Conditions: Advanced Cancer Breast Cancer Gastric Cancer Esophageal Cancer Colorectal Cancer
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

Brief summary:
There will be two phase II cohorts for pembro plus trastuzumab: one cohort will be for patients with unresectable HER2 overexpressing gastric or GEJ cancers, the other cohort will be for patients with HER2 overexpressing metastatic breast cancer (MBC). The pembro plus ado-trastuzumab emtansine phase II arm will be for patients with HER2 overexpressing MBC. There will be two phase II cohorts for pembro plus cetuximab: one cohort will be for patients with HNSCC, the other cohort will be for patients with K-ras, B-raf, N-ras wildtype metastatic CRC.

Detailed description:
Pembrolizumab 2mg/kg administered intravenously over 30 minutes every 3 weeks. Pembrolizumab will be infused prior to the start of the assigned monoclonal antibody (Mab) arm. .

Dosing for the Mab arms will begin as follows:

Arm 1: Cycle length is 21 days. Intravenous (i.v.) trastuzumab 6 mg/kg on day 1 every 21 days.

Arm 2: Cycle length is 21 days. i.v. ado-trastuzumab emtansine 3.6 mg/kg on day 1 every 21 days.

Arm 3: Cycle length is 21 days. i.v. cetuximab 400 mg/m2 on cycle 1 day 1, then i.v. cetuximab 250 mg/m2 on day 8. Each subsequent cycle will be i.v. cetuximab 250 mg/m2 on days 1 and 8 every 21 days.

Arms:
arm 1: Pembrolizumab 2mg/kg administered intravenously over 30 minutes every 3 weeks. Intravenous (i.v.) trastuzumab 6 mg/kg on day 1 every 21 days. arm 2: Pembrolizumab 2mg/kg administered intravenously over 30 minutes every 3 weeks. i.v. ado-trastuzumab emtansine 3.6 mg/kg on day 1 every 21 days. arm 3: Pembrolizumab 2mg/kg administered intravenously over 30 minutes every 3 weeks. i.v. cetuximab 400 mg/m2 on cycle 1 day 1, then i.v. cetuximab 250 mg/m2 on day 8. Each subsequent cycle will be i.v. cetuximab 250 mg/m2 on days 1 and 8 every 21 days.

Interventions: intervention 1: Pembrolizumab intervention 2: Trastuzumab intervention 3: ado-trastuzumab emtansine intervention 4: Cetuximab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None

Protocol document:
Prot_SAP_000.pdf: 
21/Jun/2016 Amd3 
 
Page 1 of 27 
Protocol: PembroMab 
 
 
 
A Phase Ib/II Study of Pembrolizumab and Monoclonal Antibody Therapy in 
Patients with Advanced Cancer (PembroMab) 
 
 
 
Protocol ID: 
WG2014028 PembroMab 
 
Site Tracking #: 
WG2014028 
 
 
 
Principal Investigator:  
Glen J. Weiss, MD, MBA 
 
Sub-Investigator:  
Vivek Khemka, MD, MBA 
 
 
Jordan Waypa, FNP-C 
 
 
 
          
 
 
 
 
 
Western Regional Medical Center, Inc.  
14200 W. Celebrate Life Way 
Goodyear, AZ  85338 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


21/Jun/2016 Amd3 
 
Page 2 of 27 
Protocol: PembroMab 
 
 
 
I. 
Study Objectives 
 Primary Objective for phase Ib: 
• Determine the recommended phase 2 dose (RP2D) of monoclonal antibody therapy 
(Mab) +/- eribulin in combination with pembrolizumab (pembro) in subjects with 
advanced cancer.  
 
Primary Objective for phase II: 
• Complete response by immune-related response criteria (irRECIST)1   
 
Secondary Objectives: 
• Frequency of grade 3 or higher treatment-related adverse events by CTCAE 4.03 
• Response rate by irRECIST and response evaluation criteria in solid tumors (RECIST) 
1.1 criteria1,2  
• To determine the overall survival (OS) and progression-free survival (PFS) 
• To characterize changes in circulating tumor DNA in patients enrolled on this study 
• Textural changes identified on imaging that is done per routine practice 
 
II. 
Background and Rationale 
An estimated 585,000 individuals diagnosed with cancer will die from their disease in 20143. 
While some may have long-term disease-free intervals, for most individuals that are 
diagnosed with metastatic disease, the survival rate is less than 5 years. For primary cancers 
such as squamous cell carcinoma of the head and neck (HNSCC), colorectal cancer (CRC), 
and HER2 overexpressed breast cancer, few individuals will live 3 years with metastatic 
disease. Patients with metastatic disease are usually treated with systemic chemotherapy, 
with the intent of prolonging survival and palliate symptoms (pain, weight loss and decrease 
in performance status). For the most common cancer types, there are defined 
recommendations for first- and/or second-line systemic therapy. Year after year, randomized 
trials are designed and launched to try and improve on median overall survival outcomes. In 
oncology, the success rate from phase I to FDA approval is a dismal 11%4. Even with the 
successful phase 3 clinical trials, the improvement in overall survival is modest, increasing 
the median by weeks to several months. For common non-hematologic cancers (and many 
rare cancers), there are no design strategies that are primarily seeking to attain complete (and 
hopefully durable) responses.  
 
There have been promising results with antibody-based immunostimulatory therapy in 
melanoma, renal cell carcinoma, and non-small cell lung cancer5,6. By irRECIST, some 
individuals may have long durable disease control. There have been recent clinical data on 
synergetic effects of chemotherapy and preclinical data on Mab given in combination with 
PD-1 immunostimulatory therapy7,8 (immunochemotherapy).  
 
In this protocol, the phase Ib portion will allow inclusion of any advanced solid tumor 
patient that meets the eligibility criteria for the selected arm. Once the RP2D is determined 
for each arm, the phase II portion begins for that treatment arm. There will be one phase II 
cohort for pembro plus trastuzumab and eribulin9: patients with unresectable HER2 
overexpressing metastatic breast cancer (MBC) for patients that have received prior 
trastuzumab. PD-1 has been reported to be overexpressed in this cancer type8. The pembro 
plus ado-trastuzumab emtansine phase II arm will be for patients with HER2 overexpressing 
MBC. There will be two phase II cohorts for pembro plus cetuximab: one cohort will be for 


21/Jun/2016 Amd3 
 
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Protocol: PembroMab 
 
 
 
patients with HNSCC, the other cohort will be for patients with K-ras, B-raf, N-ras wildtype 
metastatic CRC. PD-1 has been reported to be expressed in HNSCC10 and CRC11,12. We 
hypothesize that with optimal debulking of tumor with the combination of Mab +/- eribulin 
and immunostimulatory therapy, the response may be enhanced to achieve long durable 
complete responses. Each phase II arm is powered to at least 80% to address the primary 
objective. 
 
III. 
Subject Eligibility 
Inclusion criteria for Phase Ib and II: 
1. Patient at least 18 years old and has definitive histologically or cytologically 
confirmed unresectable or metastatic solid tumor.  
2. Patient has one or more tumor measurable as defined by RECIST 1.1 by CT scan (or 
PET/CT, if patient is allergic to CT contrast media). Tumor sites that are considered 
measureable must not have received prior radiation therapy.  For metastatic tumors 
not measurable by CT and/or PET/CT, there needs to be tumor measuring at least 
1cm in one dimension by digital calipers on physical exam. 
3. Patients can be enrolled only on one of the treatment arms on this trial. 
4. The investigator will select the appropriate treatment arm for the patient with the 
following requirements: (a) Patients cannot have had prior progression or intolerance 
to eribulin or ado-trastuzumab emtansine or cetuximab and then enrolled on the 
trastuzimab and eribulin or ado-trastuzumab emtansine or cetuximab arms plus 
pembro, respectively; (b) The systemic therapy on the arm selected must be 
considered standard of care or listed in the NCCN guidelines (www.nccn.org) for that 
cancer type. For example, a patient with K-ras, B-raf, N-ras wildtype CRC cannot be 
enrolled on the trastuzumab plus pembro arm, but can be enrolled on the cetuximab 
plus pembro arm.  
5. Have recovered from acute toxicities of prior treatment: 
a. > 3 weeks must have elapsed since receiving any investigational agent. 
b. > 2 weeks must have elapsed since receiving any radiotherapy, or ≥ 3 weeks or 5 
half-lives whichever is shorter for treatment with cytotoxic or biologic agents (≥ 6 
weeks for mitomycin or nitrosoureas). Chronic treatment with non-investigational 
gonadotropin-releasing hormone analogs or other hormonal or supportive care is 
permitted. 
6. Patient has adequate biological parameters as demonstrated by the following blood 
counts at time of screening: 
7. Absolute neutrophil count (ANC) > 1500 mm3, platelet count ≥ 100×109 L, 
hemoglobin ≥ 9 g/dL. 
8. Serum creatinine ≤2.0, total bilirubin ≤ 2 mg/dL, AST/ALT ≤ 5 times the upper limit 
of normal (ULN) range  
9. Thyroid stimulating hormone (TSH) within institutional normal limits. If TSH is 
above the upper limit of normal range, then a free T4 within institutional normal 
limits is acceptable.  
10. Persistent prior systemic therapy non-hematologic AE grade ≤ 2 (except alopecia or 
correctable electrolyte abnormality with supplementation) 
11. Patient has a Karnofsky performance status (KPS) ≥ 70.  


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Protocol: PembroMab 
 
 
 
12. Women of child-bearing potential (i.e., women who are pre-menopausal or not 
surgically sterile) must be willing to use an acceptable contraceptive method 
(abstinence, oral contraceptive or double barrier method) for the duration of the study 
and for 4 months following the last dose of pembrolizumab, 6 months for ado-
trastuzumab emtansine, and 30 days for cetuxumab,trastuzumab, and eribulin, and 
must have a negative urine or serum pregnancy test within 2 weeks prior to beginning 
treatment on this trial. Persons taking ado-trastuzumab emtansine must use at least 
one highly effective, non-hormonal method of contraception 
 
  Inclusion criteria for Phase II only: 
1. Patients must have HER2 overexpressing MBC and received prior trastuzumab to be 
enrolled on the pembro plus trastuzumab and eribulin phase II portion.  
2. Patients must have HER2 overexpressing MBC to be enrolled on pembro plus ado-
trastuzumab emtansine phase II portion.  
3. Patients must have HNSCC to be enrolled on Cohort 1 of the pembro plus cetuximab 
phase II portion. 
4. Patients must have K-ras, B-raf, N-ras wildtype CRC to be enrolled on Cohort 2 of 
the pembro plus cetuximab phase II portion. 
 
Exclusion Criteria for Phase Ib and II: 
1. Active clinically serious infection > CTCAE (version 4.03) Grade 2. 
2. Serious non-healing wound, ulcer, or bone fracture. 
3. Patient has known brain metastases, unless previously treated and well-controlled for 
at least 1 month (defined as clinically stable, no edema, no steroids and stable in 2 
scans at least 4 weeks apart). 
4. Inability to complete informed consent process and adhere to the protocol treatment 
plan and follow-up requirements. 
5. Patient has known active infection with HIV, hepatitis B, or hepatitis C (patients are 
NOT required to be tested for the presence of such viruses prior to therapy on this 
protocol). 
6. Requiring daily corticosteroid dose ≥ 10 mg prednisone or equivalent per day. A brief 
(less than 2 weeks) course of corticosteroids for prophylaxis (eg, contrast dye allergy) 
or for treatment of non-autoimmune conditions (eg, delayed-type hypersensitivity 
reaction caused by a contact allergen) is permitted (premedication for chemotherapy 
excluded). 
7. Patient has undergone major surgery, other than diagnostic surgery (e.g., surgery 
done to obtain a biopsy for diagnosis without removal of an organ), within 4 weeks 
prior to Day 1 of treatment in this study. 
8. Patient has a history of allergy or hypersensitivity to any of the study drugs or any of 
their excipients, or the patient exhibits any of the events outlined in the 
Contraindication or Special Warnings and Precautions sections of the product or 
comparator SmPC or Prescribing Information. 
9. Patient has serious medical risk factors involving any of the major organ systems, or 
serious psychiatric disorders, which could compromise the patient’s safety or the 
study data integrity. 


21/Jun/2016 Amd3 
 
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Protocol: PembroMab 
 
 
 
10. Patient will be receiving any other anti-cancer therapy during participation in this 
trial, except concurrent hormonal therapy is allowed. 
11. Prior treatment with pembro. Receipt of other PD-1 inhibitors or PD-L1 inhibitors is 
allowed. 
12. Active or prior documented autoimmune disease requiring systemic treatment within 
the past 2 years. 
 
Exclusion Criteria for phase II portion only:  
1. Patients with a history of more than one primary cancer, with the exception of: a) 
curatively resected nonmelanomatous skin cancer; b) curatively treated cervical 
carcinoma in-situ; or c) other primary solid tumor treated with curative intent and no 
known active disease present and no treatment administered during the 2 years prior 
to enrollment. 
 
IV. 
Subject Registration 
A Subject Registration Form will be completed and retained by the clinical research 
department. Subjects must begin treatment within 28 days of all baseline studies.  
Follow Table 1. Schedule of Study Procedures in the Appendix. 
 
V. 
Treatment Regimen 
Patients will be evaluated for complete eligibility and enrollment. 
 
Phase Ib portion for each treatment arm (will be analyzed separately for RP2D 
determination):  
 
• Protocol visits and procedures will be scheduled per schedule of events in Table 1. 
Required and “as indicated” planned assessments and procedures are outlined in Table 1.  
 
Dosing for pembro will be according to package insert:  
 
• 2mg/kg administered intravenously over 30 minutes every 3 weeks. Pembro will be 
infused prior to the start of the assigned systemic therapy arm. There will be no dose 
reductions for pembro. 
 
Dosing for the other systemic therapy arms will begin as follows: 
Arm 1: Cycle length is 21 days. Intravenous (i.v.) trastuzumab 8 mg/kg on cycle 1 day 1, 
then each subsequent cycle will be i.v. trastuzumab 6 mg/kg on day 1 every 21 days. I.v. 
eribulin will be 1.4 mg/m2 on days 1 and 8 every 21 days.  
Arm 2: Cycle length is 21 days. i.v. ado-trastuzumab emtansine 3.6 mg/kg on day 1 every 21 
days.  
Arm 3: Cycle length is 21 days. i.v. cetuximab 400 mg/m2 on cycle 1 day 1, then i.v. 
cetuximab 250 mg/m2 on day 8. Each subsequent cycle will be i.v. cetuximab 250 mg/m2 on 
days 1 and 8 every 21 days.  
 
Initially, 3 patients will be enrolled onto each treatment arm, and beginning on Cycle 1 Day 1 
will receive pembro 2 mg/kg followed by the other systemic therapy on that arm. 


21/Jun/2016 Amd3 
 
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Protocol: PembroMab 
 
 
 
 
Patients will be followed for 21 days. If no-dose-limiting toxicities (DLTs) are observed, this 
dose will be the highest dose tested and it will be used for further phase II study (RP2D). 
Expansion of a cohort from 3 to 6 patients will occur if 1 of 3 patients experiences a DLT at a 
given dose. If this occurs, 3 more patients will be enrolled at that dose level. If 1 or more 
patients (≥ 2/6) exhibit a DLT again, the dose level will be designated to have exceeded the 
maximum tolerated dose (MTD) and the dose level below would be tested. To be declared 
the RP2D, that lower level would require no more than 1 of 6 patients with a DLT.  
Tables 2A-C list the dose levels for each systemic therapy arm that may be tested based on 
their toxicity profiles. 
 
Maximum Tolerated Dose (MTD) 
The MTD is defined as the highest dose at which ≤ 1 of 6 evaluable patients experience a 
DLT within the first 21 days of treatment (end of cycle 1). Evaluable patients must complete 
at least 75% of their planned doses, unless missed doses are due to AEs. The cohort may be 
expanded to better define the safety profile for confirmation of the MTD.  
 
Dose-Limiting Toxicities (DLTs) 
Standard AEs will be considered DLTs that count for the determination of the MTD of 
supplementation. A DLT is a drug-related toxicity that is observed to occur within the first 21 
days of treatment (end of cycle 1) as defined below. Drug-related toxicities include any 
toxicity that is possibly, probably, or definitely drug-related. Toxicity grades will be defined 
by the NCI CTCAE v 4.03. DLTs are defined by the following: 
• Non-hematologic toxicities 
Any grade ≥ 3 non-hematologic toxicity, with the exception of self-limiting or medically 
controllable toxicities (e.g., nausea, vomiting, fatigue, electrolyte disturbances, 
hypersensitivity reactions) lasting < 3 days, and excluding alopecia. 
 
• Hematologic toxicities 
i. Febrile neutropenia not related to underlying disease (fever, > 101°C; ANC < 500) 
ii. Prolonged grade 4 neutropenia (> 7 days) 
iii. Neutropenic infection: ≥ grade 3 neutropenia with ≥ grade 3 infection 
iv. Thrombocytopenia ≥ grade 3 with bleeding or grade 4 lasting ≥ 7 days 
 
• Missed ≥ 25% of planned doses over 21 days due to treatment-related AEs in the first 
cycle. 
 
Dose delays or reductions will be implemented for patients who experience adverse drug 
reactions as indicated in Tables 3A-D. 
 
Subjects will be replaced if they do not complete the planned dose on Cycle 1 Day 1 because 
of an infusion reaction, provided that the infusion reaction is not grade 3 or higher. 
 
Initiation of phase II portion  
The decision to proceed from the dose establishment portion of the study (Phase Ib) and to 
open the expansion cohorts (Phase II) will depend on establishing the RP2D is identified. 


21/Jun/2016 Amd3 
 
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Protocol: PembroMab 
 
 
 
 
Protocol visits and procedures will be scheduled to coincide with routine clinic visits for 
treatment decision making +/- 2 days unless otherwise indicated. Required and “as indicated” 
planned assessments and procedures are outlined in Table 1.  
 
Dose Delay or Reduction 
Prior to administration of a subsequent dose of systemic treatment, a subject must meet the 
following criteria: 
• Any clinically significant systemic treatment-related toxicity must return to baseline or at 
least grade 1 
• In the event that the administration of systemic treatment was delayed for reasons of 
toxicity, the subject may receive subsequent administrations of systemic treatment at a 
reduced dose. The amount of dose reduction will be based on guidelines in Tables 2A-C 
in the Appendix. 
• In the event of toxicity that necessitates a delay of more than 4 weeks or there is 
radiographic evidence of disease progression, systemic treatment will be discontinued. 
 
The phase II portion of each treatment arm are designed to determine frequency of complete 
responses by irRECIST with immunochemotherapy 
 
The irRECIST using unidimensional measurements is defined using this table, modified from 
Nishino et al.1: 
 
 
 
Patients with metastatic solid tumors will be evaluated for complete eligibility and 
enrollment. Patients must have measurable disease by RECIST 1.1 at the time of enrollment 
and have no contraindications to receipt of pembro. Patients must meet all eligibility criteria 
and selection of treatment arm will be determined by slot availability and systemic therapy 
on the arm selected must be considered standard of care or listed in the NCCN guidelines for 
that cancer type.  
 
Dose Delay or Reduction 
Prior to administration of a subsequent dose of pembro, a subject must meet the following 
criteria: 


21/Jun/2016 Amd3 
 
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Protocol: PembroMab 
 
 
 
• Any clinically significant treatment-related toxicity must return to baseline or at least 
grade 1, AND who are receiving less than 7.5 mg prednisone or equivalent per day 
 
Discontinuation of Protocol Treatment Administration 
Pembro treatment will be discontinued in the event of any of the following: 
• *If there is continued progression by irRECIST or intolerable side effects from pembro, 
the patient will be removed from protocol, and additional systemic therapy may be 
initiated at the discretion of the treating provider.* 
• Withdrawal of consent by the subject 
• Lack of compliance by the subject 
• Changes in the subject’s medical condition that render further administration of pembro 
treatment unacceptable in the judgment of the Principal Investigator 
• Termination of study by Western Regional Medical Center, Inc. 
 
Removal of Subject from Study 
Subjects will be removed from further follow-up for any of the following reasons: 
• Request by the subject to no longer be followed 
• Completion of all study required follow-up  
• Death 
• Termination of study by Western Regional Medical Center, Inc. 
 
Use of Anti-emetics and Supportive Care 
Based on safety and efficacy data from other clinical trials involving PD-1 and PD-L1 
inhibitors, premedication on the day of chemotherapy infusion (Arm 1) with dexamethasone 
12 mg intravenously will be allowed. The anti-emetic regimen will be dictated by Western 
Regional Medical Center guidelines for the level of emetogenic risk of the chemotherapy. 
Supportive measures should be used as dictated by current standard of care at Western 
Regional Medical Center. 
 
Prohibited Concomitant Medications/Therapies 
• No prophylactic use of G-CSF in cycle 1. G-CSF can be used as prophylaxis in 
subsequent cycles if patient meets criteria for use per ASCO guidelines13.   
• Any other anti-cancer therapy including investigational therapies unless allowed at the 
time of study entry 
 
VI. 
Study Drugs 
Please see attached PDF files of package insert for pembro, trastuzumab, eribulin, ado-
trastuzumab emtansine, and cetuximab. 
 
VII. 
REGULATORY AND REPORTING REQUIREMENTS 
The study will be conducted according to the principles of the Declaration of Helsinki (as 
Scotland 2000, as clarified in 2002), the International Conference on Harmonization 
Guidance on Good Clinical Practice and the requirements of all local regulatory authorities 
regarding the conduct of clinical trials and the protection of human subjects. 
Adverse event reporting will be as per the current NCI criteria. 


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Protocol: PembroMab 
 
 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html). 
 
VIII. Institutional Review Board (IRB)/Ethics Committee (EC) 
Approval of this study will be obtained from an IRB/EC prior to enrolling subjects on study. 
 
 
 
IX. 
Public Trial Registry 
This study will be listed on a Public Trial Registry such as ClinicalTrials.gov shortly after 
IRB approval. 
 
X. 
Written Informed Consent 
Consent forms must be in a language fully comprehensible to the prospective subject, 
otherwise the document must be translated into the subject’s native language per institutional 
policy. Written, dated informed consent for the study must be obtained from all subjects 
before the start of any protocol specified procedures. 
 
XI. 
Subject Confidentiality 
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties other than those noted below is prohibited.  
Subject’s individual identifying information will be kept as confidential as possible under 
local, state, and federal law.  Data generated as a result of this study are to be available for 
inspection on request by the following: 
• Government agencies including the Food and Drug Administration (FDA) 
• Western Regional Medical Center designated research personnel, 
• or the Western Institutional Review Board.   
 
Western Regional Medical Center may retain in its files copies of subject medical 
information required for auditing of case report forms (CRFs). 
 
Individual subject identities will not be disclosed in any report or publication related to the 
study. 
 
XII. 
Financial Disclosure 
Investigators must be in compliance with the current FDA guidelines and regulations 
concerning financial disclosure. 
 
XIII. Data Quality Assurance 
Accurate, consistent, and reliable data will be ensured through the use Good Clinical 
Practices (GCP) guidelines regarding clinical data management practices and procedures. 
 
XIV. Control of the Study Materials 
The Principal Investigator or their representative will account for all study materials. All 
study materials will be kept under lock in an inaccessible location while in storage. The 


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Protocol: PembroMab 
 
 
 
Principal Investigator shall maintain adequate records of the disposition of the drug, 
including dates, quantity and use by subjects. 
 
XV. 
Adverse Events 
 
Adverse Event (AE) Definition (using CTCAE version 4.03) 
An AE is any untoward medical event that occurs to a subject following the start of study 
drug administration, whether or not the event is considered drug-related. Pre-existing 
conditions are not considered an AE unless the condition worsens by at least one grade 
following the start of study drug(s) administration. 
 
Death due to disease progression occurring 31 days or more from the day of last pembro or 
systemic therapy administration as part of this protocol will not be reported as an AE or SAE. 
 
Any drug related AE of grade 3 or higher should be followed for resolution until either 1) 
subsequent anti-cancer therapy or 2) death.  
 
Serious Adverse Event (SAE) Definition 
An SAE is any AE that results in any of the following outcomes: 
• Death 
• A life-threatening experience 
• An inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
 
An event that is not listed above but that requires intervention to prevent one of the outcomes 
listed above is also considered an SAE. 
 
Elective hospitalizations that are not in response to an AE will not be considered an SAE. 
 
Serious Adverse Event Reporting 
All SAEs must be reported to Western Regional Medical Center’s Institutional Review Board 
(IRB) within 24 hours of the Investigator becoming aware of the SAE. 
 
To report an SAE, sites will complete an SAE Report and email or FAX the SAE report to 
Western Regional Medical Center’s IRB.  
 
Site must report all SAEs that occur within 30 days after the last dose of pembro or 
systemic therapy treatment while on this study or until the subject receives additional cancer 
therapy. 
 
Relationship to pembro or systemic therapy on this study 
The relationship of an AE or SAE to pembro or systemic therapy on this study will be 
classified using the following four (4) categories: 
• Definitely related 
• Likely related 


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Protocol: PembroMab 
 
 
 
• Unlikely related 
• Definitely not related 
 
XVI. STATISTICAL AND ANALYTICAL CONSIDERATIONS 
 
Analysis Datasets 
The definitions of the analysis datasets are as follows: 
• The Evaluable for Safety Population will consist of all subjects who receive at least one 
dose of pembro 
• The Evaluable for Efficacy Population will consist of all subjects who receive at least one 
dose of pembro and who have had at least one post-baseline disease assessment 
 
Subject Disposition 
Data tabulations will summarize the following subject numbers, per dose group: 
• Enrolled 
• Received treatment 
• Evaluable for safety and efficacy 
• Who violate the protocol 
• Who complete the protocol 
• Who withdraw because of 1) adverse event(s), 2) disease progression, 3) physician’s 
recommendation, or 4) withdrawal of consent 
 
Subject Characteristics 
Demographic characteristics of subjects will be summarized using descriptive statistics: 
• Age 
• Sex 
• Ethnicity 
• Performance status 
• Tumor type 
• Prior cancer treatment 
• Smoking history 
 
Efficacy Analysis 
The primary objective of the Phase Ib is to determine the RP2D of pembro with Mab +/- 
eribulin. 
 
The primary objective of the Phase II study is designed to determine frequency of complete 
responses by irRECIST in each of the treatment arms.  
For each of the following arms, a complete response to the systemic therapy would be 
expected to be no more than the following % based on the following pivotal trial references:  
Arm 1: 6% for trastuzumab and eribulin9 plus pembro 
Arm 2: 1% for ado-trastuzumab emtansine14,15 plus pembro  
Arm 3 Cohort 1: <1% for cetuximab16 plus pembro 
Arm 3 Cohort 2: <1% for cetuximab17 plus pembro 
 


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Protocol: PembroMab 
 
 
 
For Arm 1, assuming a complete response rate of up to 6% in this setting with trastuzumab 
and eribulin and a rate of 29% for those subjects treated with trastuzumab and eribulin plus 
pembro, a sample size of 12 subjects will be required based on power of 80% and a one-sided 
alpha of 0.05. 
 
For Arm 2, and Arm 3, assuming a complete response rate of up to 1% in this setting with 
Mab and a rate of 14.5% for those subjects treated with Mab plus pembro, a sample size of 
12 subjects in each arm will be required based on power of 80% and a one-sided alpha of 
0.05. 
 
The calculations for statistical power and sample size using percentage complete response 
were computed using this: http://www.stat.ubc.ca/~rollin/stats/ssize/b1.html and confirmed 
using averages/one sample with this: 
https://www.dssresearch.com/KnowledgeCenter/toolkitcalculators/statisticalpowercalculators
.aspx  
 
Note that the cohort that determines the RP2D will be counted towards the number required 
to be included in the statistical analysis calculations for the primary objective of the Phase II 
portion above, IF the subjects in that cohort have the cancer type to be assessed in the Phase 
II portion. For example, for cetuximab plus pembro (Arm 3), if 6 patients were required to 
reach the RP2D and 2 of those patients had HNSCC and 4 had K-ras, B-raf, N-ras wildtype 
CRC, then 10 additional patients with HNSCC and 8 additional patients with K-ras, B-raf, N-
ras wildtype CRC will be required to complete the primary objective for the Phase II portion 
for Arm 3 Cohort 1 and Cohort 2, respectively.    
 
The statistical analysis will be mainly descriptive. Continuous variables will be summarized 
using descriptive statistics: N, mean, standard deviation, median, minimum and maximum. 
Categorical variables will be presented using frequencies and percentages. Time-to-event 
variables will be described by N, median, range, number censored, and Kaplan-Meier plots.  
 
All data collected on the CRF will be listed. There will be no imputations for missing data 
other than dates. A statistical analysis plan will be finalized prior to analysis. Any deviations 
from the statistical methods given in the protocol will be described and fully justified in the 
statistical analysis plan and/or in the final report as appropriate. 
 
The primary reason for discontinuation in the study will be summarized for all patients. 
 
Baseline characteristics and demographic data will be summarized for all patients who 
receive at least one treatment dose. 
 
Results for the secondary objectives will be presented descriptively and with percentages 
where applicable.   
Definitions:  
• Tumor Response: Subjects will be assigned one of the following categories based on the 
response criteria outlined in irRECIST and RECIST 1.1 as appropriate for each tumor 


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Protocol: PembroMab 
 
 
 
type: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease. 
An objective response will be defined as either a CR or PR. 
• DFS is defined as the period of time from the date of surgical resection to the date that 
the subject is determined to have disease relapse/recurrence or death due to any cause. 
• OS is defined as the period of time from the date of enrollment to the date of death due to 
any cause. 
 
Criteria response evaluation and overall response rates will be summarized by proportions 
together with exact binomial 95% confidence intervals for each dose group. Durations (DFS 
and OS) will be summarized by Kaplan- Meier methods. Median survival with 95% 
confidence intervals will be calculated and survival graphs will be presented for all Kaplan-
Meier analyses.  
 
Safety Analysis 
All subjects who receive any amount of pembro (Safety Population) will be included in the 
final summaries and listings of safety data. 
 
Frequencies of subjects experiencing at least one AE will be displayed by body system and 
preferred term according to MedDRA terminology.  Detailed information collected for each 
AE will include: description of the event, duration, whether the AE was serious, relationship 
to study drug, action taken, clinical outcome, and whether or not it was a DLT.  Severity of 
the AEs will be graded according to the CTCAE version 4.03.  Emphasis in the analysis will 
be placed on AEs classified as dose limiting. 
 
Summary tables will present the number of subjects observed with any grade AEs and 
corresponding percentages.  The denominator used to calculate incidence percentages 
consists of subjects receiving at least one dose of study drug for each dose group. Within 
each table, the AEs will be categorized by MedDRA body system and preferred term. 
Additional subcategories will be based on event severity and relationship to study drug. 
 
Deaths and other SAEs will be tabulated. 
 
XVII. Pharmacodynamic analysis 
Circulating tumor DNA in plasma provides a minimally invasive and potentially highly 
sensitive assay to meet this end. This methodology quantifies circulating tumor DNA in 
plasma and where available, matched tumor in specimens from cancer patients. It is hoped 
that this approach may provide valuable clinical decision-making information over the 
current treatment paradigm that involves periodic imaging for disease restaging.  
 
Procedures for tumor DNA analysis: 
Tissue processing. MACRODISSECTION OF TISSUES.  
The referring pathologist should mark an area of >70% tumor cells on an H&E or immune-
stained slide that must be sent with the material for testing. 5 freshly-cut serial sections of the 
tumor FFPE tissue, each with a thickness of 10 μm per slice will be prepared. For ≥ 250 
square-mm surface area: combine 2 x 5 sections, each with a thickness of 10 μm into two 
empty Eppendorf tubes (5 sections per tube, total 10 sections). For ≤250 square-mm surface 


21/Jun/2016 Amd3 
 
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Protocol: PembroMab 
 
 
 
area: combine 3 x 5 sections, each with a thickness of 10 μm in three empty Eppendorf tubes 
(5 sections per tube, total 15 sections). When preparing pathological material for DNA 
analysis, please ensure the equipment (especially the microtome blade and water bath) is 
completely clean between cases to prevent cross contamination. This can be achieved by 
wiping the microtome blade and any other surfaces with ethanol until they are free of any 
debris from earlier cases.  
 
Blood collection, processing, and shipping:  
Peripheral blood from a suitable vein or from an indwelling catheter (after blood collected for 
routine clinical care) is collected in two pre-labeled purple top K2-EDTA tubes (no heparin, 
BD or BCT). Once collected:  
1) Gently invert tubes 8-10 times.  
2) Store vacutainer tubes upright at 4ºC until centrifugation. Wait ~10mins for EDTA 
clotting. 
3) Centrifuge at 1,100-1,300g max, at 4ºC, no break on centrifuge to avoid hemolysis. 
4) Collect plasma and aliquot into sterile tubes.  
*Aliquot in amounts of 500 ul (at least 4 tubes) and 1000ul 
**Stop aliquoting plasma when the total volume of plasma remaining is less than 500 ul.  
5) Centrifuge plasma aliquots in a bench top centrifuge at 16,000-20,000g (max speed) for 10 
minutes to pellet any remaining cellular debris. 
6) Each tube will be labeled with a unique patient code, and log the date and time of blood 
draw. 
7) Snap-freeze after separation in liquid nitrogen. 
(From blood collection to aliquoting aim for less than 1 hour, preferably less than 45 
minutes) 
 
The samples will be batched and collected by TGen personnel or shipped to TGen at 445 N 
5th St, Phoenix, AZ 85004. 
 
Blood collections for circulating tumor DNA and proteomics correlates will be collected at 
up to 4 time points (starting with amendment 3, including the phase 1b portion): (1) 20 mL 
blood draw at baseline will be performed after informed consent but prior to initiation of 
C1D1, (2) after the first imaging assessment, and where applicable: (3) after imaging/exam 
confirms a complete response by irRECIST and/or (4) after imaging/exam confirmed disease 
progression by irRECIST.  
 
Blood Processing and analysis along with and tumor samples (where applicable) will occur at 
TGen. All samples given to TGen will be devoid of patient identifiers and the results 
provided by TGen to the investigators will be kept in a secure database in the Western 
Regional Medical Center research offices. At no time will TGen have access to any patient 
related identifiers. 
 
Quantitative Texture Analysis (QTA) will utilize standard imaging obtained from baseline 
and for the duration of subject participation on protocol.  QTA can be performed on all types 
of imaging scans (CT or MRI and PET/CT scans). QTA is a novel analysis platform that 
measures tumor morphology and density on a pixel-by-pixel basis and provides a quantitative 


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Protocol: PembroMab 
 
 
 
read out tumor heterogeneity. Tumor heterogeneity is an important feature of tumor behavior 
and is driven by underlying biologic changes in tumor perfusion, oxygenation, proliferation 
and extracellular architecture18. QTA can help to provide biologic, predictive and prognostic 
information about tumor behavior, mutation status, hormone receptor status and early 
indicators of response. QTA may be performed from standard of care images, such as CT 
scans, and has been shown to be more predictive of response in renal cell carcinoma to TKI 
agents19. Given this novel approach of tumor analysis, QTA will be applied to image studies 
obtained in this trial and analyzed for associations with primary and secondary endpoints.  
 
 
XVIII. Financial Responsibility 
Pembro is commercially available, and will be provided at no cost to enrolled subjects 
(unless during the course of the study it receives a FDA label for a patient with the cancer 
being treated under study—in that situation the patient would be informed before proceeding 
with treatment on study). Patients will be enrolled onto a treatment arm where the other 
systemic therapy is billed to the patient’s health plan or insurance company since it is 
commercially available and standard of care or listed in NCCN guidelines for treatment of 
their cancer. Research-related blood collection and QTA analysis will not be charged to 
enrolled subjects. The cost of treating cancer with any other treatments received (including 
imaging and supportive care medicines), the cost of standard of care blood work, and the cost 
of treating any side effects from such treatments will be billed to the patient’s health plan or 
insurance company. If medical care is needed as a result of injury while being in this study, 
medical care will be provided to the patient and the insurance company will be billed. 
 
XIX. References 
1.  
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. Developing 
a common language for tumor response to immunotherapy: immune-related response 
criteria using unidimensional measurements. Clin Cancer Res [Internet] 2013 [cited 2015 
Jan 29];19(14):3936–43. Available from: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3740724&tool=pmcentr
ez&rendertype=abstract 
2.  
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer [Internet] 2009 [cited 
2014 Feb 19];45(2):228–47. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/19097774 
3.  
Society AC. Cancer Facts & Figures. 2014;Available from: 
http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-
042151.pdf 
4.  
Hay M. BIO / BioMedTracker Clinical Trial Success Rates Study. 2011;Available from: 
http://insidebioia.files.wordpress.com/2011/02/bio-ceo-biomedtracker-bio-study-handout-
2-15-20111.pdf 
5.  
Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-
PD-1 antibody in cancer. N Engl J Med [Internet] 2012 [cited 2014 Feb 
26];366(26):2443–54. Available from: 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3544539&tool=pmcentr
ez&rendertype=abstract 


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Protocol: PembroMab 
 
 
 
6.  
Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with 
pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-
comparison cohort of a phase 1 trial. Lancet [Internet] 2014 [cited 2014 Sep 3];Available 
from: http://www.thelancet.com/journals/a/article/PIIS0140-6736(14)60958-2/fulltext 
7.  
Nivolumab. Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with 
platinum-based doublet chemotherapy (PT-DC) in advanced non-small cell lung cancer 
(NSCLC). [Internet]. 2014;1:125962. Available from: 
http://meetinglibrary.asco.org/content/125962-144 
8.  
Loi. Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage 
HER2-positive breast cancer (HER2+ BC) [Internet]. San Antonio Breast Cancer Symp. 
2013 [cited 2014 Sep 21];Abstract S1–05. Available from: 
http://www.abstracts2view.com/sabcs13/view.php?nu=SABCS13L_684 
9.  
Wilks S, Puhalla S, O’Shaughnessy J, et al. Phase 2, multicenter, single-arm study 
of eribulin mesylate with trastuzumab as first-line therapy for locally recurrent or 
metastatic HER2-positive breast cancer. Clin Breast Cancer [Internet] 2014 [cited 2016 
Jun 18];14(6):405–12. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/25024001 
10.  
Badoual C, Hans S, Merillon N, et al. PD-1-expressing tumor-infiltrating T cells are a 
favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 
[Internet] 2013 [cited 2014 Sep 21];73(1):128–38. Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/23135914 
11.  
Droeser RA, Hirt C, Viehl CT, et al. Clinical impact of programmed cell death ligand 1 
expression in colorectal cancer. Eur J Cancer [Internet] 2013 [cited 2014 Sep 
21];49(9):2233–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23478000 
12.  
Formica V, Cereda V, di Bari M-G, et al. Peripheral CD45RO, PD-1, and TLR4 
expression in metastatic colorectal cancer patients treated with bevacizumab, fluorouracil, 
and irinotecan (FOLFIRI-B). Med Oncol [Internet] 2013 [cited 2014 Sep 21];30(4):743. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/24114613 
13.  
Smith TJ, Khatcheressian J, Lyman GH, et al. 2006 Update of Recommendations for the 
Use of White Blood Cell Growth Factors: an Evidence-Based Clinical Practice Guideline. 
J Clin Oncol 2006;24(19):3187–205.  
14.  
Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced 
breast cancer. N Engl J Med [Internet] 2012 [cited 2014 Jul 12];367(19):1783–91. 
Available from: http://www.ncbi.nlm.nih.gov/pubmed/23020162 
15.  
Website A. Objective Response Rate | KADCYLA® (ado-trastuzumab emtansine) 
[Internet]. website. [cited 2014 Sep 21];Available from: 
http://www.kadcyla.com/hcp/clinical-information/efficacy/objective-response-rate 
16.  
Vermorken JB, Trigo J, Hitt R, et al. Open-label, uncontrolled, multicenter phase II study 
to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with 
recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to 
respond to platinum-based the. J Clin Oncol [Internet] 2007 [cited 2014 Aug 
23];25(16):2171–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17538161 


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Protocol: PembroMab 
 
 
 
17.  
Saltz LB, Meropol NJ, Loehrer PJ, Needle MN, Kopit J, Mayer RJ. Phase II trial of 
cetuximab in patients with refractory colorectal cancer that expresses the epidermal 
growth factor receptor. J Clin Oncol [Internet] 2004 [cited 2014 Sep 15];22(7):1201–8. 
Available from: http://jco.ascopubs.org/content/22/7/1201.long 
18.  
Win T, Miles K, Janes SM, et al. Tumor Heterogeneity as measured on the CT component 
of PET/CT Predicts Survival in Patients with Potentially Curable Non-Small Cell Lung 
Cancer. Clin Cancer Res [Internet] 2013;Available from: 
http://www.ncbi.nlm.nih.gov/pubmed/23659970 
19.  
Goh V, Nathan P, Juttla JK, Miles KA. Assessment of Response to Tyrosine Kinase 
Inhibitors in Metastatic Renal Cell Cancer : CT Texture as a Predictive Biomarker 1 
Methods : Results : Conclusion. Radiology [Internet] 2011;261:165–71. Available 
from: http://www.ncbi.nlm.nih.gov/pubmed/21813743 
 


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Protocol: PembroMab 
 
 
 
Appendix 
Table 1. Schedule of Study Procedures 
Parameter 
Baseline 
Cycle 1 
Cycle 2 
 
 
 
 
 
Cycle 3 
 
 
 
 
 
Cycle 4+ 
End of Study 
Day of study 
-28 to 
1 
 
1 
 
8 
 
15 
 
1 
 
8 
 
15 
 
1 
 
8 
 
15 
 
1 
 
8 
 
15 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete medical 
history, height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
exam 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Symptom directed 
exam 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
 
(X) 
 
(X) 
Karnofsky 
performance status 
(KPS) 
X 
X 
(X) 
 
X 
(X) 
 
X 
(X) 
 
X 
(X) 
 
X 
Vital signs (BP, HR, 
RR, temp, pain) and 
weight 
X 
X 
 
(X) 
 
X 
 
(X) 
 
X 
 
(X) 
 
X 
 
(X) 
 
X 
Review con meds, 
AEs 
X 
X 
(X) 
 
X 
(X) 
 
X 
(X) 
 
X (X) 
 
X 
ECG  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
2D echocardiogram 
q3months* (except 
for cetuximab arm) 
X* 
 
 
 
 
 
 
 
 
 
X* 
 
 
(X) 
Disease status 
(baseline, preC4 and 
then q12 +/- 1 
week) 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
(X) 
Pregnancy test 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with 
differential 
X 
X 
(X)** 
 
X 
(X)** 
 
X 
(X)** 
 
X (X)**
 
X 
Serum chemistries 
X 
X 
(X)** 
 
X 
(X)** 
 
X 
(X)** 
 
X (X)**
 
X 
TSH (or free T4 if 
baseline TSH is 
above the upper 
limit of normal 
range) 
X 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Tumor marker(s) 
X 
 
 
 
(X) 
 
 
(X) 
 
 (X)
 
 
(X) 


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Protocol: PembroMab 
 
 
 
Pharmacodynamic 
studies 
X  
 
 
 
 
 
 
 
 
 
X 
 
 
(X) 
 
Survival assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Other systemic 
therapy 
administration (d1 
+/- d8 depending on 
the arm)** 
 
X 
(X)** 
 
X 
(X)** 
 
X 
(X)** 
 
X (X)**
 
 
Pembro 
administration 
 
X*** 
 
 
X 
 
 
X 
 
 
X 
 
 
 
General 
• Blood draws and vital signs are performed prior to dosing of pembro 
• Except for Cycle 1, study visits and procedures may occur +/- 2 days of the day  
• There is no clinical value to repeat Cycle 1 Day 1 laboratory testing, IF screening 
laboratory tests were performed within two calendar days AND those screening 
laboratory tests are acceptable for enrollment and dosing.   
• X – required event 
• (X) – as indicated, visits/assessments on day 8 are required if treatment arm includes 
day 8 dosing. 
• *:  2D echocardiogram to be done at baseline (unless there is one available within 60 
days of cycle 1 day 1), and then q3 months +/- 21 days for patients enrolled and 
receiving treatment on the trastuzumab and eribulin plus pembro or ado-trastuzumab 
emtansine plus pembro arms.  
• **: Based on other systemic therapy assigned arm. See dose and schedule for each 
arm in Tables 2A-C. If the other systemic therapy therapy schedule includes day 8 
dosing, then CBC with differential and serum chemistries will be performed and 
verified within acceptable limited for dosing prior to administration of other systemic 
therapy on day 8.  
• X***: Pembro—Dosing will be according to package insert – 2mg/kg administered 
IV over 30 minutes every 3 weeks. CBC with differential and serum chemistries will 
be repeated on Cycle 1 Day 1 and confirmed to be within dosing parameters 
(inclusion #7 and 8) prior to dosing 
 
End of Study Visit–This assessment can occur +/- 30 days of last dose of treatment on protocol 
if patient is removed from protocol for disease progression or intolerable toxicity. 
Follow-up and survival assessment –Survival assessment should occur 4-6 weeks after end of 
study and can occur via phone, email, review of medical records, and then at a minimum of 3 
months thereafter until 12 months after study arm patient is on has completed enrollment. 
Disease status –All subjects should have their disease status monitored with at least a CT with 
po and iv contrast of the chest, abdomen, and pelvis (or PET/CT if iv contrast is contraindicated).  
CBC with differential – WBC, ANC, RBC, HGB, HCT, platelets, MCV, and differential.  
Serum chemistries – Sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, 
glucose, calcium, phosphate, magnesium, AST, ALT, total bilirubin, alkaline phosphatase, total 
protein, albumin.  


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Protocol: PembroMab 
 
 
 
Tumor markers: As indicated for tumor type, such as CEA, CA15-3, CA27.29 – if baseline is 
elevated above the upper limit of normal, then it will be repeated per schedule of events where 
marked (X).  
Pharmacodynamic studies: Blood collections for circulating tumor DNA, and correlates for 
PD-1 if available, will be collected at up to 4 time points (starting with amendment 3, including 
the phase 1b portion): (1) 20 mL blood draw at baseline will be performed after informed 
consent but prior to initiation of C1D1, (2) after the first imaging assessment, and where 
applicable: (3) after imaging/exam confirms a complete response by irRECIST and/or (4) after 
imaging/exam confirmed disease progression by irRECIST. Archival tumor tissue will be 
collected, where available. 
 


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Protocol: PembroMab 
 
 
 
Infusion times for the standard of care drugs below is per package insert. Premedications per 
institutional guidelines. 
 
Table 2A. Arm 1: Trastuzumab and eribulin 
 
Dose 
level 
Trastuzumab dose level 
for C1D1  
Trastuzumab dose level for 
C2D1 and beyond 
Eribulin dose level for all 
cycles 
1 
8 mg/kg on day 1 of 
cycle 1 every 21 days 
6 mg/kg on day 1 every 21 
days 
1.4 mg/m2 on days 1 and 
8 every 21 days 
-1 
6 mg/kg on day 1 of 
cycle 1 every 21 days 
4 mg/kg on day 1 every 21 
days 
1.1 mg/m2 on days 1 and 
8 every 21 days 
-2 
4 mg/kg on day 1 of 
cycle 1 every 21 days 
2 mg/kg on day 1 every 21 
days 
0.7 mg/m2 on days 1 and 
8 every 21 days 
 
 
Table 2B. Arm 2: Ado-trastuzumab emtansine 
 
Dose level 
Ado-trastuzumab emtansine dose 
1 
3.6 mg/kg on day 1 every 21 days 
-1 
3 mg/kg on day 1 every 21 days 
-2 
2.4 mg/kg on day 1 every 21 days 
 
 
Table 2C. Arm 3: Cetuximab  
 
Dose level Cetuximab dose level for C1D1 
For patients on study at C2D1 and 
beyond 
1 
400 mg/m2 on day 1 of cycle 1, then 250 
mg/m2 on day 8 of cycle 1 
250 mg/m2 on day 1 and day 8 every 
21 days 
-1 
250 mg/m2 on day 1 and day 8 every 21 
days 
200 mg/m2 on day 1 and day 8 every 
21 days 
-2 
200 mg/m2 on day 1 and day 8 every 21 
days 
150 mg/m2 on day 1 and day 8 every 
21 days 
 


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Protocol: PembroMab 
 
 
 
 
 
 
 
 
 
 
Table 3A. Dose Delay and Intervention Guidelines for Pembro  
Grade 1 immune related adverse reaction: No action. Provide symptomatic treatment  
 
Grade 2 immune related adverse reaction*: May withhold pembro. Consider systemic 
corticosteroids in addition to appropriate symptomatic treatment  
 
Grade 3 and Grade 4 immune related immune adverse reaction*: Withhold pembro. Discontinue 
if unable to reduce corticosteroid dose to < 10 mg per day prednisolone equivalent within 12 
weeks of toxicity. Systemic corticosteroids are indicated in addition to appropriate symptomatic 
treatment. May utilize 1 to 2 mg/kg prednisolone or equivalent per day. Steroid taper should be 
considered once symptoms improve to Grade 1 or less and tapered over at least 4 weeks  
 
 
* Other systemic therapy may be continued as long as there are no contraindications. 
 
Severe or life-threatening adverse reactions, including any of the following: 
 
• Colitis with abdominal pain, fever, ileus, or peritoneal signs; increase in stool frequency 
(7 or more over baseline), stool incontinence, need for intravenous hydration for more 
than 24 hours, gastrointestinal hemorrhage, and gastrointestinal perforation  
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper 
limit of normal or total bilirubin >3 times the upper limit of normal  
• Stevens-Johnson syndrome, toxic epidermal necrolysis, or rash complicated by full 
thickness dermal ulceration, or necrotic, bullous, or hemorrhagic manifestations 
• Severe motor or sensory neuropathy, Guillain-Barré syndrome, or myasthenia gravis 
• Severe immune-mediated reactions involving any organ system (eg, nephritis, 
pneumonitis, pancreatitis, non-infectious myocarditis) 
• Immune-mediated ocular disease that is unresponsive to topical immunosuppressive 
therapy 
 


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Protocol: PembroMab 
 
 
 
Table 3B. Dose Delay and Reduction Guidelines for Arm 1: Trastuzumab and eribulin plus 
Pembro 
 
For trastuzumab: 
 
 
When trastuzumab requires holding because of hematologic toxicity, reduce by 1 dose level in 
subsequent cycles. Discontinue the trastuzumab after 2 dose reductions. 
 
Dose Modifications For Non-Hematologic Adverse Reactions 
Permanently discontinue trastuzumab for any of the following 
• 
Unexplained dyspnea or other evidence of severe pulmonary toxicity 
• 
Severe hepatic toxicity 
• 
Hemolytic-Uremic Syndrome 
• 
Capillary Leak Syndrome 
• 
Withhold for ≥ 16% absolute decrease in left ventricular ejection fraction (LVEF) from 
pre-treatment values or an LVEF value below institutional limits of normal and ≥ 10% 
absolute decrease in LVEF from pretreatment values  
 
 
For eribulin: 
 
 
 
 
When eribulin requires holding because of hematologic toxicity, reduce by 1 dose level in 
subsequent cycles. Discontinue eribulin after 2 dose reductions. 
 
Dose Modifications For Non-Hematologic Adverse Reactions 
Permanently discontinue eribulin for any of the following 
• 
Unexplained dyspnea or other evidence of severe pulmonary toxicity 
• 
Severe hepatic toxicity 
• 
Hemolytic-Uremic Syndrome 
• 
Capillary Leak Syndrome 
• 
Posterior reversible encephalopathy syndrome 
 


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Protocol: PembroMab 
 
 
 
Withhold trastuzumab and/or eribulin or reduce each dose by 1 dose level for other severe 
(Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are 
recommended for alopecia, nausea, or vomiting. 


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Protocol: PembroMab 
 
 
 
Table 3C. Dose Delay and Reduction Guidelines for Arm 2: Ado-trastuzumab 
emtansine plus Pembro 
Tables imported from package insert 
Note: KADCYLA is ade-trastuzumab emtansine 
 


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Protocol: PembroMab 
 
 
 
 
 
All other grade 3 or 4 non-hematologic toxicities: withhold ado-trastuzumab emtansine or reduce 
each dose by 1 dose level for other severe (Grade 3 or 4) until resolved. No dose modifications 
are recommended for alopecia, nausea, or vomiting. 


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Table 3D. Dose Delay and Reduction Guidelines for Arm 3: Cetuximab plus Pembro 
 
When cetuximab requires holding because of hematologic toxicity, reduce by 1 dose level in 
subsequent cycles. Discontinue the cetuximab agent after 2 dose reductions. 
 
Table below imported from package insert 
Note: ERBITUX is cetuximab 
Dose Modifications For Non-Hematologic Adverse Reactions 
 
Permanently discontinue cetuximab for any of the following 
• 
Unexplained dyspnea or other evidence of severe pulmonary toxicity 
• 
Severe hepatic toxicity 
• 
Hemolytic-Uremic Syndrome 
• 
Capillary Leak Syndrome 
 
Withhold cetuximab or reduce dose by one dose level for other severe (Grade 3 or 4) non-
hematological toxicity until resolved. No dose modifications are recommended for alopecia, 
nausea, or vomiting.