A Phase II Study of Anti-PD-1 (MK-3475) Therapy in Patients With Metastatic Inflammatory Breast Cancer (IBC) or Non-IBC Triple Negative Breast Cancer (TNBC) Who Have Achieved Clinical Response or Stable Disease to Prior Chemotherapy
Phase: PHASE2
Conditions: Edema, Erythema, Estrogen Receptor Negative, HER2/Neu Negative, Peau d'Orange, Progesterone Receptor Negative, Recurrent Inflammatory Breast Carcinoma, Stage IV Inflammatory Breast Carcinoma, Triple-Negative Breast Carcinoma
Sponsor: M.D. Anderson Cancer Center

Product:  MK-3475 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2014-0533 
Protocol Title 
A phase II study of anti-PD-1 (MK-3475) therapy in 
patients with metastatic inflammatory breast cancer (IBC) 
or non-IBC triple negative breast cancer (TNBC) who have 
achieved clinical response or stable disease to prior 
chemotherapy  
Protocol Version 
30 
Version Date 
3/10/2023 
Protocol PI 
Clinton Yam 
Department 
Breast Medical Oncology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
125866 
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                                                Table of Contents 
1.0 
TRIAL SUMMARY.................................................................................................... 4 
2.0 
OBJECTIVE(S) & HYPOTHESIS(ES) .................................................................... 4 
2.1 
Primary Objective(s) & Hypothesis(es) ................................................................ 4 
2.2 
Exploratory Objective ............................................................................................ 4 
3.0 
BACKGROUND & RATIONALE ............................................................................ 4 
3.1 
Background ............................................................................................................. 4 
3.1.1 Inflammatory breast cancer (IBC) .......................................................................... 4 
3.1.2 Pharmaceutical and Therapeutic Background ........................................................ 7 
3.1.3 Preclinical and Clinical Trial Data .......................................................................... 8 
3.1.4 Rationale for the Trial and Selected Subject Population ...................................... 11 
3.1.5 Rationale for Dose Selection/Regimen/Modification ........................................... 12 
3.1.6 Study Endpoint...................................................................................................... 13 
4.0 
METHODOLOGY ................................................................................................... 13 
4.1 
Entry Criteria ........................................................................................................ 13 
4.1.1 Inclusion Criteria .................................................................................................. 13 
4.1.2 Exclusion Criteria ................................................................................................. 14 
4.2 
Treatment Plan ..................................................................................................... 15 
4.2.1 Dose Selection ...................................................................................................... 16 
4.2.2 Dose Modification ................................................................................................ 16 
4.3 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 17 
4.3.1 Acceptable Concomitant Medications .................................................................. 17 
4.3.2 Prohibited Concomitant Medications ................................................................... 18 
4.4 
Rescue Medications & Supportive Care ............................................................. 18 
4.5 
Subject Withdrawal/Discontinuation Criteria ................................................... 21 
4.6 
Criteria for Disease Control ................................................................................. 22 
4.6.1. Definition of Treatment Response ........................................................................ 22 
4.6.2. Response will not be considered evaluable in the following categories: .............. 26 
5.0 
STUDY FLOW CHART .......................................................................................... 27 
6.0 
OTHER STUDY PROCEDURES ........................................................................... 29 
6.1 
Informed Consent/Patient Registration .............................................................. 29 
6.2 
Biomarker assessments ......................................................................................... 29 
6.2.1 Tumor samples ....................................................................................................... 29 
6.2.2 Blood samples ........................................................................................................ 29 
6.2.3 Assays .................................................................................................................... 30 
6.3 
Safety Monitoring and Reporting ....................................................................... 31 
6.3.1 Adverse Event ....................................................................................................... 31 
6.3.2 Serious Adverse Event Reporting (SAE) .............................................................. 31 
6.3.3 Management of Event of Clinical Interest (ECI) and Immune-Related Adverse 
Events (irAEs) ...................................................... Error! Bookmark not defined. 
6.3.4 Evaluating Adverse Events ................................................................................... 34 
7.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 34 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 35 
8.1 
Investigational Product ........................................................................................ 35 
8.2 
Packaging and Labeling Information ................................................................. 36 
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8.3 
Clinical Supplies Disclosure ................................................................................. 36 
8.4 
Storage and Handling Requirements .................................................................. 36 
8.5 
Returns and Reconciliation .................................................................................. 36 
9.0 
DATA MANAGEMENT .......................................................................................... 36 
10.0 
REFERENCES .......................................................................................................... 37 
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
MK-3475 for metastatic IBC or non-IBC TNBC 
Trial Phase 
II 
Clinical Indication 
Anti-PD-1 immunotherapy for metastatic IBC or non-IBC TNBC 
Trial Type 
Open label, non- randomized, single center  
Type of control 
None 
Route of administration 
IV 
Trial Blinding 
No 
Treatment Groups  
one 
Number of trial subjects 
50 
Estimated duration of trial 
3-4 years 
Duration of Participation 
3 
 
 
 
2.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
2.1 
Primary Objective(s) & Hypothesis(es) 
Primary Objective: To assess the efficacy of MK-3475 as a single agent in patients with 
metastatic IBC or non-IBC TNBC 
Hypothesis:  MK-3475 maintains disease control status of patients with metastatic IBC or 
non-IBC TNBC who have achieved clinical response or stable disease from prior systemic 
therapy for metastatic disease.  
2.2 
Exploratory Objective 
(1) To investigate the association between biomarkers in the peripheral blood and tumor tissue, 
such as   PD-L1 expression, with safety and efficacy for IBC or non-IBC TNBC patients 
treated with MK-3475. 
(2) To determine the disease control rate of metastatic IBC or non-IBC TNBC patients who 
have achieved clinical response or stable disease to the systemic therapy. 
(3) To investigate the association between biomarkers and efficacy by RNA-sequencing of 
exosomes in blood and tumor for IBC or non-IBC TNBC patients treated with MK-3475. 
(4) To investigate the 5-year OS for IBC or non-IBC TNBC patients treated with MK-3475 
3.0 BACKGROUND & RATIONALE 
3.1 
Background 
3.1.1 Inflammatory breast cancer (IBC) 
Definition of IBC 
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IBC is currently defined, according to the clinical criteria outlined in the seventh edition of the 
AJCC Cancer Staging Manual of the American Joint Committee on Cancer 1, 2 as diffuse erythema, 
edema (peau d’orange) of the breast, often without an underlying tumor mass, in the presence of 
pathologic evidence of breast cancer. Histologic evidence of dermal lymphatic invasion confirms 
the diagnosis but is not mandatory. 
Metastatic IBC 
Although IBC accounts for a mere 2-6% of all breast cancers in the United States, IBC is 
responsible for a disproportionate 7% of breast cancer-related deaths.3-5 Approximately 20% to 
30% of patients with IBC present with distant metastasis at diagnosis (de novo metastasis, 
classified as stage IV disease),6-8 compared to 6% to 10% of patients with non-inflammatory breast 
cancer (non-IBC).9,10  
We have tested the hypothesis that overall survival (OS) is worse in patients with IBC than in those 
with non-IBC among patients with distant metastasis at diagnosis (stage IV disease). Survival 
curves were compared among 1504 consecutive patients with stage IV breast cancer (IBC: 206; 
non-IBC: 1298) treated at our institution from 1987 through 201239. The Cox proportional hazards 
model was used to determine predictors of OS. IBC was associated with shorter median OS time 
than non-IBC (2.3 years vs. 3.4 years; P=.01, log-rank test). In a multicovariate Cox model that 
included 1,389 patients, the diagnosis of IBC was a significant independent predictor of worse OS 
(hazard ratio = 1.4, P=.00). In summary, IBC is associated with shorter OS than non-IBC in 
patients with distant metastasis at diagnosis. (Unpublished data) These data support the prognostic 
impact of IBC among patients with stage IV breast cancer. 
The extensive invasion of lymphatic vessels by tumor emboli in IBC patients suggests that the host 
immune surveillance system is suboptimal or that the tumor cells have decreased immunogenicity 
through immune editing to avoid detection by the host. In the immunocompetent host, tumor cells 
must overcome both innate and adaptive immunologic defenses of the host. 
We have also shown that the median number of dendritic cell (DC) precursors was significantly 
lower in breast cancer patients than in healthy female donors (HFDs). Moreover, the median 
number of myeloid dendritic cells (mDCs) in the peripheral blood of locally advanced breast 
cancer (LABC), IBC, and metastatic IBC (MIBC) patients was lower than the number of mDCs in 
the peripheral blood of HFDs. Because mDC and plasmacytoid dendritic cells (pDC) subsets 
determine the type of Th1/Th2 or Tc1/Tc2 responses, our data suggest that Th1 and Tc1 responses 
would be compromised in patients with LABC, IBC, and MIBC. We observed a significantly lower 
median number of pDCs in IBC and MIBC patients than in HFDs, but the same was not true for 
the median number of pDCs in LABC and MBC patients compared with the number of pDCs in 
HFDs. These data suggest that Th2 and Tc2 responses may be lower in IBC and MIBC patients 
than in HFDs.12 
3.1.2 Metastatic TNBC 
Despite exciting progress in the understanding of breast cancer development and progression, 
and in the development of novel therapeutic strategies, breast cancer remains the second leading 
cause of cancer-related death in women, with a yearly toll of more than 40,000 deaths in the 
United States in 201440. TNBC represents 15-20% of all breast cancers41 and is verlapping, 
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but not synonymous, with the basal-like subtype defined by gene expression, as about 70% of 
TNBCs have basal-like characteristics42, 43, and is associated with poor prognosis44. Breast cancer–
related deaths are mainly due to the “incurable” nature of metastatic breast cancer (MBC) at the 
current time. It is estimated that ∼6% of patients have metastatic disease at the time of diagnosis 
and 20% to 50% patients first diagnosed with primary breast cancer will eventually develop 
metastatic disease. Even with the remarkable advances in research and clinical management, the 
current treatment strategies for breast cancer metastasis still largely rely on the use of systemic 
cytotoxic agents, which frequently deteriorate the patient's life quality due to severe side effects 
and, in many cases, have limited long-term success. The prognosis for MBC patients is poor, with 
an estimated 5-year survival of only 26%. Therefore, MBC remains the most challenging task 
facing both cancer researcher and oncologist. Distant metastasis remains the main cause of death 
in patients with breast cancer despite important medical advances11. 
Treatment of TNBC is challenging and represents an area of unmet medical need, as these 
tumors lack therapeutic targets, such as ER and HER2, and become rapidly resistant to 
chemotherapy upon local recurrence and/or metastasis (even though they are often sensitive 
to cytotoxic drugs at initial presentation)45. The majority of patients with metastatic 
TNBC (mTNBC) have experienced relapse after neoadjuvant or adjuvant therapy for early or 
locally advanced disease. In a frequently referenced study, the median OS of all (at any line 
of therapy) patients with mTNBC was 13.3 months; median duration of first line (1L) 
therapy for mTNBC was 11.9 weeks; 80% of patients received second line (2L) therapy with 
a median duration of 9 weeks, and about 50% received third line (3L) therapy with a median 
duration of 4 weeks46. 
Several studies have demonstrated that presence of tissue infiltrating lymphocytes (TILs) is the 
most consistent prognostic factor in breast cancer, thus implicating the immune system in the 
pathophysiology and potentially the treatment of such tumors. Greater lymphocytic infiltration 
confers better prognosis in breast cancer, independent of systemic therapy48, 49. In addition, 
unsupervised gene expression profiling of TNBCs has identified a gene signature enriched for 
cytotoxic CD8+ T cell genes and natural killer cell (NKC) activity, which is predictive of good 
clinical outcome50. These findings suggest that inhibition of immune checkpoints has the 
potential to improve breast cancer prognosis by increasing the efficacy of tumor-associated 
immune response in eliminating breast cancer cells51. 
 
The PD-1 ligand, PD-L1, is not detected in normal breast tissue, but has been reported to be 
expressed in about half of all breast cancers, particularly in hormone receptor (HR)-negative and 
high grade, proliferative tumors52. In addition, the presence of regulatory T cells, tumor PD-L1 
expression, and PD-1–positive TILs has been associated with high histologic grade, ER 
negativity, and prominent tumor lymphocytic infiltration53. In an independent study, PD-L1 
was found expressed in 23% of breast cancer specimens and it was again associated with 
age, tumor size, American Joint Committee on Cancer (AJCC) primary tumor classification, 
tumor grade, lymph node status, absence of ER expression, and high expression of the 
proliferation marker Ki-6754. A recent publication reported that PD-L1 messenger ribonucleic 
acid (mRNA) is expressed in nearly 60% of breast tumors, independently of HR status, and is 
positively correlated with PD-L1 protein expression and increased TILs55. 
 
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Taken together, these data provide the rationale for using anti-PD-1 maintenance therapy to 
maintain disease control status.  Chemotherapies can debulk the disease volume but cannot be used 
for maintenance.  Therefore, using an anti PD-1 monoclonal antibody is a promising approach for 
these patients for whom no currently has available agents have been proven to maintain treatment 
response. 
3.1.3 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades.13 Accumulating evidence shows a correlation between 
tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various 
malignancies. 14-18 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 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).19-20 PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic 
tail which is responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 
contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif 
(ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within 
its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70 which are involved in the CD3 T-cell signaling cascade. 19, 21-24 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. 25-26 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. 27-28 Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells.29  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. 25,30-32   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.  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).33 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. 
Recently, our group evaluated PD-L1 expression in triple negative breast cancer (TNBC).  Using 
the Cancer Genome Atlas (TCGA) RNA sequencing data, we showed significantly greater 
expression of the PD-L1 gene in TNBC (n=120) compared with non-TNBC (n=716; P<0.001).  In 
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addition, using a tissue microarray of TNBC specimens, we showed PD-L1 expression in 20% 
suggesting PD-L1 as a therapeutic target in TNBC. 34 
3.1.4 Preclinical and Clinical Trial Data 
3.1.4.1 Preclinical Data (See Investigator’s Boucher for details)  
MK-3475 is a potent and highly selective humanized mAb designed to block the interaction 
between PD-1 and its ligands, PD-L1 and PD-L2. MK-3475 potently blocks binding to both 
ligands with half maximal inhibitory concentration (IC50) values below 1 nM. MK-3475 enhances 
T cell responses in human donor blood cell cultures with an EC50 of ~0.1 to 0.3 nM. MK-3475 
binds to cynomolgus PD-1 with similar affinity, blocking activity, and demonstrates equivalent 
enhancement of cynomolgus T cell responses. It does not cross-react with rodent PD-1. MK-3475 
strongly enhances T lymphocyte immune responses in cultured blood cells from healthy human 
donors, cancer patients, and primates. The antibody potentiates existing immune responses only in 
the presence of antigen-receptor stimulation and does not nonspecifically activate all T cells. Using 
an anti-mouse PD-1 analog antibody, PD-1 blockade is demonstrated to significantly inhibit tumor 
growth in a variety of syngeneic murine tumor models. In experiments in mice, anti-PD-1 therapy 
is synergistic with chemotherapeutic agents such as gemcitabine and 5-FU and combination 
therapy results in increased efficacy and increased complete regression rates in vivo. 
Anti-mouse PD-1 (J43) was tested as a monotherapy in several syngeneic murine tumor models. 
In all monotherapy experiments, tumor cells were implanted subcutaneously in syngeneic hosts 
and were staged at 50-80 mm3 before dosing was initiated. Anti-murine PD-1 or isotype control 
antibody was administered intraperitoneally (IP) every 3 to 4 days for a total of five treatments 
(the doses and schedule were determined based on experiments published in literature). Efficacy 
was determined by monitoring tumor volumes and long term survival for each experimental 
group.  
 
The tumor growth curves in Figure 1 show that anti-mouse PD-1, administered at 10 mg/kg, 
potently inhibited the subcutaneous growth of MC38 colon adenocarcinoma tumors in most 
animals. In addition to inhibiting tumor growth, anti-mouse PD-1 administered at 10 mg/kg 
induced complete tumor regression in 50% of the animals resulting in long-term tumor free 
survival (Figure 1). At the 2 mg/kg dose, two of 10 mice in this experiment experienced 
complete rejection of their tumor. None of the mice treated with either dose of the control 
antibody demonstrated complete rejection of their tumor. 
 
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Anti-mouse PD-1, as a monotherapy, demonstrated efficacy in several syngeneic mouse 
tumor models including MC38 (colon adenocarcinoma, C57Bl/6 mice), C1498 (acute 
myeloid leukemia, C57Bl/6 mice), PDV6 (squamous cell carcinoma, C57Bl/6), and A20 
(B cell lymphoma, Balb/c). 
 
The combined treatment of MC38 colon adenocarcinomas with 5-FU and anti-mouse PD-1 
showed a significant increase in anti-tumor efficacy over the individual monotherapy groups. 
This increased efficacy was reflected in a 60% complete regression rate in the combined 
treatment protocol. In the monotherapy groups, anti-PD-1 alone induced 20% (two out of ten) 
complete responses, whereas none of the mice treated with control antibody or 5-FU plus control 
antibody demonstrated complete regression. 
 
The combined treatment of MC38 colon adenocarcinomas with gemcitabine and antimouse 
PD-1 showed a significant increase in anti-tumor efficacy over the individual monotherapies. 
This increased efficacy was reflected in an 80% complete regression rate in the combined 
treatment protocol. By comparison, gemcitabine plus control antibody or anti-PD-1 alone 
induced 20% complete regression in this experiment, whereas control antibody alone did not 
induce any regressions.  
 
MK-3475 administered once every other week over 6-month duration to cynomolgus monkeys 
was well tolerated with systemic exposure (AUC) up to approximately 67,500 μg.day/mL and 
the no observed effect level (NOEL) was ≥200 mg/kg/dose (the highest dose tested).  
 
The safety of MK-3475 was characterized in the 1-month repeat-dose toxicity study in 
cynomolgus monkeys when administered as IV doses of 6, 40 or 200 mg/kg once a week (a total 
of five doses) and in the 6-month repeat-dose toxicity study in cynomolgus monkeys when 
administered as IV doses of 6, 40 or 200 mg/kg every other week (a total of 12 doses). MK-3475 
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was well-tolerated in cynomolgus monkeys with a systemic exposure (AUC) of up to 
approximately 170,000 μg.day/mL over the course of the 1-month study, and with a systemic 
exposure (AUC) of up to approximately 67,500 μg.day/mL over the course of the 6-month study. 
No findings of toxicological significance were observed in either 1-month or 6-month toxicity 
study with MK-3475 and the NOAEL was ≥200 mg/kg. In addition, no findings of toxicological 
relevance were observed in the in vitro tissue cross-reactivity study using human and 
cynomolgus monkey tissues. There were no nonclinical findings that would preclude testing of 
MK-3475 in clinical trials. 
 
3.1.4.2 Clinical Data 
Six clinical trials are currently evaluating MK-3475: PN001, PN002, PN006, PN010, PN011, 
and PN012. 
 
PN001 is the Phase I first in human (FIH) study of MK-3475, a dose-escalation study in patients 
with progressive locally advanced or metastatic carcinomas, along with subject expansion 
cohorts in MEL and NSCLC. PN001 is an open-label study consisting of 5 primary aspects 
including the initial dose escalation and subsequent patient expansions. Part A examined 3 dose 
levels (1, 3, and 10 mg/kg) in patients with solid tumors. With no DLTs observed and no MTD 
reached, additional PK cohorts were examined at various doses (Parts A-1 and A-2). Subsequent 
cohorts were then initiated in patients with MEL [Part B (B1, B2, and B3) and D] and NSCLC 
(Parts C and F) at various dose levels and dose frequencies.  Each of the two disease specific 
cohorts (MEL and NSCLC) are enrolled to confirm tolerability and to evaluate tumor response of 
MK-3475. 
 
PN002 is a Phase II study designed to evaluate 2 doses of MK-3475 versus a chemotherapy 
control arm in patients with IPI-refractory metastatic melanoma. Patients are randomized in a 
1:1:1 ratio to receive blinded MK-3475 2 mg/kg Q3W or MK-347510 mg/kg Q3W, or 
chemotherapy (according to current clinical practice) for the treatment of MEL. Patients assigned 
to the control chemotherapy arm may cross-over to the experimental MK-3475 arm once 
progression is confirmed (approximately ≥ Week 12). 
 
PN006 is a randomized, controlled, open-label, three-arm pivotal study of two dosing regimens 
of MK-3475 versus IPI in patients with unresectable or metastatic MEL who have not received 
IPI treatment. Patients are randomized in a 1:1:1 ratio to receive 10 mg/kg Q2W, 10 mg/kg 
Q3W, or ipilimumab. 
 
PN010 is multi-center, worldwide, randomized, adaptively designed Phase II/III trial of MK-
3475 at two dosing schedules versus docetaxel in patients with NSCLC with PD-L1 positive 
tumors who have experienced disease progression after platinum-containing systemic therapy. 
Patients are randomized to receive 10 mg/kg Q3W, 2 mg/kg Q3W, or docetaxel 75 mg/m2 Q3W.  
 
PN011 is an open-label, non-randomized, multi-center Phase I study of MK-3475 alone in 
Japanese patients with advanced solid tumors, and in combination with cisplatin/pemetrexed and 
carboplatin/paclitaxel in patients with advanced NSCLC. In Part A (monotherapy 3+3 design), 
patients with advanced solid tumors are receiving escalating doses of MK-3475 2 mg/kg (Dose 
level 1) or 10 mg/kg (Dose level 2) Q2W. In Part B (combination, 3+6 design), patients with 
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advanced NSCLC will receive MK-3475 10 mg/kg Q3W in combination with  cisplatin/ 
pemetrexed (Cohort 1), or carboplatin/paclitaxel (Cohort 2). 
 
PN012 is a multicenter, nonrandomized, multi-cohort trial of MK-3475 in patients with PD-L1 
positive advanced solid tumors. All patients will receive MK-3475 10 mg/kg Q2W. Cohort A is 
enrolling patients with triple negative breast cancer, Cohort B is enrolling patients with 
squamous cell carcinoma of the head and neck, Cohort C is enrolling patients with urothelial 
tract cancer of the renal pelvis, ureter, bladder, or urethra, and Cohort D is enrolling patients with 
adenocarcinoma of the stomach or gastroesophageal junction. 
 
In addition, Phase I studies in combination with various standard-of-care agents may be initiated, 
and single-agent efficacy of MK-3475 may be evaluated in additional solid tumors. 
 
3.1.5 Rationale for the Trial and Selected Subject Population  
The prognosis for metastatic breast cancer (MBC) patients is poor, with an estimated 5-year 
survival of only 26%. Distant metastasis remains the main cause of death in patients with breast 
cancer despite important medical advances11. Therefore, MBC remains the most challenging task 
facing both cancer researcher and oncologist. 
Triple negative breast cancer (TNBC) and inflammatory breast cancer (IBC) are associated with 
younger age at diagnosis, premenopausal status, African American race, more advanced disease 
stage, higher grade, high mitotic indices, family history of breast cancer, Breast Cancer 1 
(BRCA1) mutations, and more aggressive behavior than other breast cancer subtypes4, 41.   
 
To date, no IBC-specific targeted therapeutic options exist for the treatment of metastatic IBC. 
Unfortunately, the median survival is only 2.3 years indicating that all patients will not maintain 
disease control after achieving a clinical response to systemic chemotherapy or endocrine 
therapy. Indeed, hormone receptor (HR) positive disease is not favorable prognostic biomarkers 
in IBC 35 despite of endocrine therapy. Further, our recent publication suggests that IBC has been 
suggested to have immune dysfunction (section 3.1.1).  
 
As reported in a seminal study on TNBC, 34% of all patients with TNBC experience distant 
recurrence with a median distant recurrence-free survival (DRFS) of 2.6 years, compared to a 
distant recurrence rate of 20% and a median DRFS of 5 years in other breast cancer subtypes47. 
The median survival is only 2.3 years for IBC indicating that all patients will not maintain 
disease control after achieving a clinical response to systemic chemotherapy or endocrine 
therapy. Indeed, hormone receptor (HR) positive disease is not favorable prognostic biomarkers 
in IBC35 despite of endocrine therapy. Further, our recent publication suggests that IBC has been 
suggested to have immune dysfunction (section 3.1.1).  To date, no specific targeted therapeutic 
options exist for the treatment of metastatic IBC and TNBC3.47.  
 
Therefore, we will enroll patients with HER2 negative metastatic IBC and non-IBC TNBC, which 
include both ER+ and triple negative receptor status metastatic IBC and non-IBC TNBC. HER2 
positive MBC is excluded because there are numerous anti-HER2 therapies prescribed among 
patients with HER2+ MBC.  
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Taken together, these data provide the rationale for using anti-PD-1 antibody to maintain disease 
control status of HER2 negative metastatic IBC and non-IBC TNBC. Chemotherapies can debulk 
the disease volume but cannot be used for maintenance due to their toxicities. Using an anti PD-1 
monoclonal antibody is a promising approach for these patients for whom no currently available 
agents have been proven to maintain treatment response. 
3.1.6 Rationale for Dose Selection/Regimen/Modification  
An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical 
activity of single agent MK-3475.  The dose escalation portion of this trial evaluated three dose 
levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks (Q2W) in subjects with 
advanced solid tumors.  All three dose levels were well tolerated and no dose-limiting toxicities 
were observed.  This first in human study of MK-3475 showed evidence of target engagement 
and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 
mg/kg Q2W).  No MTD has been identified to date.  10.0 mg/kg Q2W, the highest dose tested in 
PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test 
for initial tumor activity.  Recent data from other clinical studies within the MK-3475 program 
has shown that a lower dose of MK-3475 and a less frequent schedule may be sufficient for 
target engagement and clinical activity. 
 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic clearance, 
limited volume of distribution, and a long half-life (refer to IB).  Pharmacodynamic data (IL-2 
release assay) suggested that peripheral target engagement is durable (>21 days).  This early PK 
and pharmacodynamic data provides scientific rationale for testing a Q2W and Q3W dosing 
schedule.   
 
A population pharmacokinetic analysis has been performed using serum concentration time data 
from 476 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. 
 
Currently the FDA has approved a new dosage for pembrolizumab (Keytruda) of 400 mg 
administered every 6 weeks across all adult indications, whether the PD-1 inhibitor is used as 
monotherapy or in a combination regimen. This approval is especially important in light of 
reduced clinic visits to protect patients with cancer due to the coronavirus disease 2019 (COVID-
19) pandemic. The prior dosage for pembrolizumab, 200 mg every 3 weeks, will also still be a 
dosage option. 
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3.1.7 Study Endpoint 
Most patients with metastatic IBC who achieved a maximum tumor response by standard 
chemotherapies will eventually have disease progression within 4 months.  The goal of this clinical 
trial is to observe clinical activity signals of MK-3475 for disease stabilization or control as a 
maintenance therapy after achieving a maximum tumor response by standard chemotherapy.  The 
efficacy endpoint is to evaluate the rate of patients who remain progression free at the end of 4 
months from the maximum tumor response after receiving MK-347536.   
4.0 METHODOLOGY 
4.1 
Entry Criteria 
In order to be eligible for participation in this trial, the subject must meet the following criteria: 
4.1.1 Inclusion Criteria 
1. Is willing and able to provide written informed consent for the trial. 
2. Is a female or male and >/= 18 years of age  
3. Has histological confirmation of  HER2 normal breast carcinoma with a clinical diagnosis 
of IBC based on presence of inflammatory changes in the involved breast, including diffuse 
erythema and edema (peau d’orange), with or without an underlying palpable mass 
involving the majority of the skin of the breast.  Pathological evidence of dermal lymphatic 
invasion should be noted but is not required for diagnosis of inflammatory breast cancer 
regardless of ER/PR status 
OR  
Has histological confirmation of triple negative breast carcinoma (HER2 normal, ER/PR < 
10%) without clinical diagnosis of IBC 
4. Has stage IV or recurrent disease that has been treated.  
5. Has clinical response or stable disease for minimum of two months (three cycle of every 
three week chemo or 8 weeks of weekly regimen, etc.) after receiving any prior 
chemotherapy for metastatic/recurrent disease. A minimum of two cycles (6-8 weeks) of 
chemotherapy is required to determine clinical response.  
 
Per RECIST criteria 1.1, Clinical response for measurable disease is defined as complete 
response (CR) or partial response (PR); for non-measurable disease only (i.e. bone 
metastasis, ascites, pleural effusion, and pathological lymph nodes >/= 10 to <15 mm short 
axis) is defined as persistence of one or more non-target lesion(s) and no increase in overall 
tumor burden.  
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6. Is HER2 normal,  defined as HER2 0 or 1+ by IHC and negative by FISH if performed; or  
HER2 is 2+ by IHC and negative by FISH; or HER2 negative by FISH if IHC is not 
performed. 
7. Has a performance status of 0-1 on the ECOG Performance Scale. 
8. Has adequate organ function as determined by the following laboratory values:  
ANC >/= 1000 /mcL, Platelets >/=100,000 /mcL, Hgb >/= 9 g/dL, creatinine levels < 1.5 
x ULN, Total bilirubin </= 1.5 x ULN, ALT and AST </= 2.5 x ULN or </=5 x ULN for 
subjects with liver metastases. 
9. Subjects of childbearing potential should be willing to use effective methods of birth control 
or be surgically sterile, or abstain from heterosexual activity for the course of the study 
through at least 4 months after the last dose of study drug. Subjects of childbearing potential 
are those who have not been surgically sterilized or have not been free from menses for > 1 
year. Effective methods of birth control include 1). Use of hormonal birth control methods: 
pills, shots/injections, implants (placed under the skin by a health care provider), or patches 
(placed on the skin); 2).Intrauterine devices (IUDs); 3).Using 2 barrier methods (each 
partner must use 1 barrier method) with a spermicide.   Males must use the male condom 
(latex or other synthetic material) with spermicide.  Females must choose either a 
Diaphragm with spermicide, or Cervical cap with spermicide, or a sponge (spermicide is 
already in the contraceptive sponge).  
10. Has negative serum or urine pregnancy test for subjects of childbearing potential. 
4.1.2 Exclusion Criteria 
1. Is currently participating in a study of an investigational anti-cancer agent.  
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other 
form of immunosuppressive therapy. 
3. Has not recovered from adverse events due to prior therapies, i.e. monoclonal antibody, 
chemotherapy, targeted small molecule therapy, radiation therapy, or surgery.  
- 
Note:  Subjects with ≤ Grade 2 neuropathy, alopecia and general disorders and 
administration site conditions (per CTCAE version 4.0) are an exception to this 
criterion and may qualify for the study. 
4. Has a known malignancy (other than breast cancer) except basal cell carcinoma or  
squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone 
potentially curative therapy.   
5. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Subjects with previously treated brain metastases may participate if they are 
stable, and have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.   
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6. Has an active autoimmune disease requiring systemic treatment within the past 3 months 
or a documented history of clinically severe autoimmune disease, or a syndrome that 
requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved 
childhood asthma/atopy would be an exception to this rule.  Subjects that require 
intermittent use of bronchodilators or local steroid injections would not be excluded from 
the study.  Subjects with hypothyroidism stable on hormone replacement or Sjogren’s 
syndrome will not be excluded from the study. 
7. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
8. Has an active infection requiring systemic therapy. 
9. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
10. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
11. Has a known history of Human Immunodeficiency Virus (HIV). 
12. Has a known active Hepatitis B or Hepatitis C  
13. Have received a live vaccine within 30 days prior to the first dose of trial treatment.   
14. Is receiving concurrent anti-cancer therapy for metastatic disease. 
4.2 
Treatment Plan 
The treatment to be used in this trial is outlined in Table 1 below. This plan was adjusted based on 
current FDA approval for the new dosage for pembrolizumab (Keytruda) of 400 mg administered 
every 6 weeks across all adult indications, whether the PD-1 inhibitor is used as monotherapy or 
in a combination regimen.  
Drug 
Dose/Potency 
Dose Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK-3475  
200 mg 
Every 3 weeks 
IV infusion 
 Cycle 1 to 8 or 
until meet drug  
discontinuation 
criteria (See 4.5) 
Experimental 
MK-3475 400 mg 
Every 6 weeks 
IV infusion 
Cycle 9 to up to 
24 months or 
until meet drug 
discontinuation 
criteria (See 4.5) 
Experimental 
The MK-3475 dosing interval may be increased due to toxicity described in 4.2.2. 
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4.2.1 Dose Selection 
For cycle 1 to 8, each cycle is defined as 3 weeks interval. MK-3475 200 mg will be administered 
on day 1 of each cycle as approximately 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 4.2.2). For cycle 9 and beyond, each cycle is 
defined as 6 weeks interval. MK-3475 400 mg will be administered on day 1 of each cycle as 
approximately 30-minute IV infusion (treatment cycle intervals may be increased due to toxicity 
as described in Section 4.2.2). MK-3475 may be administered up to 3 days before or after the 
scheduled Day 1 of each cycle due to administrative reasons. 
The Procedures Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
4.2.2  Dose Modification  
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose or 
several months after the last dose of treatment. Pembrolizumab must be withheld for drug-related 
toxicities and severe or life-threatening AEs as per Table 2 below. See Section 4.4 and Events of 
Clinical Interest Guidance Document for supportive care guidelines (Appendix C), including use 
of corticosteroids. 
Table 2    Dose Modification Guidelines for Drug-Related Adverse Events 
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)1 
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. 
Hyperthyroidism  
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 
Hypothyroidism 
 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued 
while thyroid replacement therapy is instituted. 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Infusion Reaction 
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 Toxicity2 
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. 
1 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. 
2 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. 
In case toxicity does not resolve to Grade 0-1 or baseline within 12 weeks after last infusion, trial 
treatment will be discontinued. Subjects with a laboratory adverse event still at Grade 2 after 12 
weeks may continue treatment in the trial only if asymptomatic and controlled.   
Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of MK-3475 will be discontinued from trial treatment. 
4.3 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during 
the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination rests 
with the investigator and/or the subject's primary physician.  .  
4.3.1 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. 
Concomitant medication will be recorded as standard of care in clinic database.  
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4.3.2 Prohibited Concomitant Medications  
Subjects are prohibited from receiving the following therapies during the study.  
• Any anti-cancer agents.  
• Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain will be 
allowed.  
• 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, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated 
vaccines, and are not allowed. 
• Glucocorticoids for any purpose other than to modulate symptoms of suspected 
immunologic etiology.    
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. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
4.4 
Rescue Medications & Supportive Care 
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 and in greater detail in the ECI guidance 
document (Appendix C in PDOL). 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 is instructed 
to follow the ECI reporting guidance but does not need to follow the treatment guidance (as 
outlined in the ECI guidance document). Refer to Section 4.2.2 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. Suggested conditional procedures, as appropriate, 
can be found in the ECI guidance document (Appendix C in PDOL). 
• Pneumonitis:  
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o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve 
to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  Administer 
additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged 
steroid administration. 
 
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus).   
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
 
 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ 
Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis 
(DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria.  
 Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
• Hypophysitis: 
 
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. 
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• 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 3-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered. 
 
 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks. 
 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
 
• 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 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of MK-3475. 
 
Table 3  Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
 
 
None 
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NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
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. 
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 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 
initial improvement; 
hospitalization indicated for other 
clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
 
Stop Infusion. 
Additional appropriate medical therapy may include but is 
not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically indicated 
until the subject is deemed medically stable in the opinion 
of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial 
treatment administration. 
 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 
4.5 
Subject Withdrawal/Discontinuation Criteria 
In this study, MK-3475 administration will continue until one of the following conditions is 
observed. 
4.5.1. Disease progression [ iRECIST Criteria] 
Disease progression is defined as rapid growth of multiple measurable, non-measurable or new 
lesions, or at least a 20% increase in the sum of diameters of target (measurable) lesions, taking as 
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reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of 
at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
4.5.2 Noncompliance:   
If the patient is not able to compliant with the treatment schedule in the absence of toxicity, the 
study treatment should be discontinued for the patient.  
4.5.3. Sustained side effects: 
Study treatment will be discontinued for patients who have sustained toxic effects that are 
attributed to the study drug and require a dose interruption lasting more than 12 weeks.  
4.5.4. Initiation of new anticancer treatment:   
In patients for whom the investigator, in his or her judgment, determines new treatment for breast 
cancer is warranted, the study treatment may be discontinued.   
4.5.5. Patient withdraws consent.  
In the event that a patient withdraws consent, the reason(s) for withdrawal must be documented. 
Patients must be informed that their participation in the study is voluntary and that they may choose 
not to take part in the study or to stop taking part at any time. If a patient chooses not to take part 
in the study or to stop at any time, his/her future medical care or medical benefits will not be 
affected.  
4.5.6. Patient has completed 24 months of treatment. 
4.6 
Criteria for Disease Control 
The purpose of this study is to maintain disease control status of patients with metastatic IBC who 
have achieved clinical response from prior systemic therapy for metastatic disease. PI will be 
responsible to monitor disease control status. Date of disease progression will be documented and 
recorded in the study specific database.  
4.6.1. Definition of Treatment Response  
We will use iRECIST criteria to evaluate and define the treatment response by following the 
guideline which released in the Lancet Oncology on March 201756.  
iRECIST was developed by the RECIST working group for the use of modified Response 
Evaluation Criteria in Solid Tumours (RECIST version 1.1) in cancer immunotherapy trials, to 
ensure consistent design and data collection, facilitate the ongoing collection of trial data, and 
ultimate validation of the guideline. This guideline describes a standard approach to solid tumour 
measurements and definitions for objective change in tumour size for use in trials in which an 
immunotherapy is used.  Additionally, it defines the minimum datapoints required from future 
trials and those currently in development to facilitate the compilation of a data warehouse to use 
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to later validate iRECIST. 
 
Terminology of iRECIST 
iRECIST is based on RECIST 1.1. Responses assigned using iRECIST have a prefix of “i” (ie, 
immune)—eg, “immune” complete response (iCR) or partial response (iPR), and unconfirmed 
progressive disease (iUPD) or confirmed progressive disease (iCPD) to differentiate them from 
responses assigned using RECIST 1.1. Similar nomenclature is used for stable disease (iSD),  New 
lesions are assessed and subcategorised into those that qualify as target lesions (new lesion, target) 
or non-target lesions (new lesion, non-target).  
 
iRECIST Criteria 
iRECIST criteria are listed in below tables. Table 4 Shows the comparison of RECIST 1.1 and 
iRECIST. Table 5 shows the assignment of timepoint response using iRECIST. More details 
about this guideline is available in Appendix J in PDOL or 
http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30074-8/fulltext 
 
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 Table 4: Comparison of RECIST 1.1 and iRECIST 
 
Table 5: Assignment of timepoint response using iRECIST 
             
RECIST 1.1 
iRECIST 
Definitions of measurable and 
non-measurable disease; 
numbers and site of target 
disease  
Measurable lesions are ≥10 
mm in diameter (≥15 mm for 
nodal lesions); maximum of 
five lesions (two per organ); 
all other disease is considered 
non-target (must be ≥10 mm 
in short axis for nodal 
disease)  
No change from RECIST 1.1; 
however, new lesions are 
assessed as per RECIST 1.1 
but are recorded separately on 
the case report form (but not 
included in the sum of lesions 
for target lesions identified at 
baseline)  
Complete response, partial 
response, or stable disease  
Cannot have met criteria for 
progression before complete 
response, partial response, or 
stable disease  
Can have had iUPD (one or 
more instances), but not 
iCPD, before iCR, iPR, or 
iSD  
Confirmation of complete 
response or partial response  
Only required for non-
randomised trials  
As per RECIST 1.1  
Confirmation of stable 
disease  
Not required  
As per RECIST 1.1  
New lesions  
Result in progression; 
recorded but not measured  
Results in iUPD but iCPD is 
only assigned on the basis of 
this category if at next 
assessment additional new 
lesions appear or an increase 
in size of new lesions is seen 
(≥5 mm for sum of new 
lesion target or any increase 
in new lesion non-target); the 
appearance of new lesions 
when none have previously 
been recorded, can also 
confirm iCPD  
Independent blinded review 
and central collection of 
scans  
Recommended in some 
circumstances—eg, in some 
trials with progression-based 
endpoints planned for 
marketing approval  
Collection of scans (but not 
independent review) 
recommended for all trials  
Confirmation of progression  
Not required (unless 
equivocal)  
Required  
Consideration of clinical 
status  
Not included in assessment  
Clinical stability is 
considered when deciding 
whether treatment is 
continued after iUPD  
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Timepoint 
response with 
no previous 
iUPD in any 
category 
Timepoint response with 
previous iUPD in any category*  
Target lesions: iCR; non-target 
lesions: iCR; new lesions: no  
iCR  
iCR  
Target lesions: iCR; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no  
iPR  
iPR  
Target lesions: iPR; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no  
iPR  
iPR  
Target lesions: iSD; non-target 
lesions: non-iCR/non-iUPD; new 
lesions: no  
iSD  
iSD  
Target lesions: iUPD with no 
change, or with a decrease from 
last timepoint; non-target 
lesions: iUPD with no change, or 
decrease from last timepoint; 
new lesions: yes  
Not applicable  
New lesions confirm iCPD if new 
lesions were previously identified 
and they have increased in size (≥5 
mm in sum of measures for new 
lesion target or any increase for 
new lesion non-target) or number; 
if no change is seen in new lesions 
(size or number) from last 
timepoint, assignment remains 
iUPD  
Target lesions: iSD, iPR, iCR; 
non-target lesions: iUPD; new 
lesions: no  
iUPD  
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in the size of non-target 
disease (does not need to meet 
RECIST 1.1 criteria for 
unequivocal progression)  
Target lesions: iUPD; non-target 
lesions: non-iCR/non-iUPD, or 
iCR; new lesions: no  
iUPD  
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in sum of measures ≥5 
mm; otherwise, assignment 
remains iUPD  
Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: no  
iUPD  
Remains iUPD unless iCPD is 
confirmed based on a further 
increase in previously identified 
target lesion iUPD in sum of 
measures ≥5 mm or non-target 
lesion iUPD (previous assessment 
need not have shown unequivocal 
progression)  
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Target lesions: iUPD; non-target 
lesions: iUPD; new lesions: yes  
iUPD  
Remains iUPD unless iCPD is 
confirmed on the basis of a further 
increase in previously identified 
target lesion iUPD sum of 
measures ≥5 mm, previously 
identified non-target lesion iUPD 
(does not need to be unequivocal), 
or an increase in the size or 
number of new lesions previously 
identified  
Target lesions: non-iUPD or 
progression; non-target lesions: 
non-iUPD or progression; new 
lesions: yes  
iUPD  
Remains iUPD unless iCPD is 
confirmed on the basis of an 
increase in the size or number of 
new lesions previously identified  
* non-iCR/non-iUPD = criteria for neither CR nor PD have been met. 
 
4.6.2. Response will not be considered evaluable in the following categories: 
4.6.2.1. Early Deaths: Patients who die within the first 2 weeks of the initiation of drug therapy 
owing to concurrent disease. These cases will be considered treatment failures in the intent-to-
treat analysis. 
4.6.2.2. Lost to Follow-up:  Patients for whom there is inadequate information to judge tumor 
response because of loss of contact with our institution (>2 months after a missed appointment) 
and with referring physician in spite of repeated attempts to locate them. These cases will be 
considered treatment failures in the intent-to-treat analysis. 
4.6.2.3. Major Protocol Violation:  Patients who significantly deviate from the treatment program 
by either adding or deleting another agent or another therapeutic maneuver or by modifying 
schedule substantially (delay treatment ≥7 days without administration reason) of the drug under 
evaluation. Patients who do not fulfill the requirements outlined under Patient Eligibility are also 
included in this category. . 
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5.0 STUDY FLOW CHART 
 
 
a. Demographics include patient’s age, gender and race. Medical history includes primary breast cancer 
pathological diagnosis, ER/PR/HER2 status, and metastatic disease sites.  prior therapies and 
procedures for breast cancer, 
b. Complete physical exam during the screening period. This will not be repeated if done within 8 (+/- 3 
days) days before the start of treatment. During treatment, Physical Exam as clinically indicated prior 
to trial treatment administration.  Adverse events and ECOG performance status assessment can be 
done within 8 (+/- 3 days) days before the start of treatment. Adverse events and ECOG will be 
assessed every 3 weeks either in the clinic visit or by calling through the end of treatment. 
c. Hematologic and biochemical profiles (CBC, albumin, alkaline phosphatase, ALT, AST, LDH, uric 
acid, calcium, glucose, phosphorus, potassium, sodium, magnesium, total bilirubin, total protein, 
Trial Period: 
Screening  
Phase 
Treatment Cyclesj 
End of 
Treatment 
Post-Treatment 
Survival 
Follow 
Upk 
Treatment Cycle/Title: 
Screening 
/Baseline 
1 
2 
3 
4 
5 
6 
7 
8 
Cycle 
9 and 
beyond 
If pt 
returns for 
follow up 
Safety 
F/U f 
Follow-
Upg, 
 
 
 
 
Scheduling Window (Days): 
Within 28 
days 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
± 
3 
 
 
1 
month 
after 
last 
dose 
3 
months 
after 
last 
dose  
Annually 
for at 
least 5 
years 
 
 
 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Breast Cancer History a 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medication Review per SOC 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examb, V/S  
x 
X   x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Adverse Events b 
x 
X  x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
ECOG Performance Status b  
x 
x  x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Pregnancy Test – Urine or Serum β-HCG 
(for women with childbearing potential) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC and Biochemical Profiles c 
x 
 x  x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
EKG, ECHO or MUGA as SOCd 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH, Free T4 and Totalcortisoli 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
Radiological Evaluation as clinically 
indicated and as SOC d 
x 
 
 
x 
 
x 
 
x 
 
x 
x 
 
 
 
Archived biopsy or surgical specimens 
(block or unstained slides) obtained at any 
time prior to treatment.  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection e 
x 
 
 
x 
 
 
x 
 
 
x 
 
 
 
 
MK-3475 Administration  
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
x 
x 
Optional biopsy at disease progression h 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
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BUN, as standard of care (will not be repeated if done within 8 (+/- 3 days) days before the start of 
treatment). During treatment, an earlier evaluation will be performed if clinically indicated. 
d. Radiological evaluation may include CT of the chest and abdomen, Ultrasound, bone Scan and X-
Rays, brain MRI as clinically indicated for standard of care. PET/CT, Chest wall/breast photos, EKG 
and ECHO or MUGA may also be performed as indicated for standard of care. During treatment, an 
earlier evaluation will be performed if clinically indicated. The same method of evaluation, specific 
to the subject's condition, will be performed according to the time points. 
e. Peripheral blood and serum for correlative studies. Approximately 50cc of blood will be drawn at 
baseline, cycle 3rd, 6th, 9th, then every 2 cycles (i.e.11th, 13th, 15th, etc.) and at disease progression.  
f. 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. Safety Follow-Up Visit can be 
done in the clinic, or by phone if patient is not willing to come to the clinic for follow up.   
g. 3 months follow up can be performed in the clinic, or by phone if patient is not willing to come to the 
clinic for follow up. 
h. Optional biopsy at disease progression. 
i. 
TSH, Free T4 and Total cortisol will be monitored at baseline, every other cycle during Cycle 1-8 and 
every cycle for Cycle 9 and beyond as standard of care. 
j. 
Cycle 1-8 are defined as 3 weeks per cycle, Cycle 9 and beyond are defined as 6 weeks per cycle, 
pembrolizumab (200mg or 400mg) will be given on Day 1 of each cycle as section 4.2. 
k. registration 
 
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6.0 OTHER STUDY PROCEDURES 
6.1 
Informed Consent/Patient Registration 
The study will be discussed with the patient, and any patient wishing to participate must give 
informed consent.  A signed, Institutional Review Board (IRB) approved, informed consent must 
be obtained from patients before any study specific procedures or registration for study treatment 
can occur.  All patients will be registered in the OnCore system. 
6.2 
Biomarker assessments 
Tumor tissue and peripheral blood will be collected prior to therapy and at selected time points on 
treatment.  Residual sample material available after completion of the designated analyses may be 
used in the future for identification of additional predictive markers or to enhance understanding 
of disease biology. If biomarker samples are drawn but study drug is not administered, samples 
will be retained.  A description of each assay system is described below. 
6.2.1 Tumor Samples  
Collection 
Archived biopsy or surgical specimens (block or unstained slides) obtained at any time prior to 
treatment will be collected from all consenting subjects.  Optional biopsies will be obtained from 
patients with disease progression and accessible lesions. 
Evaluation 
• Characterization of tumor infiltrating lymphocytes (TIL).  
• Immunohistochemistry (IHC) will be used to assess the immune infiltrates in order to 
define the immune cell subsets present within formalin-fixed, paraffin-embedded tumor 
tissue.  These IHC analyses will include but not necessarily be limited to:  CD4, CD8, 
FOXP3, PD-1, and PD-L1. PD-L1 IHC will be performed by both MD Anderson and 
QualTek.  
• Genetics profiling performed by Insight Genetics (only done for the prior biopsy and/or 
surgery tumor samples). 
6.2.2 Blood samples 
Collection and processing 
Multiple blood draws will be required for this trial. All blood tubes will be labeled only with the 
patients’ unique study number.  Approximately 100cc will be drawn for each immunologic 
assessment (at baseline; prior to dosing of study drug with every third cycle i.e. cycle 3, 6, 9, 12 
etc , or every other cycle after for patients who start Pembrolizumab 400mg at C9 and beyond; and 
at disease progression). 10cc will be collected into a BD Vacutainer Rapid Serum tube (BD, 
Franklin Lakes, NJ) which contains a clot activator and silicone coated interior.  After 
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centrifugation, serum will be collected, aliquoted in 1cc vials and frozen.  70cc will be collected 
into BD Vacutainer CPT Cell Preparation tubes  which contain an anticoagulant (sodium heparin 
or sodium citrate) with FICOLL HYPAQUE density gradient fluid and a polyester gel barrier.  The 
density gradient fluid and the gel barrier allow for the separation of peripheral blood mononuclear 
cells (PBMC) from the red blood cells by a single step centrifugation process.  The PBMC fraction 
will be collected by centrifugation and suspended in RPMI-1640 (GIBCO, Invitrogen Corporation, 
Carlsbad, CA) with 10% FCS (Gemini Bio-Products, West Sacramento, CA) and antibiotics. 
Plasma will be collected from CPT Cell Preparation tubes and stored.  20cc blood will be collected 
in heparin 10ml green top tubes for FACS assay. 
6.2.3 Assays 
Serum 
• Soluble factors such as cytokines and chemokines present in serum collected at baseline, during, 
and after treatment will be quantified using a multiplex assay which has the capability to 
simultaneously measure multiple analytes from a single sample.  Factors to be evaluated may 
include but not necessarily be limited to IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-7, IL-10, IL-12, IL-15 
and IL-17. 
• Additional immunoassays will be performed to quantify soluble receptors present in the serum.  
Analyses may include but not necessarily be limited to soluble CD25, soluble PD-1, and soluble 
LAG-3. 
Peripheral blood mononuclear cells 
• The proportion of specific lymphocyte subsets to include T cells, B cells, and the proportion of 
memory and effector T cell subsets will be quantified by flow cytometry. 
• The expression levels of T cell co-stimulatory and co-inhibitory markers including but not 
necessarily limited to PD-1, PD-L1, other B7 family members, and ICOS will be quantified by 
flow cytometry. 
Plasma 
•  Exosomal RNA-sequencing will be performed with RNA extracted from plasma by Insight 
Genetics, Inc along with the tumor sample listed in section 6.2.1. There is only one time point 
plasma sample needed, and plasma samples at baseline will be preferred, but samples collected at 
other time points can be substitute if the baseline sample is unavailable. 
•  Plasma will be stored for future research purpose. 
FACS assay  
• Intracellular cytokine synthesis by T-cells activated through the T-cell receptor (TCR).  
• Cytokine production by dendritic cells activated with Toll-like receptor (TLR) agonist.  
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• The NK cell assay. 
6.3 
Safety Monitoring and Reporting 
6.3.1 Adverse Event 
Adverse events will be assessed according to the CTCAE version 4.0. All study patients who have 
received any dose of MK-3475 will be evaluable for safety. Unexpected adverse events including 
laboratory adverse events deemed clinically significant by the investigator will be graded and 
recorded. 
The ongoing review of safety data will include review of clinical AEs and SAEs. The NCI-CTC 
version 4.0 will be used to grade all AEs.   
AEs (>/=2 non-hematological and >/=3 hematological AEs) occurring after informed consent 
signing observed by the investigator or reported by the subject (whether or not attributed to 
investigational product), will be documented in the medical record and recorded in  REDCap 
database. Abnormal laboratory values will not be reported as AEs; however, any clinical 
consequences of the abnormality should be reported as AEs.  
6.3.2 Serious Adverse Event Reporting (SAE)  
6.3.2.1 Internal SAE reporting to IND Office 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the adverse 
experience as it occurred. It does not include an adverse experience that, had it occurred 
in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse (21 CFR 312.32). 
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• Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the INDIND Sponsor, IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined 
in “University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Unanticipated Adverse Events for Drugs and 
Devices”.  Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event).                                                                       
 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, 
must have a written report submitted within 24 hours (next working day) of knowledge of 
the event to the Safety Project Manager in the IND Office. 
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete 
and laboratory tests have returned to baseline, progression of the event has stabilized, 
or there has been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time period that 
are related to the study treatment must be reported to the IND Office. This may 
include the development of a secondary malignancy. 
 
6.3.2.2  Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the 
protocol guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
6.3.2.3 Investigator Communication with Supporting Companies: 
The MDACC Internal SAE Report Form will be used for reporting to Merck Global Safety (FAX:  
+1-215-661-6229), and reporting timeline is as below: 
 
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Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Merck: 
 
 
 
 
 
Serious Adverse Event 
(SAE) including Cancer 
and Overdose 
Report if: 
- due to protocol-
specified 
intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-
in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of receipt of 
information 
Pregnancy/Lactation 
Exposure 
Report if: 
 
-  participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in) 
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event. 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of receipt of 
information 
Event of Clinical 
Interest (require 
regulatory reporting) 
Report if: 
- due to 
intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of receipt of 
information 
 
 
 
 
 
 
 
Events of clinical interest (ECI) for this trial include: 
1.  An overdose of MK-3475that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, an overdose of  MK-3475 will be defined as any 
dose of 1,000 mg or greater.  No specific information is available on the treatment of overdose of 
pembrolizumab. In the event of overdose, the participant should be observed closely for signs of 
toxicity.  Appropriate supportive treatment should be provided if clinically indicated.  
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 
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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.  
 
 
6.3.4 Evaluating Adverse Events 
An investigator or a designee will evaluate and record adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0 as standard practice per 
institution guidelines.  
7.0 STATISTICAL ANALYSIS PLAN  
The primary objective of this phase II trial is to assess the efficacy of MK-3475 as a single agent 
in metastatic IBC and non-IBC TNBC patients. The primary endpoint is the rate of disease control 
measured at the end of 4 months from the start of therapy. 
The disease control rate is defined as the percentage of patients either 1) with measurable disease 
that achieve iCR, iPR, iSD, or 2) with non-measurable disease that achieve iCR or iSD, , by 4 
months or more in all evaluable patients. We will also perform secondary analysis on intent-to-
treat patient population where those patients who drop out early will be considered as progression.  
The trial will be conducted using Simon’s optimal two-stage design and the rate of disease control 
will be estimated accordingly. It is assumed that the MK-3475 single agent will have a disease 
control rate of 30%. A disease control rate of 10% or lower will be considered treatment failure 
and the regimen will be rejected under this circumstance.  When the probability of accepting a 
“bad” regimen (i.e. disease control rate 10% or lower) is 0.10 and the probability of rejecting a 
“good” regimen (i.e. disease control rate 30% or higher) is also 0.10, Simon’s optimal 2-stage 
design requires 12 patients enter in the first stage. The study accrual will be delayed until all 12 
patients are evaluable for disease control status.  If 1 or no patients maintain disease control on 
treatment, the trial will be stopped and the regimen will be declared as ineffective.  If 2 or more 
patients maintain disease control, 23 more patients will be enrolled to the study to reach a total of 
35 treated patients.  By the end of the study, the new regimen will be rejected if rate of disease 
control is less than or equal to 5/35 and will be considered worthy of further investigation 
otherwise. 
However, with a larger sample size, we will be able to detect a smaller target disease control rate 
of 0.25.  It is assumed that the MK-3475 single agent will have a disease control rate of 25%. A 
disease control rate of 10% or lower will be considered treatment failure and the regimen will be 
rejected under this circumstance.  When the probability of accepting a “bad” regimen (i.e. disease 
control rate 10% or lower) is 0.10 and the probability of rejecting a “good” regimen (i.e. disease 
control rate 25% or higher) is also 0.10, Simon’s optimal 2-stage design requires 21 patients enter 
in the first stage. The study accrual will be delayed until all 21 patients are evaluable for disease 
control status.  If  2 or less patients maintain disease control on treatment, the trial will be stopped 
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and the regimen will be declared as ineffective.  If 3 or more patients maintain disease control, 29 
more patients will be enrolled to the study to reach a total of 50 treated patients.  By the end of the 
study, the new regimen will be rejected if rate of disease control is less than or equal to 7/50 and 
will be considered worthy of further investigation otherwise. But, that will not happen based on 
the current disease control rate. 
At any time after first 5 patients are treated, if >=30% patients experience serious adverse events 
(SAE) within 2 cycles of treatment, we will stop the trial and claim that the regimen is too toxic. 
SAE is defined as an adverse event is serious, unexpected, and related to the study drug. 
Patients’ characteristics will be summarized at the end of the study. For discrete or categorical 
data, descriptive statistics will be generated including tabulations of frequencies.  For continuous 
data, summary statistics including sample size, mean, standard deviation, median, minimum and 
maximum will be computed.  A 95% exact binomial confidence interval on disease control rate 
will be computed.  
 
Various biomarker endpoints will be measured in various specimens.  Correlation among 
biomarkers at baseline in each specimen and between different specimens will be assessed.  The 
association among various continuous and discrete biomarkers or disease status groups will be 
assessed by the exploratory data analysis using scatter plot matrix, box plots, BLiP plot 37 and 
trellis plot, etc, and may be tested by t-test/ANOVA/Wilcoxon rank sun test/Kruskal-Wallis test, 
whichever is appropriate. Correlation between continuous biomarkers will be examined by 
Pearson or Spearman rank correlation coefficients. The association between discrete biomarkers 
will be tested by chi-square or Fisher’s exact test.  Paired t-test/Wilcoxon rank sum test and 
McNemar’s test may be used to test the change of a single continuous biomarker and discrete 
biomarker, respectively, over time within each treatment group.  Repeated measures analysis 
including mixed effects model will be performed to analyze the correlation between disease 
control and biomarkers change over time. 38   Disease control survival and overall survival time 
from the registration date will be estimated using Kaplan-Meier method. 
 
All statistical tests will be performed at a two-sided significance level of 5% using SAS or S-
Plus, as appropriate.  
 
8.0 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 11. 
Table 6  Product Descriptions 
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Product:  MK-3475  
36 
Protocol/Amendment No.: 2014-0533 
PI: Clinton Yam 
 
Date:  3-10-2023 
 
 
  
 
Confidential  Limited Access 
 
Product Name & Potency 
Dosage Form 
 
 
MK-3475 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. 
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. 
9.0  DATA MANAGEMENT 
Data collected from the study will be entered in REDCap database. The Principal Investigator is 
responsible for assuring that the data entered into the database are complete and accurate and that 
data entry is performed in a timely manner.  Deidentified data will be shared with University of 
Hawaii Cancer Center (UHCC) for review and analysis. 
9.1 Data collection for this study including: 
1) demographic information (sex, race, and date of birth),   
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Product:  MK-3475  
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Protocol/Amendment No.: 2014-0533 
PI: Clinton Yam 
 
Date:  3-10-2023 
 
 
  
 
Confidential  Limited Access 
 
2) date of initial breast cancer diagnosis, pathology report of primary breast cancer, biomarker 
status, and date and location of distant metastases; 
3) history of breast cancer surgery, and radiation therapy, if applicable; 
4) date and type of chemotherapy and/or hormonal therapy for metastatic disease;  
5) all AEs will be collected, however only >/=2 non-hematologic AEs and >/=3 hematological 
AEs will be recorded.  Other abnormal laboratory values will not be reported as AEs; 
however, any clinical consequences of abnormality should be reported as AEs.  
6) Concomitant medication will be recorded per standard of care in clinic database, and will 
not be recorded in the study database.  
9.2. Data confidentiality plan 
All laboratory and clinical data gathered in this protocol will be stored in a password-protected 
database. All patient information will be handled using anonymous identifiers. Linkage to patient 
identity will be possible only after accessing a password-protected database. Access to the database 
will be available only to individuals directly involved in the study. 
Information gathered for this study will not be reused or disclosed to any other person or entity, or 
for other research. Once the research has been completed, identifiers will be retained for as long 
as is required by law and by institutional regulations, and at that point will be destroyed. 
 
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Protocol/Amendment No.: 2014-0533 
PI: Clinton Yam 
 
Date:  3-10-2023 
 
 
  
 
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Date:  3-10-2023 
 
 
  
 
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35. 
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