 mutation. These patients appear 
to have a longer clinical course than those without oncogenic driver mutations, and a subset 
of these patients tend to develop CNS progression with LMD. The median survival for 
patients with LMD is estimated at 3-6 months in recently published studies33,39,66. While this 
is relatively rare group of patients, there are no established treatment options for this group of 
patients. These patients thus constitute a critical mass with an empty therapeutic niche. This, 
coupled with compelling early signals of therapeutic efficacy for pembrolizumab in patients 
with BM as detailed above, and the fact that pembrolizumab is a generally well-tolerated 
therapy, makes the use of this agent in patients with LMD an exciting potential treatment 
option. 
 
4.1.4.6 Rationale for Biomarker Discovery in Patients with Leptomeningeal Disease 
 
Response to therapy in patients with LMD has been historically difficult to assess. In 
randomized trials, radiologic response has been assessed by contrast-enhanced MRI scans, and 
CSF response by clearance of initially positive CSF cytology67. However, novel genomic 
biomarkers of tumor burden have been identified in recent years include circulating tumor 
DNA (ctDNA) in the plasma68-70 and in anatomically-relevant fluids such as sputum in lung 
cancer patients71 and endocervical fluid in ovarian/cervix cancer patients72. Furthermore, 
Bettegowda, Vogelstein and colleagues at JHH were able to detect appreciable levels of tDNA 
in the CSF of patients with primary brain tumors, which was more sensitive for tumors that 
abutted a CSF reservoir, and in high-grade tumors73,74. In addition, it has been shown that the 
presence of an effector T-cell population in solid tumors74,75, and the expression of immune 
checkpoint markers such as PD-L1 in infiltrating tumor and immune cells in the tumor 
microenvironment, correlates with prognosis and response to anti-PD-1 therapy in solid tumors 
including NSCLC20 and other solid tumors76. The tumor microenvironment in patients with 
LMD is the CSF, and an assessment of the genomic and immunologic landscape of tumor 
cells/tDNA and immune cells present in the CSF has not been previously described. Since 


J16156 / Protocol version 2.0/ December 4, 2018 
 
13 
 
LMD is in direct contact with CSF reservoirs, this may represent a population of patients in 
which to assess for the presence of CSF t-DNA, and if detectable, potentially expand its use to 
quantify tumor burden and measure response to therapy in these patients.  
4.1.4.7 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) was 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 patients. 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 rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 
2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships 
of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
14 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 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 patient 
exposures in the exposure range established in melanoma as associated with maximal efficacy 
response and 3) will maintain individual patients exposure in the exposure range established 
in melanoma that are well tolerated and safe.  
A fixed dose regimen 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. 
4.1.5 Rationale for Endpoints 
Immune checkpoint blockade has demonstrated benefit in patients with parenchymal BM, but 
has not been studied in LMD. This study will provide an underserved group of patients with 
a treatment option that may benefit them. In addition, next-generation genomic and 
immunologic studies from CSF and serum may uncover new biomarkers in LMD. 
 
4.1.5.1 Efficacy Endpoints 
4.1.5.1.1 Primary Endpoint:  
 
The primary efficacy endpoint is to evaluate CNS response with pembrolizumab in patients 
with LMD from solid tumors. CNS response will be defined either as radiologic response, 
cytologic response, or clinical response, whichever is easier to assess. Radiologic response 
will be defined as a reduction in size of a measurable lesion on a contrast-enhanced MRI scan 
of the brain. Cytologic response will be defined as a negative CSF cytology result in 2 
consecutive samples, in patients who have initial positive cytology prior to treatment, or a 
clinical response, defined as an improvement in objective neurologic signs or symptoms 
attributable to LMD (Table 8). Response assessment is detailed in section 6.1.2.7. 
 
4.1.5.1.2 Secondary Endpoints: 
1. CNS Progression-free Survival: A secondary endpoint of this study is to evaluate CNS-
PFS, which will be defined as the time from study enrollment until CNS progression 
(radiologic, cytologic or clinical), or death, whichever occurs first. CNS progression will be 
classified as radiologic (determined by contrast-enhanced MRI scan), cytologic (determined 
by pathologic assessment of CSF cytology including cell count, differential, glucose) or 
clinical progression (defined as new objective neurologic signs or symptoms, attributable to 
LMD), as detailed in section 6.1.2.7. 
2. Overall Survival: A secondary endpoint of this study is to evaluate OS, which will be 
defined as the time from study enrollment until death from any cause. Deaths from progressive 
disease will be stratified as related to CNS progression, related to systemic progression, or 
both.  
8A 


J16156 / Protocol version 2.0/ December 4, 2018 
 
15 
 
3. Safety: Safety will be evaluated according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE) version 4.027 safety will be 
determined by the number of treatment-related toxicities of > grade 3 severity by CTCAE 
Version 4.0.  
4.1.5.2 Biomarker Research 
Biomarker research will be aimed at identifying prognostic factors for patients with LMD, 
factors important for pembrolizumab therapy, and factors important for predicting response or 
resistance to pembrolizumab and other immunologic targets. Planned biomarker analyses are 
detailed in Table 2 below.   
4.1.5.2.1. Genomic Correlates in CSF 
CSF will be stored in 1 mL aliquots in cryovials, and flash frozen at -80C. Circulating tumor 
DNA will be assessed by Safe-SeqSwith primers and probes specific for tumor mutations as 
described above. CSF tumor cells will be isolated by microdissection. CSF will be collected 
as described in section 6.1.2.8.3.  
Total circulating DNA is defined as the extracellular genome and mitochondrial DNA that is 
present in the CSF. It includes normal as well as mutant DNA and will be quantified by real-
time PCR of a human LINE sequence. Additionally, size distribution of total circulating 
DNA will be determined by amplicons of varying lengths.  
Due to low cellularity, a limited number of analyses can be done on CSF tumor cells. The 
presence of CSF-tDNA in patients with LMD has not been previously assessed at our 
institution. Depending on the number of tumor cells isolated and quantity of CSF-t-DNA 
available, we will assess: 1. Tumor cells and CSF-tDNA by next-generation sequencing, using 
described methods73. From here, candidate neoantigens may be identified using a 
bioinformatics platform.  
4.1.5.2.2 Genomic Correlates in Blood 
Circulating tumor cells and cell-free DNA in serum obtained at pre-selected timepoints in this 
study, will be interrogated genomically. Circulating tumor cells and cfDNA will be obtained 
using methods described by Bettegowda and colleagues. Depending on the number of tumor 
cells isolated and quantity of cf-DNA available, we will assess: 1. Tumor cells and cf-DNA by 
whole-exome sequencing, using methods outlined by Bettegowda and colleagues69, from here, 
candidate neoantigens may be identified using a bioinformatics platform.  
Tumor-specific circulating DNA distinguishes from normal DNA by the occurrence of point 
mutations in tumor derived DNA. We will use Safe-SeqS, a next-generation sequencing 
assay that enables the detection of tumor specific DNA in a high background of normal DNA 
with high sensitivity and specify. In this study a panel of frequent point mutation or other 
genetic mutations specific for each tumor type is used to identify and monitor the fraction of 
tumor DNA. Tumor-specific circulating DNA as measured by the Safe-SeqS assay will be a 
continuous variable and shall be represented as a ratio between the mutant and wild-type 
allele evaluated. The development of techniques to analyze genetic alterations in blood of 


J16156 / Protocol version 2.0/ December 4, 2018 
 
16 
 
patients is a rapidly changing field. The methods used to adequately detect mutated DNA and 
to differentiate it from wild type DNA will be adjusted and modified as appropriate on an 
ongoing basis.  Total circulating DNA is defined as the extracellular genome and 
mitochondrial DNA that is present in the cell-free portion of the blood e.g. plasma or serum. 
It includes normal as well as mutant DNA and will be quantified by real-time PCR of a 
human LINE sequence. Additionally, size distribution of total circulating DNA will be 
determined by amplicons of varying lengths.  We will also collect whole blood in 2x10 mL 
plasma preparation tubes with EDTA (PPT, BD Vacutainer, Franklin Lakes, NJ) and gently 
swirl tubes to mix blood with EDTA. Within two hours of collection, the sample will be 
processed using standard procedures for plasma separation. Plasma will be divided into 1 ml 
aliquots and stored at -80 degrees C. Pellets from this separation procedure will be washed in 
PBS and then divided into aliquots and also stored at -80C. These samples will be collected 
as detailed in section 6.1.2.8.2  
 
4.1.5.2.3. Immunologic Correlates in CSF 
 
Due to low cellularity, a limited number of analyses can be done on CSF immune cells. 
Depending on the number of cells available, analyses will include but may not be limited to: 
1. Quantify the numbers of activated immune cells in the CSF by isolating immune cells with 
cytospin or flow cytometry, and then performing multi-color immunofluorescence with CD3 
and additional immune markers such as PD-1, TIM-3, LAG-3. 2. We will assess immune 
activation markers present in the CSF and multiplex immune cytokine analyses. 
4.1.5.2.4 Immunologic Correlates in Blood 
 
PBMCs and serum will be banked first, and analyses will be prioritized depending on 
numbers of cells available for analysis and CSF findings. Planned analyses may include but 
may not be limited to: 1. T-cell phenotyping of peripheral blood lymphocytes (PBLs) 
evaluated by multi-color flow cytometry for selected immune markers 2. Immune ligand 
expression of PBLs explored using multi-color flow cytometry 3. Soluble immune factors 
using ELISA 4. Antigen-specific T-cells using MHC-multimer assays.  
 
4.1.5.2.5 Tumor Tissue Analyses 
 
Archival tissue, pre-treatment biopsy tissue or on-treatment biopsy tissue will be analyzed in 
patients where this tissue is available. From a genomic perspective, analyses from available 
tumor cells may include but may not be limited to: next generation sequencing of tumor and 
matched normal tissue, this will define the genomic landscape of these tumor cells. 
Candidate neoantigen determination using a bioinformatics platform. From an immunologic 
perspective, analyses from available tumor cells may include but may not be limited to by 
immunohistochemistry using monoclonal antibodies for immune checkpoint ligands and TIL 
populations, immune ligand expression of TILs using multi-color flow cytometry, assessment 
of soluble immune factors in the tumor microenvironment, and assessment for the presence 
of antigen-specific T-cells using MHC-multimer assays. Analyses will be prioritized 
depending on the amount of tissue available for analysis.  
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
17 
 
Table 2: Biomarker Analysis Table 
 
 
 
Pre-Tx 
C1D1 
C2D1 
C3D1 
C4D1 
Post-4 
cycles 
Co-Investigators/ 
Site of Testing 
Pembrolizumab 
 
X 
X 
X 
X 
 
 
Biospecimen collection for analysis 
CSF 
X 
 
 
X 
 
X 
 
PBMCs/Serum 
X 
 
 
X 
 
X 
 
Tumor tissue* 
X* 
 
 
 
 
 
 
Tumor correlates (serum +/- tumor tissue* if available) 
Cell-free DNA 
X 
 
 
X 
 
X 
Bettegowda/ 
Vogelstein Lab 
Immune activation* 
X* 
 
 
 
 
 
Venkatesan Lab 
T-cell correlates (PBLs +/- tumor TILs* if available) 
Immune activation in PBLs 
X 
 
 
X 
 
X 
Venkatesan Lab 
Immune activation in 
TILs* 
X* 
 
 
 
 
 
Venkatesan  Lab 
CSF analysis (tumor cells, CSF- tDNA, immune cells) 
CSF tumor cells 
X 
 
 
X 
 
X 
Bettegowda/ 
Vogelstein Lab 
CSF- tDNA 
X 
 
 
X 
 
X 
Bettegowda/ 
Vogelstein Lab 
CSF immune correlates 
X 
 
 
X 
 
X 
Venkatesan Lab 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
18 
 
 
METHODOLOGY 
 
4.2 
Patient Sample 
4.2.1 Sample Size: The accrual objective for this study is 18 eligible and evaluable patients 
4.2.2 Accrual Rate: The expected accrual rate for this study is approximately 1 patient per 
month 
4.2.3 Gender: Male and Female subjects  
4.2.4 Race: Minorities will be actively recruited. 
4.2.5 Diagnosis/Condition for Entry into the Trial: Patients with advanced solid tumors  
4.2.6 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 for the trial. 
2. Be  18 years of age on day of signing informed consent. 
3. Patients with a histologically or cytologically confirmed solid tumor malignancy. 
4. Cytologically-confirmed LMD or radiologically detectable LMD defined as either/or: 
A) A measurable lesion on contrast-enhanced MRI of either the Brain or Total-Spine  
>3mm that has not been radiated within the last 3 months prior to commencement 
of study therapy.  
B) Positive CSF cytology as defined in section 6.1.2.7. 
5. Patients may be newly diagnosed or have received any number of lines of prior anti-
cancer therapy. However, patients are required to have received available therapies for 
their primary disease, as deemed appropriate by the treating investigator. 
6. Non-escalating steroid requirement at the time of consent and study drug initiation for 
the treatment of CNS symptoms.  
7. Local radiation therapy (RT) is allowed as needed to manage symptoms appropriately, 
as long as there remains a measurable lesion in the CNS.  
8. Whole-brain RT may be used, without a pre-defined washout period, prior to 
commencement of study therapy if the lesion that has been radiated is not the sole 
measurable lesion, or the patient is eligible based on positive CSF cytology. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
19 
 
9. Patients may continue therapy with a targeted agent if CNS disease developed while 
receiving the agent, and for defined regimens that have been deemed safe when 
combined with anti-PD-1 therapy.  
10. Be willing to provide tissue from an archival tissue specimen in selected patients, where 
available.   
11. Have a performance status of 0-1 on the ECOG Performance Scale. 
12. Demonstrate adequate organ function as defined in Table 3, all screening labs should 
be performed within 10 days of treatment initiation.   
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 
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. 
 
13. 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 confirmed as negative, a serum pregnancy test will 
be required.   
14. Female subjects of childbearing potential (Section 4.8.2) must be willing to use an 
adequate method of contraception as outlined in Section 4.8.2 – Contraception,  for the 
course of the study through 120 days after the last dose of study medication. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
20 
 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
15. Male subjects of childbearing potential (Section 4.8.2) must agree to use an adequate 
method of contraception as outlined in Section 4.8.2- Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
4.2.7 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks or 5 half-lives of the first dose of treatment, whichever is shorter. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy that 
exceeds a maximum amount of 10mg of prednisone/day or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment.  
3. Has a known history of active TB   (Bacillus Tuberculosis) 
 
4. Hypersensitivity to pembrolizumab or any of its excipients. 
5. 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. 
6. Has had prior chemotherapy, targeted small molecule therapy other than pre-specified 
allowed agents detailed in section 4.2.6, or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
7. All major surgery including prior surgery to the brain within 3 weeks of 
commencement of study therapy. 
8. 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. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
21 
 
9. Subjects with previously treated brain metastases may participate provided they are not 
using escalating steroids for brain metastases at the time of trial consent and study drug 
initiation, and there remains a measurable lesion in the CNS, as per section 4.2.6. 
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 (e.g. thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
11. Has history of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease or active, non-infectious pneumonitis. 
12. Has an active infection requiring systemic therapy. 
13. Prior disease progression on anti-PD-1 therapy 
14. 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 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.   
15. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
16. 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. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
19. Has received a live vaccine within 30 days of planned start of study therapy. 
20. Contraindication to MRI. 
21. Patients with a condition related to their cancer or leptomeningeal disease requiring 
urgent intervention that has not been clinically managed or stabilized prior to the time 
of consent. 
22. Brain metastases with risk of mass effect that would contraindicate lumbar puncture, 
as detailed in section 6.1.2.8.3. 
23. Live vaccines within 30 days prior to the first dose of trial treatment.  Note:  Seasonal 
influenza vaccines for injection are generally inactivated flu vaccines and are allowed; 


J16156 / Protocol version 2.0/ December 4, 2018 
 
22 
 
however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
4.2.8 Eligibility Screening   
Eligible patients will be reviewed at the weekly Johns Hopkins Neuro-Oncology 
Multidisciplinary Tumor Board for unbiased confirmation of diagnosis and treatment 
candidacy prior to enrollment.  
4.2.9 Patient Registration Procedures   
4.2.9.1. General Registration Guidelines   
All patients entered on any Johns Hopkins trial, whether treatment, companion, or cancer 
control trial, must be registered with the Sidney Kimmel Comprehensive Cancer Center and 
complete Informed Consent. Patients will be registered through CRMS and must be 
registered prior to the initiation of treatment.   
4.2.9.2 Recruitment 
 
 Patients will be recruited through the Brain Cancer Program and the Upper 
Aerodigestive Division (UAD) at Johns Hopkins Medicine. Patients will be recruited 
from the Sidney Kimmel Comprehensive Cancer Center and 1-2 other participating 
sites if accrual is slow. 
 Patient referrals will be accepted from other Johns Hopkins Medicine sites which 
include The Johns Hopkins Hospital, Johns Hopkins Bayview Medical Center, 
Howard County General Hospital, Sibley Memorial Hospital, and Suburban Hospital, 
and the other site. 
 In addition, Johns Hopkins coordinates the Johns Hopkins Clinical Research Network 
(JHCRN) which was founded in 2009 as an integrated network of select academic 
and community-based medical institutions established within the Johns Hopkins 
Institute for Clinical and Translation Research. The JHCRN is comprised of the 6 
hospitals within the Johns Hopkins Medicine, Anne Arundel Medical Center, Greater 
Baltimore Medical Center, INOVA Health Systems, Peninsula Regional Medical 
Center and Reading Hospital and Health System.  
 Referrals from clinicians at these or other facilities will be accepted. In such a case, 
communication will be directed to the Principal Investigator of the study. This contact 
may be in the form of telephone, email, etc. The Principal Investigator may inquire as 
to patient age, diagnosis, prior treatment, timing of prior treatment, and extent of 
current disease to determine whether the patient would meet global criteria for the 
study. This information will not be collected, maintained or stored in any way. 
Patients referred in such a manner will be required to meet in person for review of 
eligibility, registration and informed consent. These patients will be referred to the 
study team members in the Brain Cancer Program and UAD Program at the Johns 


J16156 / Protocol version 2.0/ December 4, 2018 
 
23 
 
Hopkins main campus to review eligibility.  
 Additional potential participants will be identified during routine clinic visits to the 
UAD and Brain Cancer Program at Johns Hopkins. Individuals will be approached by 
the provider or study team to determine willingness to learn more about a study for 
which they may be eligible. Discussions regarding study participation will take place 
privately and individuals will be provided with the IRB approved consent form.  
 In addition, potential participants may contact the study team directly. This contact 
may be in the form of telephone, email, etc. Initial discussions regarding study  
4.3 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 4: 
Table 4: Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment Period 
Use 
Pembrolizumab 
200 mg 
Q3W 
IV infusion 
Day 1 of each 3 week cycle 
Experimental 
 
Trial treatment should begin on the day of registration or as close as possible to the date on 
which treatment is allocated/assigned. 
4.3.1 Dose Selection/Modification 
4.3.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.   
Details on preparation and administration of pembrolizumab (MK-3475) are provided in the 
Pharmacy Manual.   
4.3.1.2 Dose Modification (Escalation/Titration/Other) 
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 5 below. See Section 4.7 for 
supportive care guidelines, including use of corticosteroids. 
Table 5. Dose Modification Guidelines for Drug-Related Adverse Events 


J16156 / Protocol version 2.0/ December 4, 2018 
 
24 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)a 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new onset Type 
1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence 
of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4
Toxicity resolves to Grade 0-1. Therapy 
with pembrolizumab can be continued 
while endocrine replacement therapy is 
instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidis
m  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidis
m 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
 
Infusion 
Reaction 
2b 
Toxicity resolves to Grade 0-1  
Permanently discontinue if toxicity develops despite 
adequate premedication  
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicityc 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 
50% relative to baseline and lasts for at least 1 week then patients should be discontinued. 
b 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 pre-medicated for the next 
scheduled dose; Refer to– Infusion Treatment Guidelines for further management details. 
c Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue 
study drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-1 within 
12 weeks of the last dose. 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
25 
 
4.3.2 Timing of Dose Administration 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 5.0).  Trial treatment may 
be administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
4.3.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
4.4 
Registration or Treatment Allocation 
Assignment of the treatment/allocation number will be directed by the Lead Study Coordinator 
at Johns Hopkins. All enrolled subjects will be allocated to receive pembrolizumab 200mg 
Q3W as monotherapy in an unblinded fashion. 
4.5 
Stratification 
No stratification based on age, sex or other characteristics will be used in this trial. 
4.6 
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.  
4.6.1 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 on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 


J16156 / Protocol version 2.0/ December 4, 2018 
 
26 
 
and fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
Palliative and supportive care is permitted during the course of this trial for underlying medical 
conditions and the management of symptoms. Major surgery for tumor control or symptom 
management is not permitted during the study or within 3 weeks of study commencement, as 
outlined in section 4.2.7. Palliative radiotherapy is permitted if considered medically necessary 
by the treating physician as long as the lesion is not the patient’s sole measurable lesion on 
brain or spine MRI or a defined target lesion in the body by RECIST 1.1, as detailed in section 
4.2.6. Trial therapy should be held during the course of palliative radiation, and should be 
resumed no early than the next schedules dose of trial therapy. The specifics of the radiation 
treatment given, including location, will be recorded. Additionally, patients who receive 
radiation therapy will be analyzed separately to assess the potential impact of radiation therapy 
on clinical outcomes.  
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 6.2. 
4.6.2 Prohibited Concomitant Medications 
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 chemotherapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic lesion or to the brain may be allowed 
as per the inclusion criteria, detailed in section 4.6.1, or at the investigator’s 
discretion.   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
 Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
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. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
27 
 
The Exclusion Criteria describes other medications that are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.7 
Rescue Medications & Supportive Care 
4.7.1 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 
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 does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 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.  
 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, administer oral corticosteroids.  


J16156 / Protocol version 2.0/ December 4, 2018 
 
28 
 
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
 Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
 Hepatic: 


J16156 / Protocol version 2.0/ December 4, 2018 
 
29 
 
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.  
 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 6 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 6. 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); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
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.
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). 
 
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 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
No subsequent dosing 


J16156 / Protocol version 2.0/ December 4, 2018 
 
30 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
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.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
 
4.8 
Diet/Activity/Other Considerations 
4.8.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
4.8.2 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.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   


J16156 / Protocol version 2.0/ December 4, 2018 
 
31 
 
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
Acceptable methods of contraception are‡: 
Single method (one of the following is acceptable): 
• 
intrauterine device (IUD) 
• 
vasectomy of a female subject’s male partner  
• 
contraceptive rod implanted into the skin 
Combination method (requires use of two of the following): 
• 
diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
• 
cervical cap with spermicide (nulliparous women only)   
• 
contraceptive sponge (nulliparous women only)  
• 
male condom or female condom (cannot be used together) 
• 
hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection 
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception.  
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region. 
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 subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy.  If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
32 
 
4.8.3 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 and followed as 
described above and in Section 6.2.2. 
4.8.4 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. 
4.9 
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.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
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. 
 CNS progression (as detailed in Table 8) 
 Unacceptable adverse experiences as described in Section 6.2. 
 Intercurrent illness that prevents further administration of treatment 
 Investigator’s decision to withdraw the subject 
 The subject has a confirmed positive serum pregnancy test 
 Noncompliance with trial treatment or procedure requirements 
 The subject is lost to follow-up 


J16156 / Protocol version 2.0/ December 4, 2018 
 
33 
 
 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. 
 Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 5.0 (Trial Flow 
Chart). 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 6.1.5.1).  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. 
4.9.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab beyond the date when the initial CR was declared.  
4.9.2 Subject Replacement Strategy 
A subject who discontinues from the trial will not be replaced.  
4.10 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.


J16156 / Protocol version 2.0/ December 4, 2018 
 
34 
 
5.0 TRIAL FLOW CHART 
Table 7: Study Flow Chart 
Trial Period: 
Screenin
g Phase 
Treatment Cyclesa 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title:
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
Cycles 5+ only in patients 
showing clinical benefit. 
May continue >8 cycles 
Discon9 
Safety 
Follow-up
Follow Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days):
-28 to -1 
± 38 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
discon 
30 days 
post 
discon 
Every 6-9 
weeks post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Post-study anticancer therapy status 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Vital Signs, Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Oxygen saturation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Pembrolizumab Administration 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum -HCG1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
35 
 
Trial Period: 
Screenin
g Phase 
Treatment Cyclesa 
End of Treatment 
Post-Treatment 
Treatment Cycle/Title:
Study 
Screening 
(Visit 1) 
1 
2  
3 
4 
Cycles 5+ only in patients 
showing clinical benefit. 
May continue >8 cycles 
Discon9 
Safety 
Follow-up
Follow Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days):
-28 to -1 
± 38 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
discon 
30 days 
post 
discon 
Every 6-9 
weeks post 
discon 
Every 
12 
weeks  
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TSH2 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
 
Hepatitis B, C, HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
MRI Brain and Full-spine with contrast 
X 
 
 
X3 
 
X3 
 
 
 
X3 
 
X4 
 
CT chest/abdomen/pelvis with contrast 
X 
 
 
X3 
 
X3 
 
 
 
X3 
 
X4 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
Archival Tissue Collection5  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood collection for Genomics 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
Blood collection for Immune correlates 
X 
 
 
X 
 
X 
 
 
 
X 
 
 
 
CSF sample acquisition6 
X 
 
 
X 
 
X7 
 
 
 
X7 
 
 
 
CSF sample correlates 
X 
 
 
X 
 
X7 
 
 
 
X7 
 
 
 
1 In women of childbearing potential only. If urine test is positive or not evaluable, serum test is required 
2 T3 and Free T4 will be done if TSH is abnormal 
3 Restaging with MRI Brain and CT scan should be completed anytime between cycle 2 and 3, and anytime between cycle 4 and 5. In patients who only received the planned 4 doses of therapy, this is 
replaced with the end of treatment MRI and CT, which should be done within +/-4 weeks of the last dose of therapy 
4 Re-imaging in follow-up will be completed every 9 weeks +/- 7 days or at the treating physician’s discretion.   
5 In patients were tissue is available  
6 Via lumbar puncture or use of a CSF-device if available  
7 In patients who receive +4 treatments, a CSF sample will be taken prior to the 5th treatment. In patients who only received the planned 4 doses of therapy, the second CSF sample and blood collection for 
both genomic and immune correlates is an end-of-treatment sample and should be taken within 2 weeks of the last dose of therapy.  
8Screening labs may be used for Cycle 1 Day 1 if they are done within 3 days of C1D1.  
9the end of treatment visit will be considered to be performed at the date of the last dose of therapy, if the study participant goes on to receive a new anti-cancer agent within 30 days of last  study therapy.


J16156 / Protocol version 2.0/ December 4, 2018 
 
36 
 
6.0 TRIAL PROCEDURES 
6.1 
Trial Procedures 
The Trial Flow Chart – Section 5.0 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. 
6.1.1 Administrative Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
6.1.2.8 General Informed Consent 
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. 
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. 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
37 
 
6.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
6.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
6.1.1.5 Prior and Concomitant Medications Review 
6.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
6.1.1.5.2 Concomitant Medications 
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. 
6.1.1.6 Disease Details and Treatments 
6.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
6.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
6.1.1.6.3 Subsequent Anti-Cancer 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 end-of treatment 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.  


J16156 / Protocol version 2.0/ December 4, 2018 
 
38 
 
6.1.1.7 Assignment of Screening Number 
All consented subjects will be given a unique screening number that will be used to identify 
the subject. Each subject will be assigned only one screening number. Screening numbers must 
not be re-used by different subjects. 
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit. 
Specific details on the screening visit requirements (screening/rescreening) are provided in 
section 6.2.5.3. 
6.1.1.8 Assignment of Treatment Number 
All eligible subjects will be allocated by non-random assignment, and will receive a treatment 
allocation number. The allocation number identifies the subject for all procedures occurring 
after treatment allocation. Once an allocation number is assigned to a subject, it can never be 
re-assigned to another subject. A single subject cannot be assigned more than one allocation 
number. 
6.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol-specified treatment for greater than 12 weeks between 
pembrolizumab doses due to non-drug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management. 
The total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose of pembrolizumab administered. The instructions for the 
preparing and administering of pembrolizumab are provided in the Pharmacy Manual.  
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 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 Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0.  Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  
Please refer to section 6.2 for detailed information regarding the assessment and recording of 
Aes.   


J16156 / Protocol version 2.0/ December 4, 2018 
 
39 
 
6.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  
6.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
6.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
6.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 10.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
6.1.2.6 Post-study Anti-Cancer Therapy Status 
The investigator or qualified designee will review all the new anti-cancer 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. 
6.1.2.7 Tumor Imaging and Assessment of Response  
Evaluation of response will include an evaluation of neurologic signs and symptoms (normal, 
improved, stable, deteriorated), CSF obtained from a previous positive site (lumbar or 
ventricular), and repeated radiologic evaluation of all ancillary studies (MRI Brain and Total 
spine with gadolinium contrast enhancement and CT scans of the body). Patients will be 
evaluated for CNS response based on a 4-point scale: complete response, improvement, stable 
disease and progression, as detailed in the Table below: 
Table 8: Determination of Response to LMD 
Clinical Assessment 
(Neurologic Function) 
Size of LMD disease on MRI or 
CSF cytology 
Overall Response 
Determination 
No neurologic symptoms 
None detectable 
Complete response 


J16156 / Protocol version 2.0/ December 4, 2018 
 
40 
 
Improved 
Stable 
Improved 
Stable 
Improved 
Improved 
Stable 
Stable 
Stable 
Improved 
Progression 
Progression 
Stable 
Progression 
Progression 
Progression 
Improved or Stable 
Progression 
 
We will define a positive CSF cytology result either detectable malignant cells in the CSF, or 
a pathology read that is reported as “suspicious for malignancy.” We will define a negative 
CSF cytology result as either no detectable malignant cells in CSF, or a pathology read of 
“abnormal CSF cytology response,” which will indicate conversion from positive/suspicious 
to negative/abnormal CSF cytology31,32. 
A complete responder will be defined as a patient with a normal neurologic examination, 
negative CSF cytology and no measurable leptomeningeal masses on radiologic imaging. 
Improved patients will be defined as those that have demonstrated improvement in neurologic 
signs or symptoms and/or a 50% decrease in CSF tumor cells or persistent positive CSF 
cytology as defined above, a 50% shrinkage in the bidirectional measurements of 
leptomeningeal disease. Patients with stable disease will be defined as less than 50% 
improvement in number of CSF tumor cells or abnormal CSF cytology response as defined 
above, or reduction in size of LMD on radiologic assessment, without evidence of progression. 
Progression will be defined as more than 25% increase in the number of tumor cells or 
persistent positive CSF cytology as defined above, an increase in size of LMD masses on 
radiologic assessment, or the development of new neurologic signs or symptoms after at least 
2 cycles of pembrolizumab therapy. 
Tumor imaging should be performed by computed tomography (CT) for body imaging 
(preferred) and for the CNS, gadolinium-enhanced MRI imaging of the brain and total spine 
including T1- weighted, T2-weighted, fluid attenuated inversion recovery and post-gadolinium 
sequences. The same imaging technique should be used throughout the trial. CT imaging 
should include the chest, abdomen and pelvis at baseline and all subsequent follow-up time-
points, additional details are in the Site Imaging Manual (SIM). 
6.1.2.7.1. Initial Tumor Imaging 
Initial tumor imaging and screening should be performed within 28 days prior to the date of 
allocation. The site study team must review screening images to confirm the subject is 
assessable for response based on MRI, CSF cytology or clinical presentation, as detailed in 
Table 8.  


J16156 / Protocol version 2.0/ December 4, 2018 
 
41 
 
Tumor imaging performed as part of routine clinical management are acceptable for use as 
initial tumor imaging if they are of diagnostic quality, include all anatomy as described in the 
SIM, and performed within 28 days of the date of allocation. 
6.1.2.7.2. Tumor Imaging During the Trial 
The first on study imaging assessment should be performed anytime between cycle 2 and 3 
of planned therapy, and the second set of imaging should be performed anytime between 
cycle 4 and 5. In patients who only receive the planned 4 doses of therapy, this is replaced 
with the end of treatment MRI and CT, which should be done within 2 weeks of the last dose 
of therapy. Subsequent tumor imaging should be performed Q9W (±7 days) or more 
frequently if clinically indicated until PD. Imaging should not be delayed for delays in cycle 
starts or extension of pembrolizumab cycle intervals.  
To assess radiologic response in the CNS, there are no standard radiologic response criteria 
for LMD on CT or MRI. The RANO group has proposed criteria for measuring BM77, but 
not for LMD. From an extensive review of published literature of clinical trials and 
assessments of LMD in the modern MRI era33,78, we propose using a radiologic cut-off of 
3mm for measurable disease in the neuro-axis by gadolinium-enhanced MRI imaging of the 
brain and total spine including T1- weighted, T2-weighted, fluid attenuated inversion 
recovery and post-gadolinium sequences. 
To assess for response outside of the CNS, per RECIST 1.1, partial or complete response 
should be confirmed by a repeat tumor imaging assessment not less than 4 weeks from the 
date the response was first documented. The tumor imaging for confirmation of response 
may be performed at the earliest 4 weeks after the first indication of response, or at the next 
scheduled tumor imaging (i.e. 9 weeks later), whichever is clinically indicated. Subjects will 
then return to regular scheduled imaging Q9W, starting with the next scheduled imaging time 
point. Subjects who obtain a confirmation imaging assessment do not need to undergo 
scheduled tumor imaging if it is < 4 weeks later and may wait until the next scheduled 
imaging time point.  
Per irRECIST, if radiologic imaging identifies PD, tumor assessment should be repeated ≥ 4 
weeks later in order to confirm PD with the option of continuing treatment while awaiting 
radiologic confirmation of progression. Subjects who obtain confirmation tumor imaging do 
not need to undergo scheduled tumor imaging if it is < 4 weeks later and may wait until the 
next scheduled imaging time point if clinically stable.  
Imaging should continue to be performed until either CNS progression as per Table 8, 
withdrawal of consent, death, or notification by the Sponsor, whichever occurs first.  
If the subject is clinically stable but has radiologic PD outside of the CNS, it is the discretion 
of the PI to continue to treat and image the subject at least 4 weeks after the first tumor 
imaging indicating PD by RECIST 1.1 by the site. irRECIST would then be followed by the 
study site to determine if the follow-up tumor imaging confirms PD (irPD). Subjects who 
have unconfirmed PD may continue on treatment and follow the regular imaging schedule 
intervals until subsequent PD (irPD) is confirmed by the site per irRECIST provided they 


J16156 / Protocol version 2.0/ December 4, 2018 
 
42 
 
have met the conditions detailed in Section 6.1.2.7.5 (Table 8). 
6.1.2.7.3. End of Treatment and Follow-up Tumor Imaging 
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window). If a previous CT scan for body imaging and 
MRI for CNS imaging was obtained within 4 weeks prior to the date of discontinuation, then 
a scan at treatment discontinuation isn’t mandatory.  
6.1.2.7.4 RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be applied as an assessment of systemic tumor response outside the CNS.  
During the follow-up period, imaging will be repeated every Q9W (±7 days) until PD. See 
the Trial Flow Chart for further information. 
6.1.2.7.5 Immune-related RECIST 
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may produce 
anti-tumor effects by potentiating endogenous cancer-specific immune responses. The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and cam manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. RECIST may not provide an 
accurate response assessment of immunotherapeutic agents such as pembrolizumab. Immune-
related RECIST (irRECIST) is RECIST 1.1 adapted as described below to account for the 
unique tumor response seen with immunotherapeutics. Following site identification of PD, 
irRECIST will be used by site investigators to assess tumor response and progression and make 
treatment decisions. 
If radiologic imaging by the site identifies PD by RECIST 1.1, imaging should be repeated >4 
weeks later in order to confirm PD with the option of continuing therapy per below while 
awaiting radiologic confirmation of progression. 
If repeat imaging shows <20% tumor burden compared to nadir, stable or improved previous 
new lesion (if identified as cause for initial PD), and stable/improved non-target disease, if 
identified as cause of initial PD), PD is not confirmed. Treatment may continue and 
subsequently follow the regular imaging schedule. 
If repeat imaging confirms PD (irPD) due to any of the scenarios listed below, this will be 
recorded. However, pembrolizumab may be continued in patients if they have not 
demonstrated CNS progression, as detailed in Table 8, at the discretion of the treating 
investigator. 
If determining whether or not the tumor burden has increased or decreased, site study team 
should consider all target lesions as well as non-target lesions. 
Scenarios where PD is confirmed at repeat imaging: 


J16156 / Protocol version 2.0/ December 4, 2018 
 
43 
 
 Tumor burden remains >20% and at least 5mm absolute increase compared to nadir 
 Non-target disease resulting in initial PD is worse (qualitative) 
 New lesion resulting in initial PD is worse (qualitative) 
 Additional new lesion(s) since last evaluation 
 Additional new non-target progression since last evaluation 
In subjects who have initial evidence of radiologic PD by the site, it is at the discretion of 
the site investigator whether to continue the subject of study treatment, until repeat imaging 
is obtained. This clinical judgment decision should be based in the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Subjects 
may receive study treatment while waiting for confirmation of PD if they are clinically 
stable, as defined by the following criteria: 
 Absence of symptoms and signs indicating clinically significant progression of 
disease including worsening laboratory values 
 No decline in ECOG performance status 
 Absence of rapid progression of disease 
 Absence of progressive tumor at critical anatomical sites (e.g. spinal cord 
compression) requiring urgent alternative medical intervention 
When feasible subjects, radiologic progression should be confirmed. This takes into 
account the observation that some subjects can have transient tumor flare in the first 
few months after the start of immunotherapy, but with subsequent disease response. 
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation of PD.  
Pembrolizumab may be continued in patients with radiologic PD in the body if a subject 
is clinically stable and has not demonstrated CNS progression, as detailed in Table 8 
and Table 9, at the discretion of the treating investigator. 
These details are summarized in Table 9, below. 
Table 9: Imaging and Treatment after First Radiologic Evidence of PD  
 
Clinically Stable 
Clinically Unstable 
 
Tumor imaging 
Treatment 
Tumor imaging 
Treatment 
1st radiologic 
evidence PD 
Repeat tumor 
imaging at > 4 
weeks at site to 
May continue 
study treatment 
at the local site 
Repeat tumor 
imaging at > 4 
weeks to 
Discontinue 
treatment  


J16156 / Protocol version 2.0/ December 4, 2018 
 
44 
 
confirm PD  
 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging 
by site  
 
confirm PD per 
physician 
discretion only  
 
 
Repeat imaging 
confirms PD 
No additional 
tumor imaging 
required 
May continue 
treatment, at 
discretion of 
treating 
investigator 
 
No additional 
tumor imaging 
required  
 
Discontinue 
treatment  
 
Repeating 
imaging show 
SD, PR, CR 
Continue 
regularly 
scheduled 
tumor imaging 
assessments  
 
Continue study 
treatment at the 
local site 
investigator’s 
discretion  
 
Continue 
regularly 
scheduled 
tumor imaging 
assessments  
 
May restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per local site 
investigator’s 
discretion  
 
 
In determining whether or not the tumor burden has increased or decreased, local 
study site investigators should consider all target lesions as well as non-target lesions 
as per irRECIST. Subjects that are deemed clinically unstable are not required to have 
repeat tumor imaging for confirmation.   
For a clinically stable subject with first radiologic evidence of PD (i.e., unconfirmed 
progression of disease), it is at the discretion of the site investigator to continue 
treating the subject with the assigned treatment per protocol until progression of 
disease is confirmed at least 28 days from the date of the tumor imaging first 
suggesting PD. Pembrolizumab may be continued in patients if they have not 
demonstrated CNS progression, as detailed in Table 8, at the discretion of the treating 
investigator.  
irRECIST data will be collected in the clinical database.  
6.1.2.8 Tumor Tissue Collection and Correlative Studies: Blood and CSF Sampling 
6.1.2.8.2 Tumor Tissue Collection 


J16156 / Protocol version 2.0/ December 4, 2018 
 
45 
 
 
Submission of archival tumor tissue is optional in this study. If tumor tissue is available, 
exploratory analyses may be undertaken as detailed in section 4.1.5.2. If there is any leftover 
blood, the tissue will be stored for future research purposes if he/she consents to any separate 
tissue banking protocol. If not, the remaining tissue will be destroyed. 
 
    6.1.2.8.2. Blood collection for Correlative Studies 
 
Additional biomarker research to identify factors important for pembrolizumab therapy as 
detailed in section 4.1.5.2, may be pursued. If there is any leftover blood, the blood will be 
stored for future research purposes if he/she consents to any separate tissue banking protocol. 
If not, the remaining blood will be destroyed. 
 
6.1.2.8.3. CSF Sample collection  
Patients will undergo a lumbar puncture using routine clinical care procedures to collect up to 
10-15cc of CSF for research purposes, after routine clinical CSF is obtained. In patients with 
a CSF-access device such as an Ommaya reservoir or shunt reservoir, the study team may use 
this device to obtain CSF as an alternative to lumbar puncture. A CSF sample will be 
obtained during screening to obtain a “baseline” sample, and assess for eligibility based on 
CSF cytology. In patients who proceed with the study, repeat CSF samples will be obtained 
prior to administration of cycle 3 of therapy and 2-3 weeks after administration of cycle 4 (if 
last treatment, as end-of-treatment sample) or prior to cycle 5, if the patient is planned to 
receive cycle 5. The maximum number of lumbar punctures from an individual patient is 
four. In order to safely complete an LP for the acquisition of a CSF sample, patients must: 
a) Have an ECOG performance status < 2 
b) Have normal laboratory criteria as defined below:  
-Platelets >100,000/mcL  
-PTT above institutional limits  
-INR above institutional limits  
c) No clinical or radiographic evidence of elevated intracranial pressure (such as 
papilledema, obstructive hydrocephalus, or signs of herniation).  
d) Not be taking blood-thinning products such as clopidogrel, low-molecular weight heparin, 
or coumadin.  
5) For patients undergoing an LP, no history of LP complication such as hematoma, 
infection, herniation, or blood patch, and a complicated LP procedure in the past. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
46 
 
6.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided in the trial flow chart. 
6.1.3.1 Local Laboratory Assessments 
Laboratory tests for screening should be performed within 10 days prior to the first dose of 
trial treatment. After cycle 1, pre-dose laboratory tests can be conducted up to 72 hours prior 
to dosing. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Unresolved abnormal 
laboratory tests that are drug-related AEs should be followed until resolution. Laboratory 
tests do not need to be repeated after the end of the treatment if laboratory values are within 
normal range. 
 
6.1.3.2. Serum and Urine Pregnancy Tests 
 
All women who are being considered for participation in the trial who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of 
treatment and 30 days post the last dose of study treatment. If a urine test is positive or not 
evaluable a serum test will be required. Subjects must be excluded/discontinued from the 
study in the event of a positive or borderline-positive test result.  
 
 
 
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
47 
 
Table 10.  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 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free tyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or bicarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
PK 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
48 
 
6.1.3.3. Pharmacokinetic/Pharmacodynamic Evaluations 
6.1.3.3.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
6.1.4 Other Procedures 
6.1.4.1 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 6.2. - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment. After discontinuing treatment, these subjects 
should return to the site for a Safety Follow-up Visit and then proceed to the Follow-Up Period 
of the study as per the Trial Flow Sheet, unless they begin a new anti-cancer agent within 30 
days of the last study treatment, in which case the end of treatment visit will be the day of the 
last dose of study therapy (section 5.0). 
6.1.4.2 Blinding/Unblinding 
This is an open label trial; there is no blinding for this trial.  
6.1.5 Visit Requirements 
Visit requirements are outlined in the Trial Flow Chart- Section 5.0.  Specific procedure-related 
details are provided in section 6.0. 
6.1.5.1 Screening 
6.1.5.1.1 Screening Period 
Approximately 28 days prior to treatment allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.0. Screening 
procedures may be repeated.  
Results of a test performed prior to the subject signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:  
. Laboratory tests and ECOG PS are to be performed within 10 days prior to the first dose of 
trial treatment.   
For women of reproductive potential, a serum pregnancy test will be performed within 72 


J16156 / Protocol version 2.0/ December 4, 2018 
 
49 
 
hours prior to the first dose of trial treatment. A urine test may be considered if serum test is 
not appropriate.  Subjects may be rescreened after initially failing to meet the 
inclusion/exclusion criteria. Results from assessments performed during the initial screening 
period are acceptable in lieu of repeat screening test if performed within the specified time 
frame and the inclusion/exclusion criteria is met. Subjects who are rescreened will retain 
their original screening number.  
6.1.5.2 Treatment Period 
Visit requirements are outlined in the Trial Flow Chart (Section 5.0). Specific procedure- 
related details are provided above in the Trial Procedures (Section 6.0). 
6.1.5.3 Post-Treatment Visits 
6.1.5.3.1. Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur 
within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  
6.1.5.3.2. Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than CNS progression will move 
into the Follow-Up Phase and should be assessed every 6-9 weeks by radiologic imaging to 
monitor disease status.  After 1 year, the imaging time point will occur every 9 weeks (± 7 
days). Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, end of the study.  Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
6.1.5.3.3. Survival Follow-up 
Once a subject experiences confirmed CNS progression or starts a new anti-cancer therapy, 
the subject moves into the survival follow-up phase and should be contacted by telephone 
every 12 weeks to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  
6.2. 
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-


J16156 / Protocol version 2.0/ December 4, 2018 
 
50 
 
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 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/registration must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation through 30 days following cessation of treatment, the 
investigator must report all adverse events. Such events will be recorded 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 7.2.3.1. The investigator will make 
every attempt to follow all subjects with non-serious adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.  
 
6.2.1 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. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
51 
 
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 intentional 
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) 
6.2.2 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) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/registration must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/registration 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies 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) 
6.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
6.2.3.1 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; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is another important medical event  


J16156 / Protocol version 2.0/ December 4, 2018 
 
52 
 
 Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
 Is a new cancer (that is not a condition of the study); 
 Is associated with an overdose. 
 
Refer to Table 11 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/registration, 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 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-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation/registration 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 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 (reference Table 11 for additional details), whether or not related to the Merck product, 
must be reported within 24 hours to the Sponsor and within 2 working days to Merck Global 
Safety. 
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 following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
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. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
53 
 
6.2.4 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/registration, 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-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation 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 6.2.1 - 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.  
6.2.5 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
 
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 6.2.3- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 


J16156 / Protocol version 2.0/ December 4, 2018 
 
54 
 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
6.2.6 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. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
55 
 
Table 11.  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 for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); 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) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. 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 to the Sponsor and to 
Merck within 2 working days. 
 
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 †). 


J16156 / Protocol version 2.0/ December 4, 2018 
 
56 
 
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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that 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 Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to 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 
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 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
57 
 
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 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 Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to 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) 
Sponsor’s 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 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 Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR 
the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 


J16156 / Protocol version 2.0/ December 4, 2018 
 
58 
 
 
 
6.2.7 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.  
7. 
STATISTICAL ANALYSIS PLAN 
7.1. 
Statistical Analysis Plan Summary 
Key elements of the statistical plan are summarized in Table 12 below. A comprehensive plan 
is detailed in section 7.2 
Table 12: Statistical Overview 
Study Design Overview 
Open-label, 
single 
arm 
phase 
II 
study 
of 
pembrolizumab in patients with advanced solid 
tumors with leptomeningeal carcinomatosis (LMD) 
Treatment Assignment 
pembrolizumab 200mg Q3W 
Analysis Population 
Eligible patients who receive at least one dose of 
pembrolizumab 
Primary Endpoint 
CNS response at 12 weeks based on either radiologic, 
cytologic or clinical evidence 
Statistical Methods for  
Key Efficacy Analyses 
The proportion of CNS response and associated 95% 
exact confidence interval will be provided 
Statistical Methods for  
Key Safety Analyses 
Descriptive analysis based on Clopper-Pearson’s 
exact binomial confidence interval method. 
Multiplicity 
N.A. 
Sample Size and Power 
No formal statistical inference will be provided.  The 
proposed sample size will provide appropriate 
estimation precision for the primary efficacy 
endpoint. 
 
7.2. 
Statistical Analysis Plan 
7.2.1 Statistical Plan 
This is an open-label phase II study aimed at establishing the efficacy of single agent 
pembrolizumab, at the FDA-approved dose of 200mg every 3 weeks, in patients with solid 


J16156 / Protocol version 2.0/ December 4, 2018 
 
59 
 
tumors and LMD. The primary endpoint will be CNS response at 12 weeks/after 4 cycles of 
therapy. The sample size is calculated with Clopper-Pearson’s exact binomial confidence 
interval method. With 16 analyzable patients, defined as eligible patients who receive at least 
one dose of pembrolizumab, we determine that we will have an appropriate level of 
estimation accuracy for the first study of this experimental regimen.  The following table 
summarizes the two-sided 90% exact confidence interval for different observed CNS 
response rate. Guarding against a 10% rate of patients either being ineligible or dropping out, 
the final sample size is 18 patients. If a higher rate of ineligible and drop-out rate is observed 
during the study conduct, the protocol may be amended to ensure at least 16 analyzable 
cases. 
 
No. of patients with CNS 
response (%) 
90% Confidence Interval for Observed CNS 
Response Rate (N=16) 
Lower (%) 
Upper (%) 
1 (6.3%) 
0.3 
26.4 
2 (12.5%) 
2.3 
34.4 
3 (18.8%) 
5.3 
41.7 
4 (25%) 
9.0 
48.4 
5 (31.3%) 
13.2 
54.8 
6 (37.5%) 
17.8 
60.1 
 
Secondary endpoints will include CNS-PFS, OS and safety. Kaplan-Meier curves will be 
used to assess CNS-PFS and OS. Cause of death will be recorded. Safety will be assessed as 
detailed above, and monitored as per JHH SKCCC Data Safety and Monitoring Plan. 
Exploratory endpoints will include genomic testing of tumor cells and cell-free DNA in CSF 
and serum, and immunologic studies of immune cells in CSF and serum at pre-defined time-
points. These data will be presented descriptively. Genomic and immunologic correlates 
from available tissue in selected patients, will be presented descriptively. Means and standard 
deviations of all markers will be computed and 95% confidence intervals will be constructed. 
For serum markers, linear regression model (with proper transformation of the data) will be 
used to compare slopes in repeated measures between pre-defined time-points. Our 
institution sees 250 new patients per year with advanced lung cancer, 5% of which will have 
LMD (n=18 in 18 months), 200 new patients with breast cancer, 5% of which will have 
LMD (n=15 patients in 18 months), and selected patients with other solid tumors per year 
with LMD (n=10 per year), not including patients in follow-up. Taking into account that this 
may be a less fit patient population, we conservatively estimate that we will accrue 1 patient 
per month at our institution and 1 additional site that have agreed to participate in the study. 
Study duration will be approximately 24 months, allowing 18 months for accrual and 6 
months for follow-up and data analysis. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
60 
 
 
7.2.2 Responsibility for Analyses  
The statistical analysis of the data obtained from this study will be the responsibility of the 
institution, which is the study sponsor of this trial.  
This trial is being conducted as an open-label study, i.e., subjects, investigators, and sponsor 
personnel will be aware of subject treatment assignments after each subject is enrolled and 
treatment is assigned.  
The Clinical Biostatistics department of the sponsor will generate the allocation schedule.  
7.2.3 Hypotheses/Estimation  
Objectives and hypotheses of the study are stated in Section 3.0.  
7.2.4 Primary Efficacy Endpoint 
CNS response 
CNS response rate is defined as the proportion of the subjects in the analysis population who 
have a radiologic reduction in size of measurable CNS tumor lesions on an MRI brain scan, 
develop clearance of positive CSF cytology on 2 consecutive CSF specimens after an initial 
positive specimen has been obtained, or an improvement in neurologic function, as detailed 
in Table 8. In patients with more than one available response criterion, the most easily 
assessable criterion will be used.  
7.2.5.  Secondary Efficacy Endpoints 
 CNS Progression-Free Survival (PFS) 
PFS is defined as the time from first day of study treatment until date of progression. 
Progression will be stratified into CNS progression (radiologic or cytology or clinical). CNS 
radiologic progression will be assessed by MRI criteria, CNS cytologic progression will be 
determined pathologically, and neurologic progression will be determined as per section 
6.1.2.7 and Table 8 respectively. PFS will be calculated using the Kaplan-Meier method. 
Overall Survival  
Overall survival will be defined as the date of study entry until date of death from any cause. 
Cause of death will be recorded. 
3. Safety  
The primary safety objective of this trial is to characterize the safety and tolerability of 
pembrolizumab in subjects with LMD. The primary safety analysis will be based on subjects 
who experienced toxicities as defined by CTCAE, Version 4.0 criteria (Appendix 2). The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 


J16156 / Protocol version 2.0/ December 4, 2018 
 
61 
 
medications administered will be recorded. AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, specific immune-related 
adverse events (irAEs) will be collected and designated as immune-related events of clinical 
interest (ECIs) as described in Section 6.2.3.2  
8. 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
8.1. 
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 as summarized in Table 13. 
Table 13.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2. 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
8.3. 
Clinical Supplies Disclosure 
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. 
8.4. 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
62 
 
8.5. 
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 investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange 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. 
9. 
ADMINISTRATIVE AND REGULATORY DETAILS 
9.1. 
Confidentiality 
9.1.1 Confidentiality of Data  
The investigator affirms to the Sponsor that information furnished to the investigator by the 
Sponsor will be maintained in confidence, and such information will be divulged to the 
institutional review board, ethics review committee (IRB/ERC) or similar or expert 
committee; affiliated institution and employees, only under an appropriate understanding of 
confidentiality with such board or committee, affiliated institution and employees. Data 
generated by this trial will be considered confidential by the investigator, except to the extent 
that it is included in a publication as provided in the Publications section of this protocol.  
9.1.2. Confidentiality of Subject Records  
The investigator agrees that the Sponsor (or Sponsor representative), IRB/ERC, or regulatory 
authority representatives may consult and/or copy trial documents in order to verify 
worksheet/case report form data. By signing the consent form, the subject agrees to this 
process. If trial documents will be photocopied during the process o f verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.  
By signing this protocol, the investigator agrees to treat all subject data use d and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.  
9.1.3 Confidentiality of Investigator Information  
The investigator recognizes that certain personal identifying information with respect to the 
investigator, and all co-investigators and trial site personnel, may be used and disclosed for 
trial management purposes, as part of a regulatory submissions, and as required by law. This 
information may include:  
. name, address, telephone number and e-mail address;   


J16156 / Protocol version 2.0/ December 4, 2018 
 
63 
 
. hospital or clinic address and telephone number;   
. curriculum vitae or other summary of qualifications and credentials; and   
. other professional documentation.   
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators. By signing this protocol, the investigator expressly consents to these uses and 
disclosures.  
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.  
9.1.4 Confidentiality of IRB/IEC Information  
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial. The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.  
9.2. 
Compliance with Financial Disclosure Requirements 
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/co-investigator's 
responsibility to comply with any such request.  
The investigator/co-investigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/co-investigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/co-investigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.  
9.3. 
Compliance with Law, Audit and Debarment 
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 


J16156 / Protocol version 2.0/ December 4, 2018 
 
64 
 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.  
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1- 
Merck Code of Conduct for Clinical Trials.  
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.  
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.  
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.  
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.  
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements. This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae. By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product. 
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention 


J16156 / Protocol version 2.0/ December 4, 2018 
 
65 
 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained. The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.  
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.  
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.  
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.  
A Sponsor must designate an overall coordinating investigator for a multi-center trial 
(including multinational). For a single-center trial, the Protocol CI is the principal 
investigator. In addition, the Sponsor must designate a principal or coordinating investigator 
to review the trial report that summarizes the trial results and confirm that, to the best of 
his/her knowledge, the report accurately describes the conduct and results of the trial 
[Clinical Study Report (CSR) CI]. The Sponsor may consider one or more factors in the 
selection of the individual to serve as the Protocol CI and or CSR CI (e.g., availability of the 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones). The 
Protocol CI must be a participating trial investigator.  
This is a DSMP Level II study under the SKCCC Data Safety Monitoring Plan 
(12/06/2012). Data monitoring of this protocol will occur on a regular basis with the 
frequency dependent on the rate of subject accrual and the progress of the study. The 
protocol will be monitored internally at SKCCC by the Principal Investigator and externally 
by the SKCCC CRO in accordance with SKCCC guidelines. Trial monitoring and reporting 
will be done through the Safety Monitoring Committee (SMC) at SKCCC. 
 
9.4. 
Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 


J16156 / Protocol version 2.0/ December 4, 2018 
 
66 
 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
9.5. 
Quality Management System 
The Sponsor agrees to be responsible for implementing and maintaining a quality 
management system with written development procedures and functional area standard 
operating procedures (SOPs) to ensure that trials are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of Good 
Clinical Practice, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical trial.  
9.6. 
Data Management 
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data. The investigator acknowledges that his/her electronic signature is the legally 
binding equivalent of a written signature. By entering his/her electronic signature, the 
investigator confirms that all recorded data have been verified as accurate. Detailed 
information regarding Data Management procedures for this protocol will be provided 
separately.  
The study case report forms (CRFs) are the primary data collection instrument for the study. 
All data requested on the CRF will be recorded for each subject. If a procedure was not done 
or a question was not asked, this will be recorded as “N/D”. If the item is not applicable to 
the individual case, this will be recorded as “N/A”. CRFs will be built electronically in 
CRMS. All data will be entered electronically onto the electronic CRF through CRMS by the 
Study Coordinator and/ or Data Manager from each site. 
 
 


J16156 / Protocol version 2.0/ December 4, 2018 
 
67 
 
10. APPENDICES 
10.1. 
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. 
 
10.2. 
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) 
10.3. 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumors 
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study. 
* As published in the European Journal of Cancer: 
 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, 
D. Lacombe, J. Verweij. New response evaluation criteria in solid tumors: Revised RECIST 
guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
In addition, volumetric analysis will be explored by central review for response assessment. 
List of References  


J16156 / Protocol version 2.0/ December 4, 2018 
 
68 
 
1. 
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. 
Clin Cancer Res. Apr 1 2007;13(7):2151-2157. 
2. 
Cai G, Karni A, Oliveira EM, Weiner HL, Hafler DA, Freeman GJ. PD-1 ligands, 
negative regulators for activation of naive, memory, and recently activated human 
CD4+ T cells. Cell Immunol. Aug 2004;230(2):89-98. 
3. 
Blank C, Mackensen A. Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
an update on implications for chronic infections and tumor evasion. Cancer Immunol 
Immunother. May 2007;56(5):739-745. 
4. 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 
on tumor cells in the escape from host immune system and tumor immunotherapy by 
PD-L1 blockade. Proc Natl Acad Sci U S A. Sep 17 2002;99(19):12293-12297. 
5. 
Tsushima F, Tanaka K, Otsuki N, et al. Predominant expression of B7-H1 and its 
immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol. Mar 
2006;42(3):268-274. 
6. 
Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med. Jun 30 2011;364(26):2517-2526. 
7. 
Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med. Aug 19 2010;363(8):711-723. 
8. 
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
anti-PD-1 antibody in cancer. N Engl J Med. Jun 28 2012;366(26):2443-2454. 
9. 
Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab 
(anti-PD-1) in melanoma. N Engl J Med. Jul 11 2013;369(2):134-144. 
10. 
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced 
Melanoma. N Engl J Med. Jun 25 2015;372(26):2521-2532. 
11. 
Weber JS, D'Angelo SP, Minor D, et al. Nivolumab versus chemotherapy in patients 
with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 
037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. Apr 
2015;16(4):375-384. 
12. 
Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus Docetaxel in Advanced 
Nonsquamous 
Non-Small-Cell 
Lung 
Cancer. 
N 
Engl 
J 
Med. 
Oct 
22 
2015;373(17):1627-1639. 
13. 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in Advanced 
Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. Jul 9 2015;373(2):123-
135. 
14. 
Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell 
lung cancer. N Engl J Med. May 21 2015;372(21):2018-2028. 
15. 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in 
Advanced Renal-Cell Carcinoma. The New England journal of medicine. Nov 5 
2015;373(19):1803-1813. 
16. 
Ansell SM, Lesokhin AM, Borrello I, et al. PD-1 blockade with nivolumab in relapsed 
or refractory Hodgkin's lymphoma. The New England journal of medicine. Jan 22 
2015;372(4):311-319. 
17. 
Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with 
locally advanced and metastatic urothelial carcinoma who have progressed following 


J16156 / Protocol version 2.0/ December 4, 2018 
 
69 
 
treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. 
Lancet. May 7 2016;387(10031):1909-1920. 
18. 
Larkin J, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or 
Monotherapy in Untreated Melanoma. N Engl J Med. Sep 24 2015;373(13):1270-1271. 
19. 
Gillison ML BG, Fayette J, Guigay J, Dimitrios Colevas A, Licitra L, Harrington K, 
Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, 
Rordorf F, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Schactman M, Kopit 
J, Shaw JW, Ferris RL. Nivolumab (nivo) vs investigator’s choice (IC) for recurrent or 
metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): CheckMate-141 
American Association for Cancer Research (AACR) Annual Meeting; April 16-20, 
2016; New Orleans, LA. USA. 
20. 
Herbst RS, Soria JC, Kowanetz M, et al. Predictive correlates of response to the anti-
PD-L1 antibody MPDL3280A in cancer patients. Nature. Nov 27 2014;515(7528):563-
567. 
21. 
Le DT, Uram JN, Wang H, et al. PD-1 Blockade in Tumors with Mismatch-Repair 
Deficiency. The New England journal of medicine. Jun 25 2015;372(26):2509-2520. 
22. 
Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of 
durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b 
study. The Lancet. Oncology. Mar 2016;17(3):299-308. 
23. 
Rizvi NA GS, Goldman JW, Hellmann MD, Chow LQ, Juergens R, Borghaei H, 
Brahmer JR, Shen Y, Harbison C, Nathan F, Ready N, Antonia SJ. Safety and Efficacy 
of First-Line Nivolumab (NIVO; Anti-Programmed Death-1 [PD-1]) and Ipilimumab 
in Non-Small Cell Lung Cancer (NSCLC) International Association for the Study of 
Lung Cancer (IASLC) Annual Meeting; September 6-9, 2015; Denver, CO. USA. 
24. 
Lassman AB, DeAngelis LM. Brain metastases. Neurol Clin. Feb 2003;21(1):1-23, vii. 
25. 
Prins RM, Vo DD, Khan-Farooqi H, et al. NK and CD4 cells collaborate to protect 
against melanoma tumor formation in the brain. J Immunol. Dec 15 
2006;177(12):8448-8455. 
26. 
Wilson EH, Weninger W, Hunter CA. Trafficking of immune cells in the central 
nervous system. J Clin Invest. May 2010;120(5):1368-1379. 
27. 
Queirolo P, Spagnolo F, Ascierto PA, et al. Efficacy and safety of ipilimumab in 
patients with advanced melanoma and brain metastases. J Neurooncol. May 
2014;118(1):109-116. 
28. 
Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and 
brain metastases: an open-label, phase 2 trial. Lancet Oncol. May 2012;13(5):459-465. 
29. 
Kluger HM GS, Sznol M, Tsiouris J, Vortmeyer A, Jilaveanu L, Ralabate AL, Rivera 
AL, Burke MM, Hegbe UP, Cohen JV, Yao X, Speaker S, Madura M, Knapp-Perry E, 
Mahajan A, Chiang V. Safety and activity of pembrolizumab in melanoma patients 
with untreated brain metastases. J Clin Oncol. 2015;33:suppl; abstr 9009. 
30. 
Goldberg SB GS, Mahajan A, Herbst R, Chiang A, Tsiouris A, Vortmeyer J, Jilaveanu 
L, Speaker S,  Madura M, Rowen E, Gerrish H, Yao X, Chiang V, Kluger H. . A Phase 
II Trial of Pembrolizumab for Untreated Brain Metastases from Non-Small Cell Lung 
Cancer. Paper presented at: J Thorac Oncol2015; Denver, Colorado, USA. 
31. 
Grossman SA, Finkelstein DM, Ruckdeschel JC, Trump DL, Moynihan T, Ettinger DS. 
Randomized prospective comparison of intraventricular methotrexate and thiotepa in 
patients with previously untreated neoplastic meningitis. Eastern Cooperative 


J16156 / Protocol version 2.0/ December 4, 2018 
 
70 
 
Oncology Group. Journal of clinical oncology : official journal of the American Society 
of Clinical Oncology. Mar 1993;11(3):561-569. 
32. 
Glantz MJ, Jaeckle KA, Chamberlain MC, et al. A randomized controlled trial 
comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal 
methotrexate in patients with neoplastic meningitis from solid tumors. Clinical cancer 
research : an official journal of the American Association for Cancer Research. Nov 
1999;5(11):3394-3402. 
33. 
Clarke JL, Perez HR, Jacks LM, Panageas KS, Deangelis LM. Leptomeningeal 
metastases in the MRI era. Neurology. May 4 2010;74(18):1449-1454. 
34. 
Scott BJ, van Vugt VA, Rush T, et al. Concurrent intrathecal methotrexate and 
liposomal cytarabine for leptomeningeal metastasis from solid tumors: a retrospective 
cohort study. Journal of neuro-oncology. Sep 2014;119(2):361-368. 
35. 
Glantz MJ, Cole BF, Recht L, et al. High-dose intravenous methotrexate for patients 
with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary? 
Journal of clinical oncology : official journal of the American Society of Clinical 
Oncology. Apr 1998;16(4):1561-1567. 
36. 
Lassman AB, Abrey LE, Shah GD, et al. Systemic high-dose intravenous methotrexate 
for central nervous system metastases. Journal of neuro-oncology. Jul 2006;78(3):255-
260. 
37. 
Ozdemir Y, Yildirim BA, Topkan E. Whole brain radiotherapy in management of non-
small-cell lung carcinoma associated leptomeningeal carcinomatosis: evaluation of 
prognostic factors. Journal of neuro-oncology. Jun 15 2016. 
38. 
Chamberlain MC. Carcinomatous meningitis. Arch Neurol. Jan 1997;54(1):16-17. 
39. 
Morris PG, Reiner AS, Szenberg OR, et al. Leptomeningeal metastasis from non-small 
cell lung cancer: survival and the impact of whole brain radiotherapy. Journal of 
thoracic oncology : official publication of the International Association for the Study 
of Lung Cancer. Feb 2012;7(2):382-385. 
40. 
Kim DY, Lee KW, Yun T, et al. Comparison of intrathecal chemotherapy for 
leptomeningeal carcinomatosis of a solid tumor: methotrexate alone versus 
methotrexate in combination with cytosine arabinoside and hydrocortisone. Jpn J Clin 
Oncol. Dec 2003;33(12):608-612. 
41. 
Cole BF, Glantz MJ, Jaeckle KA, Chamberlain MC, Mackowiak JI. Quality-of-life-
adjusted survival comparison of sustained-release cytosine arabinoside versus 
intrathecal methotrexate for treatment of solid tumor neoplastic meningitis. Cancer. 
Jun 15 2003;97(12):3053-3060. 
42. 
Jackman DM, Cioffredi LA, Jacobs L, et al. A phase I trial of high dose gefitinib for 
patients with leptomeningeal metastases from non-small cell lung cancer. Oncotarget. 
Feb 28 2015;6(6):4527-4536. 
43. 
Lee E, Keam B, Kim DW, et al. Erlotinib versus gefitinib for control of leptomeningeal 
carcinomatosis in non-small-cell lung cancer. J Thorac Oncol. Aug 2013;8(8):1069-
1074. 
44. 
Grommes C, Oxnard GR, Kris MG, et al. "Pulsatile" high-dose weekly erlotinib for 
CNS metastases from EGFR mutant non-small cell lung cancer. Neuro Oncol. Dec 
2011;13(12):1364-1369. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
71 
 
45. 
Kawamura T, Hata A, Takeshita J, et al. High-dose erlotinib for refractory 
leptomeningeal metastases after failure of standard-dose EGFR-TKIs. Cancer 
Chemother Pharmacol. Jun 2015;75(6):1261-1266. 
46. 
Ahn HK, Han B, Lee SJ, et al. ALK inhibitor crizotinib combined with intrathecal 
methotrexate treatment for non-small cell lung cancer with leptomeningeal 
carcinomatosis. Lung Cancer. May 2012;76(2):253-254. 
47. 
Arrondeau J, Ammari S, Besse B, Soria JC. LDK378 compassionate use for treating 
carcinomatous meningitis in an ALK translocated non-small-cell lung cancer. J Thorac 
Oncol. Aug 2014;9(8):e62-63. 
48. 
Gainor JF, Chi AS, Logan J, et al. Alectinib Dose Escalation Reinduces Central 
Nervous System Responses in Patients with Anaplastic Lymphoma Kinase-Positive 
Non-Small Cell Lung Cancer Relapsing on Standard Dose Alectinib. J Thorac Oncol. 
Feb 2016;11(2):256-260. 
49. 
Gandhi L, Drappatz J, Ramaiya NH, Otterson GA. High-dose pemetrexed in 
combination with high-dose crizotinib for the treatment of refractory CNS metastases 
in ALK-rearranged non-small-cell lung cancer. J Thorac Oncol. Jan 2013;8(1):e3-5. 
50. 
Peled N, Zach L, Liran O, Ilouze M, Bunn PA, Jr., Hirsch FR. Effective crizotinib 
schedule for brain metastases in ALK rearrangement metastatic non-small-cell lung 
cancer. J Thorac Oncol. Dec 2013;8(12):e112-113. 
51. 
Kim YH, Ozasa H, Nagai H, et al. High-dose crizotinib for brain metastases refractory 
to standard-dose crizotinib. J Thorac Oncol. Sep 2013;8(9):e85-86. 
52. 
Kim DW, Barcena E, Mehta UN, et al. Prolonged survival of a patient with metastatic 
leptomeningeal melanoma treated with BRAF inhibition-based therapy: a case report. 
BMC Cancer. 2015;15:400. 
53. 
Wilgenhof S, Neyns B. Complete Cytologic Remission of V600E BRAF-Mutant 
Melanoma-Associated Leptomeningeal Carcinomatosis Upon Treatment With 
Dabrafenib. J Clin Oncol. Oct 1 2015;33(28):e109-111. 
54. 
Sakji-Dupre L, Le Rhun E, Templier C, Desmedt E, Blanchet B, Mortier L. 
Cerebrospinal fluid concentrations of vemurafenib in patients treated for brain 
metastatic BRAF-V600 mutated melanoma. Melanoma Res. Aug 2015;25(4):302-305. 
55. 
Segura PP, Gil M, Balana C, et al. Phase II trial of temozolomide for leptomeningeal 
metastases in patients with solid tumors. Journal of neuro-oncology. Aug 
2012;109(1):137-142. 
56. 
Kumthekar P, Grimm SA, Avram MJ, et al. Pharmacokinetics and efficacy of 
pemetrexed in patients with brain or leptomeningeal metastases. Journal of neuro-
oncology. Apr 2013;112(2):247-255. 
57. 
Sause WT, Crowley J, Eyre HJ, et al. Whole brain irradiation and intrathecal 
methotrexate in the treatment of solid tumor leptomeningeal metastases--a Southwest 
Oncology Group study. Journal of neuro-oncology. Sep 1988;6(2):107-112. 
58. 
Boogerd W, van den Bent MJ, Koehler PJ, et al. The relevance of intraventricular 
chemotherapy for leptomeningeal metastasis in breast cancer: a randomised study. 
European journal of cancer. Dec 2004;40(18):2726-2733. 
59. 
Brower JV, Saha S, Rosenberg SA, Hullett CR, Ian Robins H. Management of 
leptomeningeal metastases: Prognostic factors and associated outcomes. J Clin 
Neurosci. Jan 8 2016. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
72 
 
60. 
Liao BC, Lee JH, Lin CC, et al. Epidermal Growth Factor Receptor Tyrosine Kinase 
Inhibitors for Non-Small-Cell Lung Cancer Patients with Leptomeningeal 
Carcinomatosis. J Thorac Oncol. Dec 2015;10(12):1754-1761. 
61. 
Riess JW, Nagpal S, Iv M, et al. Prolonged survival of patients with non-small-cell 
lung cancer with leptomeningeal carcinomatosis in the modern treatment era. Clin Lung 
Cancer. May 2014;15(3):202-206. 
62. 
Yap HY, Yap BS, Tashima CK, DiStefano A, Blumenschein GR. Meningeal 
carcinomatosis in breast cancer. Cancer. Jul 1978;42(1):283-286. 
63. 
Chamberlain MC, Johnston SK. Neoplastic meningitis: survival as a function of 
cerebrospinal fluid cytology. Cancer. May 1 2009;115(9):1941-1946. 
64. 
Seute T, Leffers P, ten Velde GP, Twijnstra A. Leptomeningeal metastases from small 
cell lung carcinoma. Cancer. Oct 15 2005;104(8):1700-1705. 
65. 
Yust-Katz S, Mathis S, Groves MD. Leptomeningeal metastases from genitourinary 
cancer: the University of Texas MD Anderson Cancer Center experience. Med Oncol. 
Mar 2013;30(1):429. 
66. 
Lee SJ, Lee JI, Nam DH, et al. Leptomeningeal carcinomatosis in non-small-cell lung 
cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 
Feb 2013;8(2):185-191. 
67. 
Chamberlain MC, Junck L. Defining patients at risk for neoplastic meningitis: what 
parameters can be used to determine who should be treated? Expert Rev Neurother. Jul 
2004;4(4 Suppl):S3-10. 
68. 
Diehl F, Schmidt K, Choti MA, et al. Circulating mutant DNA to assess tumor 
dynamics. Nat Med. Sep 2008;14(9):985-990. 
69. 
Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- 
and late-stage human malignancies. Sci Transl Med. Feb 19 2014;6(224):224ra224. 
70. 
Dawson SJ, Rosenfeld N, Caldas C. Circulating tumor DNA to monitor metastatic 
breast cancer. N Engl J Med. Jul 4 2013;369(1):93-94. 
71. 
Hubers AJ, Prinsen CF, Sozzi G, Witte BI, Thunnissen E. Molecular sputum analysis 
for the diagnosis of lung caner. Br J Cancer. Aug 6 2013;109(3):530-537. 
72. 
Kinde I, Bettegowda C, Wang Y, et al. Evaluation of DNA from the Papanicolaou test 
to 
detect 
ovarian 
and 
endometrial 
cancers. 
Sci 
Transl 
Med. 
Jan 
9 
2013;5(167):167ra164. 
73. 
Wang Y, Springer S, Zhang M, et al. Detection of tumor-derived DNA in cerebrospinal 
fluid of patients with primary tumors of the brain and spinal cord. Proc Natl Acad Sci 
U S A. Aug 4 2015;112(31):9704-9709. 
74. 
Schalper KA. PD-L1 expression and tumor-infiltrating lymphocytes: Revisiting the 
antitumor immune response potential in breast cancer. Oncoimmunology. 
2014;3:e29288. 
75. 
Velcheti V, Schalper KA, Carvajal DE, et al. Programmed death ligand-1 expression 
in non-small cell lung cancer. Lab Invest. Jan 2014;94(1):107-116. 
76. 
Carbognin L, Pilotto S, Milella M, et al. Differential Activity of Nivolumab, 
Pembrolizumab and MPDL3280A according to the Tumor Expression of Programmed 
Death-Ligand-1 (PD-L1): Sensitivity Analysis of Trials in Melanoma, Lung and 
Genitourinary Cancers. PLoS One. 2015;10(6):e0130142. 
77. 
Lin NU, Lee EQ, Aoyama H, et al. Response assessment criteria for brain metastases: 
proposal from the RANO group. Lancet Oncol. Jun 2015;16(6):e270-278. 


J16156 / Protocol version 2.0/ December 4, 2018 
 
73 
 
78. 
Chamberlain M, Soffietti R, Raizer J, et al. Leptomeningeal metastasis: a Response 
Assessment in Neuro-Oncology critical review of endpoints and response criteria of 
published randomized clinical trials. Neuro Oncol. Sep 2014;16(9):1176-1185.