Clinical trial NCT02865811
Conditions: Ovarian Cancer Fallopian Tube Cancer Peritoneal Cancer
Keywords: Ovarian Cancer
Sponsor: Dana-Farber Cancer Institute
Start date: 2016-09-15; Completion date: 2022-03-01
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying the combination of Pegylated Liposomal Doxorubicin (PLD) and Pembrolizumab as a possible treatment for Recurrent Ovarian, Fallopian Tube or Peritoneal Cancer that is resistant to platinum therapy.

The following interventions will be used in this study:

* Pegylated liposomal doxorubicin (PLD)
* Pembrolizumab

Detailed description:
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational drug to learn whether the drug works in treating a specific disease. "Investigational" means that the drug is being studied.

The investigators are looking to see if combining the standard therapy, PLD, and the study drug, Pembrolizumab, will be better than PLD alone. Pembrolizumab is a drug called a monoclonal antibody. Pembrolizumab blocks and interferes with a protein called PD-1; PD-1 can help the cancer cell evade the immune system, and thereby blocking PD-1 may help the immune system recognize and kill cancer cells.

This will be the first time this combination will be tested for participants with Ovarian, Fallopian Tube or Peritoneal Cancer. Therefore, a group of 6 participants will be treated in a "safety lead in" portion of the trial. This lead in will determine the safest dose of PLD when given in combination with the study drug Pembrolizumab. These 6 participants will be treated with Pembrolizumab and PLD at the FDA approved dose to see if the combination is well tolerated or too severe. If the combination is well tolerated, 20 additional participants will be added. If the side effects are too severe, the dose of PLD will be lowered.

The FDA (the U.S. Food and Drug Administration) has approved PLD as a treatment option for this disease, but has not approved Pembrolizumab.

Arms: arm 1: A safety lead in with 6 patients will be studied prior the start of the treatment.

* If 2 out of the first 6 patients develop a dose limiting toxicity (DLT), the dose of PLD will be reduced.
* If no more than 1 patient of the first 6 patients has evidence of dose limiting toxicities, the dose level will be considered the maximum tolerated dose (MTD)
* Pegylated Liposomal Doxorubicin (PLD) pre-determine dosage will be administered every 4 weeks via IV
* Pembrolizumab will be administered as a 30 min IV infusion every 3 weeks at a pre-determine dosage
Interventions: intervention 1: Pembrolizumab intervention 2: Pegylated Liposomal Doxorubicin (PLD)
Intervention descriptions: intervention 1: Please see "Arms" for description. intervention 2: Please see "Arms" for description.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
STATUS PAGE 
PROTOCOL 16-257 
 
 
Closed To New Accrual 
 
 
Closure Effective Date: 07/17/2017 
Reason: Study Accrual Goal Met 
 
 
No new subjects may be enrolled in the study as described above. 
Any questions regarding this closure should be directed to the study’s 
Principal Investigator 


Page 1 of 1 
Date Submitted: 05/24/2017 
Alert Page  
DF/HCC Protocol #:  16-257 
 
Revised: 01.08.16 
 
 
 
Safety / Drug (includes preparation, administration, dose modifications, 
equations) 
  
Protocol Section 6.1: Dose modifications for Pegylated Liposomal 
Doxorubicin 
 
Toxcity  
Dose Adjustment  
Neutropenia and Thrombocytopenia  
Grade 1 
No dose reduction 
Grade 2 
Delay until ANC ≥ 1500 and plts ≥ 
100,000; resume treatment at previous 
dose 
Grade 3 
Delay until ANC ≥ 1500 and plts ≥ 
100,000; resume treatment at previous 
dose 
Grade 4 
Delay until ANC ≥ 1500 and plts ≥ 
100,000; resume at 25% dose reduction or 
continue previous dose with prophylactic 
granulocyte growth factor. 
 
 


 
 
 
 
 
 
 
Office for Human Research Studies 
 
DANA-FARBER / HARVARD CANCER CENTER 
Version: 09.23.16 
 
 
Protocol Front Sheet 
DFCI Protocol No.: 16-257  
 
1.  PROTOCOL INFORMATION 
 
Title: A Phase II Study of Pembrolizumab combined with pegylated liposomal doxorubicin (PLD) for recurrent platinum resistant ovarian, fallopian tube 
or peritoneal cancer 
Phase: Phase 2 
Sponsor Study Number: N/A 
 
2.  DF/HCC STUDY CONTACT INFORMATION 
 
Primary Study Contact: Juliadele Male  
Email:  jmale@partners.org 
Phone:  617-632-7496 
 
INVESTIGATORS:  (List only those under DFCI IRB, i.e., from institutions listed in Section 6 below) 
Overall PI: 
Ursula A. Matulonis, MD 
Phone: 617-632-2334 
Institution(s): DFCI 
Mgmt group: 
GYN Oncology 
Site Responsible PI: Richard Penson, MD 
Phone: 617-724-4800 
Institution(s): MGH 
Mgmt group: 
GYN Oncology 
 
 
3.  DRUG / DEVICE INFORMATION    N/A: 
  
 
 Drug(s), Biologic(s):  Pembrolizumab, Doxil 
 Device(s) Name:        
Provided by: Merck 
IND Exempt: 
        ‐or‐ 
IND#: 130120 Holder Type: DF/HCC Investigator    
IND Holder Name: Ursula A. Matulonis, MD  
Provided by:      
IDE Exempt: 
        ‐or‐ 
IDE #:            Holder Type: [pull down]    
IDE Holder Name:        
 
4.  PROTOCOL COORDINATION, FUNDING, MODE 
 
Regulatory Sponsor: 
Funding/Support (check all that apply): 
Primary Disease Group:  GYN Oncology 
DF/HCC Investigator  Ursula A. Matulonis, MD 
 Industry: Merck 
 
 
 Federal Organization:       
 
CTEP Study: No 
      Grant #:       
 
 
 Internal Funding:       
 
 
 Non-Federal:       
 
 Other:       
 
Protocol Involves (check all that apply as listed in the protocol document, even if not part of the research but is mandated by the protocol document): 
 Chemotherapy 
 Hormone Therapy 
 Medical Record Review 
 Immunotherapy 
 Vaccine 
 Questionnaires/Surveys/Interviews 
 Surgery 
 Engineered Cell Therapy (ECT) 
 Data Repository 
 Radiological Exams 
 Bone Marrow/Stem Cell Transplant 
 Exercise/Physical Therapy 
 Required Biopsy Study 
 Cell Based Therapy 
 Genetic Studies 
 Human Embryonic Stem Cell 
 Gene Transfer (use of recombinant DNA or 
synthetic nucleic acid molecules) 
 Human Material Banking 
 Quality of Life 
 
 Radiation Therapy 
 Human Material Collection 
 Other:       
 
5.  SUBJECT POPULATION (also applies to medical record review and specimen collection studies) 
 
Total Study-Wide Enrollment Goal: 26 
Greater than 25% of the overall study accrual will be at DF/HCC: 
 Yes   
 No 
Total DF/HCC Estimated Enrollment Goal: 26 
Adult Age Range: 18+ 
Pediatric Age Range: N/A 
Will all subjects be recruited from pediatric clinics?    
 Yes    
 No 
If enrolling both adults and pediatric subjects, anticipated percent of pediatric subjects: N/A 
Retrospective Medical Record Reviews only (Please provide date range): from       to       
 
6.  DF/HCC PARTICIPANTS UNDER DFCI IRB (check all that apply) 
 
 Beth Israel Deaconess Medical Center (BIDMC) 
 Beth Israel Deaconess Medical Center – Needham (BIDMC-Needham) 
 Boston Children’s Hospital (BCH) 
 Dana-Farber/New Hampshire Oncology-Hematology (DFCI @ NHOH) 
 Brigham and Women’s Hospital (BWH) 
 Dana-Farber at Steward St. Elizabeth’s Medical Center (DFCI @ SEMC) 
 Dana-Farber Cancer Institute (DFCI) 
 Dana-Farber at Milford Regional Cancer Center (DFCI @ MRCC) 
 Massachusetts General Hospital (MGH) 
 Mass General/North Shore Cancer Center (MGH @ NSCC) 
 
 Mass General at Emerson Hospital – Bethke (MGH @ EH) 
 
 DF/BWCC in Clinical Affiliation with South Shore Hospital (DFCI @ SSH) 
 
 
7.  NON-DF/HCC PARTICIPANTS UNDER DFCI IRB (check all that apply) 
 
 
Cape Cod Healthcare (CCH)  
 
Lowell General Hospital (LGH)  
 
New Hampshire Oncology-Hematology-P.A. (NHOH)  
 
Newton-Wellesley Hospital (NWH) 
 Faulkner Hospital (FH) 
 New England Cancer Specialists (NECS)  
 Broad Institute 
 


Protocol Front Sheet 
 
FS Page: 2 
 
8.  DF/HCC INITIATED STUDIES ONLY  - INSTITUTIONAL PARTICIPANTS UNDER OTHER IRB  (N/A: 
) 
 
 
DF/HCC Multi-Center Protocols:  (list institution/location) 
 
DF/PCC Network Affiliates: (list institution/location) 
Northwell Health/ Monter Cancer 
Center 
Lake Success, NY 
     
      
 


Log Sheet 
Page 1 of 1 
 
Protocol Number: 16-257 
 
Approval Date:  07/19/2016  (IRB meeting date when protocol/consent  
 approved or conditionally approved) 
 
Activation Date: 09/01/2016 (Date when protocol open to patient entry) 
 
Approval signatures are on file in the Office for Human Research Studies, tel. 617-632-3029. 
 
Date 
Posted 
Revised Sections 
IRB Approval 
Date 
OnCore 
Version Date 
09/30/16 
Protocol replaced due to Amendment # 1 
08/31/16 
n/a 
Date 
Posted 
Revised Sections 
Approved 
Date 
Version Date 
(OnCore) 
11/04/16 
MGH site added but not active: Consent Form and 
Front Sheet replaced due to Amendment #2 
10/12/16 
10/24/16 
11/14/2016 
Protocol, Eligibility Checklist and Consent Form 
replaced due to Amendment #3 
10/31/2016 
11/14/2016 
12/29/16 
Delayed Activation Amendment Status Page removed: 
MGH now active  
N/A 
N/A 
01/10/17 
Front Sheet replaced due to Amendment #4 
01/05/17 
N/A 
01/11/17 
Protocol and Eligibility Checklist replaced due to 
Amendment #5 
01/01/17 
N/A 
03/10/17 
Protocol, Eligibility Checklist and Consent Form 
replaced due to Amendment #6 
03/06/17 
03/10/17 
06/15/17 
Protocol replaced; Alert Page added due to 
Amendment #7 
05/04/17 
N/A 
07/17/17 
Study Closed – Study Accrual Goal Met 
07/17/17 
n/a 
07/17/17 
Study renewal/ Consent Form footer replaced per 
Continuing Review #1 
06/15/2017 
06/23/2017 
09/11/17 
Consent Form and Front Sheet replaced due to 
Amendment #8 
08/18/2017 
08/29/2017 
12/29/2017 
Consent Form, Protocol replaced per Amendment #9 
12/09/2017 
12/26/2017 
04/24/2018 
No updates to Online Documents per Amendment #10 
04/18/2018 
N/A 
05/22/2018 
Study renewal/Consent Form footer replaced per 
Continuing Review #2 
05/22/2018 
05/22/2018 
09/19/2018 
Protocol, Consent Form replaced per Amendment #12 
09/19/2018 
09/19/2018 
09/19/18 
Correction AM#12: AM 12 not ready to activate; 
previous documents posted 
N/A 
N/A 
10/17/2018 
Consent Form, Protocol replaced per Amendment #11 
09/04/2018 
n/a 
10/17/2018 
Consent Form, Protocol replaced per Amendment #12 
09/19/2018 
10/17/2018 
04/24/2019 
Study renewal/Consent Form footer replaced per 
Continuing Review #3 
04/24/2019 
04/24/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


DF/HCC Protocol #: 16-257 
Protocol Version Date: August 29, 2018  
 
 
   1 
 
DF/HCC Protocol #: 16-257 
 
 
TITLE:  A Phase II Study of Pembrolizumab combined with pegylated liposomal doxorubicin 
(PLD) for recurrent platinum resistant ovarian, fallopian tube or peritoneal cancer.   
 
 
Coordinating Center: 
 
 
Dana-Farber Cancer Institute  
450 Brookline Ave.  
Boston, MA 02215 
 
Principal Investigator (PI): 
Ursula Matulonis, M.D.  
 
Dana-Farber Cancer Institute  
 
450 Brookline Ave.  
 
Boston, MA  02215 
 
617 632 2334 (phone) 
 
617 632 3479 (fax) 
 
Email:  Ursula_matulonis@dfci.harvard.edu  
 
Statistician: 
 
 
William Barry, Ph.D 
Dana-Farber Cancer Institute 
450 Brookline Ave.  
617-632-5134 (phone) 
 
Email:   bbarry@jimmy.harvard.edu 
 
 
 
 
 
Responsible Research Nurse: 
  
Christin Whalen, R.N.  
 
Dana-Farber Cancer Institute 
450 Brookline Ave.  
Boston, MA 02215 
617-582-7738 (phone) 
617-582-7921 (fax) 
Email:  christin_whalen@dfci.harvard.edu 
 
 
 
Project Manager: 
Jennifer Curtis, MS 
Dana-Farber Cancer Institute 
450 Brookline Ave. 
617-582-7183 (phone) 
617-582-7921 (fax) 
Email: Jennifer_curtis@dfci.harvard.edu 
 
Agents: 
Pegylated liposomal doxorubicin 
Pembrolizumab (MK3475) 
 
IND #:  130120 
IND Sponsor:  Ursula Matulonis, M.D.  
 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
2 
 
 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Start at 
recommended 
phase II doses of 
PLD and 
pembrolizumab 
Treat cohort of 
6 patients to 
determine if 
excess toxicities 
are present 
If no excess toxicities, an 
additional 20 patients will be 
added to complete the phase II 
study cohort 
If  excess toxicities are 
observed in the first 6 patients, 
the dose of PLD will be 
reduced. 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
3 
 
TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
1. 
OBJECTIVES ......................................................................................................................5 
1.1 
Study Design ............................................................................................................5 
1.2 
Primary Objectives ...................................................................................................5 
1.3 
Secondary Objectives ...............................................................................................5 
2. 
BACKGROUND .................................................................................................................5 
2.1 
Study Disease:  Ovarian Cancer ..............................................................................5 
2.2 
Pegylated Liposomal Doxorubicin (PLD) ...............................................................6 
2.3 
Pembrolizumab ........................................................................................................6 
2.4 
Rationale ..................................................................................................................8 
2.5 
Correlative Studies Background ..............................................................................9 
3. 
PARTICIPANT SELECTION ...........................................................................................10 
3.1 
Participant Inclusion Criteria .................................................................................10 
3.2 
Participant Exclusion Criteria ................................................................................11 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
REGISTRATION PROCEDURES ...................................................................................14 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................14 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................14 
4.3 
General Guidelines for Other Investigative Sites ..................................................14 
4.4 
Registration Process for Other Investigative Sites .................................................14 
5. 
TREATMENT PLAN ........................................................................................................15 
5.1 
Treatment Regimen ................................................................................................15 
5.2 
Pre-Treatment Criteria ...........................................................................................16 
5.3 
Agent Administration .............................................................................................16 
5.4 
Definition of Dose-Limiting Toxicity (DLT) ........................................................18 
5.5 
General Concomitant Medication and Supportive Care Guidelines ......................19 
5.6 
Criteria for Taking a Participant Off Protocol Therapy .........................................20 
5.7 
Duration of Follow Up ...........................................................................................21 
5.8 
Criteria for Taking a Participant Off Study ...........................................................21 
6. 
DOSING DELAYS/DOSE MODIFICATIONS................................................................22 
6.1 
Dose modifications for Pegylated Liposomal Doxorubicin ...................................22 
6.2 
Dose Modifications for Pembrolizumab: ...............................................................24 
6.3 
Rescue Medications & Supportive Care ................................................................26 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................29 
7.1. 
Expected Toxicities ................................................................................................29 
7.3  
Expedited Adverse Event Reporting ......................................................................31 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) ......................32 
7.5 
Expedited Reporting to Hospital Risk Management .............................................32 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
4 
 
7.6 
Routine Adverse Event Reporting .........................................................................32 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................33 
8.1 
Pegylated Liposomal Doxorubicin ........................................................................33 
8.2 
Pembrolizumab ......................................................................................................34 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................37 
10. 
STUDY CALENDAR .......................................................................................................38 
11. 
MEASUREMENT OF EFFECT........................................................................................39 
11.1 
Antitumor Effect – Solid Tumors ..........................................................................39 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................46 
12.1 
Data Reporting .......................................................................................................46 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to ODQ according to the schedule set by the ODQ. ................................................46 
12.2 
Data Safety Monitoring ..........................................................................................46 
12.3 
Multicenter Guidelines ...........................................................................................47 
13. 
STATISTICAL CONSIDERATIONS...............................................................................47 
13.1 
Study Design/Endpoints.........................................................................................47 
13.2 
Sample Size, Accrual Rate and Study Duration ....................................................48 
13.3 
Interim Monitoring Plan ........................................................................................49 
13.4 
Analysis of Primary Endpoints ..............................................................................49 
13.5 
Analysis of Secondary Endpoints ..........................................................................49 
14. 
PUBLICATION PLAN .....................................................................................................49 
REFERENCES ..............................................................................................................................50 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................52 
APPENDIX B: EVENTS OF CLINICAL INTEREST GUIDANCE DOCUMENT ...................53 
APPENDIX C: BIOASSAY TEMPLATES ..................................................................................53 
APPENDIX D: DATA SAFETY MONITORING PLAN ............................................................63 
 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
5 
 
 
1. OBJECTIVES 
 
 
1.1 
Study Design 
 
This is a phase II study with a safety lead in of the combination of the recommended phase II 
doses of pegylated liposomal doxorubicin (PLD) and pembrolizumab for the treatment of 
platinum resistant recurrent ovarian, fallopian tube or peritoneal cancer.   
 
1.2 
Primary Objectives 
  
 
 
1.2.1 To assess the clinical benefit (complete response + partial response or stable disease > 24 
weeks) of the combination of PLD and pembrolizumab in patients with platinum resistant 
recurrent ovarian cancer.  Initially, a six patient safety lead in will be performed of these 2 drugs 
combined together when used to treat patients with recurrent ovarian, peritoneal or fallopian tube 
cancer.  If no more than 1 patient of the first 6 patients has evidence of dose limiting toxicities, 
an additional 20 patients will be added to complete the phase II study.   
 
1.3 
Secondary Objectives 
 
1.3.1 To gain an estimate of toxicities for these agents when combined to treat platinum 
resistant recurrent ovarian, fallopian tube or peritoneal cancer   
 
1.3.2 To gain an estimate of preliminary response rate for these agents when combined for the 
treatment of platinum resistant ovarian cancer, progression free survival (PFS), overall survival 
(OS), time to progression (TTP), and duration of response.   
 
1.3.3 To perform exploratory translational studies on formalin fixed paraffin embedded tumor 
that include nanostring as well as PDL1 and exploratory immune markers.  
 
 
2. BACKGROUND 
 
2.1 
Study Disease:  Ovarian Cancer 
 
Ovarian cancer is a lethal cancer that affects women globally, is diagnosed at an advanced stage 
in most patients and has no effective screening tests for early detection (1-3).  The worldwide 
incidence of this cancer is 225,500 diagnoses per year; in the United States in 2015, 
approximately 21,980 women will be diagnosed with ovarian cancer (1, 2).  Global mortality of 
this cancer remains high with 140,200 deaths per year, and minimal improvement in mortality 
has been observed for women diagnosed with advanced ovarian cancer over the past decade (1, 
2).   
 
Treatment strategies that have led to an overall survival (OS) improvement for newly diagnosed 
patients have included the addition of paclitaxel to platinum, the use of intraperitoneal cisplatin 
in patients with optimally cytoreduced cancer (<1 cm of residual cancer after upfront 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
6 
 
cytoreductive surgery), and incorporation of weekly paclitaxel versus every 3 week paclitaxel as 
part of upfront treatment for ovarian cancer (4-6).  Neoadjuvant chemotherapy has emerged as a 
treatment alternative especially in patients who are unable to undergo upfront cytoreductive 
surgery because of the extent of cancer or those patients who are too ill or frail to undergo 
upfront cytoreductive surgery (7, 8).  Anti-angiogenics, specifically bevacizumab, were the first 
biologic to be tested in ovarian cancer but to date addition of bevacizumab in randomized trials 
has demonstrated progression free survival (PFS) benefit, but no OS benefit (9-11).    
 
Unfortunately, most patients will recur after being diagnosed with advanced ovarian cancer; for 
patients with platinum-sensitive recurrence (defined as cancer recurring ≥6 months after the last 
platinum), additional platinum-based therapy is given.  For patients with recurrent platinum 
resistant cancer (defined as cancer recurring <6 months after last platinum), single agent 
chemotherapy is administered.  New agents and rationale combinations of biologics and 
chemotherapy are needed to improve outcomes in women with recurrent ovarian cancer, such as 
chemotherapy combined with immunotherapy agents.   The first 2 agents since the last approval 
in 2006 (carboplatin and gemcitabine for platinum sensitive recurrence) were approved by the 
Food and Drug Administration (FDA) in 2014:  bevacizumab in combination with chemotherapy 
in patients with platinum resistant ovarian cancer and the oral PARP inhibitor olaparib for 
women with a gBRCA mutation, recurrent ovarian cancer and who have received at least 3 lines 
of prior chemotherapy.   
 
Many chemotherapy options exist for women with recurrent ovarian cancer but none of them are 
curative, and most agents used in the platinum resistance recurrent setting have response rates 
that are 10% or less.  Pegylated liposomal doxorubicin (PLD) is a standard of care treatment for 
recurrent ovarian cancer (12-14).   
 
2.2 
Pegylated Liposomal Doxorubicin (PLD) 
 
PLD is approved in the U.S., Canada, and Europe for use in ovarian cancer following 
progression of cancer after platinum-based chemotherapy and represents a standard of care 
treatment for women with relapsed ovarian cancer (15). 
 
PLD has demonstrated anti-cancer activity in both phase II and III studies; phase III studies have 
compared PLD to topotecan as well as other agents.  Response rates for platinum resistant 
recurrent ovarian cancer are approximately 10%.  Progression-free survival (PFS) for PLD in 
patients with recurrent ovarian cancer is approximately 3-4 months (12-14).  Known toxicities of 
PLD include:  hand-foot syndrome, mucositis, cardiotoxicity, myelosuppression, liver 
impairment, and infusion-related reactions.  See the PLD Package Insert for other reported 
toxicities and additional details of clinical studies as well as toxicity management.   
 
2.3 
Pembrolizumab  
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information 
on MK-3475. 
 
The importance of intact immune surveillance in controlling outgrowth of neoplastic 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
7 
 
transformation has been known for decades.  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member related 
to CD28 and CTLA-4 which has been shown to negatively regulate antigen receptor signaling 
upon engagement of its ligands (PD-L1 and/or PD-L2).  The structure of murine PD-1 has been 
resolved.  PD-1 and family members are type I transmembrane glycoproteins containing an Ig 
Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 
tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and 
an immunoreceptor tyrosine-based switch motif (ITSM).  Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic 
tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 
which are involved in the CD3 T-cell signaling cascade.  The mechanism by which PD-1 down 
modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules 
regulate an overlapping set of signaling proteins.  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer 
cells.  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells.  The ligands for PD-1 
(PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including non-hematopoietic tissues as well as in various tumors.  Both ligands are type I 
transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region 
and contain short cytoplasmic regions with no known signaling motifs.  Binding of either PD-1 
ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-
cell function in peripheral tissues.  Although healthy organs express little (if any) PD-L1, a 
variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  PD-1 
has been suggested to regulate tumor-specific T-cell expansion in participants with melanoma 
(MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune 
evasion and should be considered as an attractive target for therapeutic intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, PD-
L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in the United States 
for the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 
 
 


 
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2.4 
Rationale 
 
2.4.1 Rationale for testing PLD and pembrolizimab in recurrent ovarian cancer 
 
The rationale to combine the anti-PD1 monoclonal antibody pembrolizumab with chemotherapy 
to treat ovarian cancer includes the following;   
 
1) PDL1 is overexpressed in ovarian cancer and PD1 is overexpressed in TILs. The presence of 
TILs in advanced stage ovarian carcinomas predicts for a better overall outcome with improved 
PFS and OS compared to those cancers which lack TILs (1,2).  Increased frequency of Treg cells 
in patients with ovarian cancer can predict a poorer survival.   
 
2) Anti-cancer synergy has been demonstrated with anti-PD1 antibodies and chemotherapy (16-
18).   Several clinical trials are open using both chemotherapy and immunotherapy agents.    
 
3)  Reduction in tumor burden through chemotherapy can potentiate an immune response, thus 
the rationale exists to combine a chemotherapy agent such as PLD with a PD1 inhibitor (16-18).   
 
2.4.2  Rationale for flat dose of pembrolizumab 
 
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 participants 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 


 
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exposure margins of 0.5 – 5.0 for MK-3475 in the melanoma indication. The exposure margins 
are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the 
proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population 
PK evaluation revealed that there was no significant impact of tumor burden on exposure. In 
addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in 
solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 
mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-response relationships of 
pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (as assessed by the population PK model) and 4) the assumption that the 
dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab showing that the fixed 
dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those 
obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in 
the exposure range established in melanoma as associated with maximal efficacy response and 3) 
will maintain individual patients exposure in the exposure range established in melanoma that 
are well tolerated and safe.  
A fixed dose regimen simplifies the dosing regimen to be more convenient for physicians and to 
reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity in the 
logistical chain at treatment facilities and reduce wastage. 
2.5 
Correlative Studies Background 
FFPE will be collected for exploratory immune markers as tested by immunohistochemical 
(IHC) staining of specific markers and PDL1 expression to be done at Merck.      
 
1)  Formalin fixed-paraffin embedded (FFPE) tumor slices will be prepared and H&E stained for 
assessment of TIL in tumor samples. To identify different immune cell populations 
(effector/memory/ CD8 cells, T regulatory cells, dendritic cells, tumor associated macrophages, 
NK cells, TEM) IHC staining will be performed on FFPE tumor slices using the following 
antibodies:   CD3, CD4, CD8, CD25, FoxP3, Indoleamine 2,3 deoxygenase-1 (IDO), CD11c, 
CD83, CD86, CD56, CD14, and CD16.   Also included will be recently developed IHC staining 
on FFPE samples for PD-L1, PD-L2, TIM-3 and LAG-3 through the center for Immuno-
oncology Pathology Core at the Dana-Farber Cancer Institute (Scott Rodig, M.D., Ph.D. Core 
Director).   
 
2)  PDL1 IHC staining at Merck:  Merck has asked that tumor samples also be sent to their 
facility for PDL1 staining using their technique and staining.  QualTek has developed and 
validated a PD-L1 IHC assay using Merck's proprietary 22C3 antibody.  This assay has served as 
the prototype companion diagnostic assay and has been used by QualTek to test thousands of 
clinical samples, including those for prospective enrollment in other clinical trials.  The PD-L1 
IHC assay has been validated and tested in over 20 different tumor indications in various clinical 


 
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studies and on thousands of archived FFPE samples.   
 
3)  Nanostring analysis will be performed at Merck.  Merck will perform gene profiling analysis 
using the nanostring platform to identify new biomarkers and gain insight to molecular basis of 
anti-PD-1 resistance with samples from this study.  For each patient enrolled in the study, 4 
unstained slides (4-5 micron sections) per sample of FFPE tumor will be sent to Merck. Samples 
will be analyzed for gene expression using nanostring which is an 800 gene immune-response 
focused panel and results will be shared with the overall PI, Dr. Matulonis. 
 
3. PARTICIPANT SELECTION 
 
3.1 
Participant Inclusion Criteria 
In order to be eligible for participation in this trial, the participant must meet the following 
eligibility criteria: 
 
3.1.1 
Be willing and able to provide written informed consent/assent for the trial. 
3.1.2 
Be  18 years of age on day of signing informed consent. 
3.1.3 
Have measurable disease based on RECIST 1.1 criteria.   
3.1.4 
Have a histologically confirmed diagnosis of epithelial ovarian cancer, fallopian tube or 
peritoneal cancer. All histologies of epithelial ovarian cancer are eligible except for 
carcinosarcomas. 
 
3.1.5 
Patients must have had one prior platinum-based chemotherapeutic regimen for 
management of primary disease containing carboplatin, cisplatin, or another 
organoplatinum compound. This initial treatment may have included intraperitoneal 
therapy, consolidation, biologic/targeted (non-cytotoxic) agents (e.g., bevacizumab) or 
extended therapy administered after surgical or non-surgical assessment.   
 
3.1.6 
Patients must have platinum resistant cancer with a platinum free interval of < 6 
months.  Progression after last platinum is based on investigator assessment.   
3.1.7 
Patients are allowed to receive, but are not required to receive, up to two additional 
cytotoxic regimens for management of recurrent or persistent disease, with no more 
than 1 prior non-platinum cytotoxic chemotherapeutic regimen.   
 
Patients are allowed to receive, but are not required to receive, biologic/targeted (non-
cytotoxic) therapy as part of prior treatment.   For the purposes of this study, Poly 
(ADP-ribose) polymerase (PARP) inhibitors will be considered “cytotoxic.”  Patients 
are allowed to receive, but are not required to receive, PARP inhibitors for management 
of primary or recurrent/persistent disease (either alone or in combination with cytotoxic 
chemotherapy). Single agent hormonal therapies will not be counted as a line of 
treatment. 
 


 
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3.1.8 
Have confirmation of available tissue from an archived specimen of ovarian cancer. If 
there is no archival tissue available, the participant will be required to undergo a biopsy 
to obtain a fresh tumor sample. 
3.1.9 
Have a performance status of 0 or 1 on the ECOG Performance Scale (Appendix A). 
3.1.10 
Demonstrate adequate organ function as defined in Table 1, all screening labs must be 
performed within 14 days of treatment initiation. 
Table 1  Adequate Organ Function Laboratory Values 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,500 /mcL 
Platelets 
≥100,000 / mcL 
Hemoglobin 
≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR
 
≥60 mL/min for participant with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for participants with total bilirubin levels 
> 1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR
≤ 5 X ULN for participants with liver metastases 
Albumin 
>2.5 g/dL 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of 
intended use of anticoagulants 
≤1.5 X ULN unless participant is receiving anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
3.1.11 
Female participants of childbearing potential must have a negative serum pregnancy 
within 72 hours prior to receiving the first dose of study medication.  If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.   
3.1.12 
Female participants of childbearing potential must be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication.  Participants of 
childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > 1 year.  
3.2 
Participant Exclusion Criteria 
The participant must be excluded from participating in the trial if the participant has any of  


 
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      the following: 
 
3.2.1 
Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
3.2.2 
Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
3.2.3 
Patients cannot have primary platinum refractory cancer, i.e. documented cancer 
progression while receiving platinum or within one month of receipt of a platinum 
based regimen.   
3.2.4 
Has received a prior anthracycline chemotherapy either for ovarian cancer treatment or 
another previous malignancy.   
3.2.5 
Left ventricular ejection fraction (LVEF) defined by multigated acquisition (MUGA) or 
echocardiogram which is below the institutional lower limit of normal prior to starting 
study treatment.   
3.2.6 
Has a known history of active TB (Bacillus Tuberculosis) 
3.2.7 
Known hypersensitivity to pembrolizumab or any of its excipients and/or liposomal 
doxorubicin. 
 
3.2.8 
Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
i. Note:  If participant underwent major surgery, they must have recovered 
adequately from the toxicity and/or complications from the intervention 
prior to starting therapy.   
ii. Note: Participants with alopecia are an exception to this criterion. 
3.2.9 
Has a known additional malignancy that is progressing or requires active treatment.  In 
addition, patients cannot have been diagnosed with another malignancy within 3 years 
of starting treatment.   Exceptions include fully resected basal cell carcinoma of the 
skin or squamous cell carcinoma of the skin, in situ cervical cancer, fully resected 
ductal carcinoma in situ, and stage IA, noninvasive grade I endometrial cancer, that has 
undergone curative therapy. 
3.2.10 
Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis.  Participants with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least four 
weeks prior to the first dose of trial treatment and any neurologic symptoms have 


 
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returned to baseline), have no evidence of new or enlarging brain metastases, and are 
not using steroids for at least 7 days prior to trial treatment.  This exception does not 
include clinically active and significant carcinomatous meningitis which is excluded 
regardless of clinical stability.   
3.2.11 
Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
3.2.12 
Has known history of, or any evidence of active, non-infectious pneumonitis. 
3.2.13 
Has an active infection requiring systemic therapy. 
3.2.14 
Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the participant’s participation 
for the full duration of the trial, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.   
3.2.15 
Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
3.2.16 
Is pregnant or breastfeeding, or expecting to conceive within the projected duration of 
the trial, starting with the pre-screening or screening visit through 120 days after the 
last dose of trial treatment. 
3.2.17 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
3.2.18 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
3.2.19 
Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
3.2.20 
Has received a live vaccine within 30 days of planned start of study therapy.   
Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
3.2.21 
The following are additional exclusion criteria for patients enrolling post safety run in: 
3.2.21.1 
Any clinical or radiographic evidence of a partial or complete bowel 
obstruction (small or large bowel) currently or within the past 6 months. 
3.2.21.2 
No current dependency on total parental nutrition (TPN) or within the past 
30 days. 
 


 
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3.3 
Inclusion of Women and Minorities 
 
Women of all races and ethnic groups are eligible for this trial. 
 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS)  
OnCore. Registrations must occur prior to the initiation of protocol therapy. Any participant not 
registered to the protocol before protocol therapy begins will be considered ineligible and 
registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
ODQ protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol therapy. Issues that would cause 
treatment delays should be discussed with the Overall Principal Investigator (PI). If a participant 
does not receive protocol therapy following registration, the participant’s registration on the 
study must be canceled. Registration cancellations must be made in OnCore as soon as possible. 
 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
Exception: DF/PCC Affiliate sites must fax the entire signed consent form including HIPAA 
Privacy Authorization and the eligibility checklist to the Network Affiliate Office. The Network 
Affiliate Office will register the participant with the ODQ. 
 
4.3 
General Guidelines for Other Investigative Sites 
 
Eligible participants will be entered on study centrally at the Dana-Farber Cancer Institute by the 
Project Manager. All sites should email or fax the documentation listed in section 4.4 to the  
Project Manager to verify treatment availability.    
 
Following registration, participants should begin protocol therapy within 5 days.   Issues that 
would cause treatment delays should be discussed with the Overall PI.  If a participant does not 
receive protocol therapy following registration, the participant’s registration on the study must be 
canceled.  The Project Manager should be notified of cancellations as soon as possible. 
 
4.4 
Registration Process for Other Investigative Sites 
 
To register a participant, the research nurse or study coordinator should email the following 
documentation to the Project Manager or fax to 617-394-2662: 


 
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 Copy of clinic visit note documenting medical history and physical exam  
 Lab documentation as per eligibility criteria 
 Pathology report 
 CT (chest/abdomen/pelvis) scan report 
 ECHO/MUGA report 
 EKG report 
 Signed participant consent form, and consent process note 
 HIPAA authorization form 
 Completed Eligibility checklist 
 
To complete the registration process, the Project Manager will  
 follow the DF/HCC Standard Operating Procedure for Human Subject Research Titled 
Subject Protocol Registration (SOP #: REGIST-101) and register the participant on the 
protocol  
 call and fax or email the research nurse or data manager at the participating site with the 
participant study number, and to confirm registration  
 
NOTE: Registration can only be conducted during the business hours of 8:00 AM and 5:00 
PM Eastern Time Monday through Friday. Same day treatment registrations will only be 
accepted with prior notice and discussion with the DF/HCC Lead Institution.  
 
 
5. TREATMENT PLAN 
 
5.1 
Treatment Regimen 
 
The treatment to be used in this trial is outlined below in Table 2: 
 
Table 2  Trial Treatment 
 
Drug* 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pegylated 
Liposomal 
Doxorubicin  
40 mg/m2 
Once 
every 4 
weeks 
IV infusion 
over one hour 
per FDA 
package insert 
One cycle = 28 
days 
FDA approved 
treatment for 
platinum 
resistant 
ovarian cancer 
Pembrolizumab 200 mg as a 
flat dose  
    Once   
   every 3  
   weeks   
IV infusion per 
the FDA 
package insert  
    One cycle = 28  
             days  
Experimental 
*The drugs may be held independent of one another, however, the study clock will not stop as far as determining the 
cycle/day of treatment. 
 
If there are 2 DLTs within the first 6 patients during the safety lead-in, the dose of PLD will be 
lowered to 30 mg/m2.  
 


 
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5.2 
Pre-Treatment Criteria 
 
5.2.1 Cycle 1, Day 1 
Participants must continue to meet all eligibility criteria prior to dosing on Cycle 1, 
Day 1, as outlined in Protocol Section 3.1. 
 
5.2.2 Subsequent Cycles, on PLD treatment days: Patients must have all of the following: 
Absolute Neutrophil Count: ≥ 1,500/mcL 
Hemoglobin: ≥ 9g/dL 
Platelets: ≥ 100,000/mcL 
Serum Creatinine ≤ 1.5 x ULN 
Liver Function Test ≤ 2.5 x ULN 
ECOG performance status of 0-1 
 
5.3 
Agent Administration 
 
5.3.1 Pegylated Liposomal Doxorubicin (PLD): 
 
5.3.1.1 
Administration  
PLD is administered intravenously, and the first dose of PLD should be administered at a range 
of 1 mg per minute as per the FDA package insert.   If no infusion reactions occur, the infusion 
rate can be increased to complete the administration of the drug over one hour.  The infusion line 
should not be rapidly flushed.  
 
5.3.1.2 
Dosing  
The dose used in this study will be 40 mg/m2 IV once every 4 weeks.  The drug may be 
administered +3 days from the scheduled next infusion because of vacations, weather, holidays, 
etc.  The dose should be calculated using the weight and height on the day of infusion, and actual 
body weight should be used as per the package insert.    
 
5.3.1.3 
Drug, Tubing and Filtration 
PLD should not be used with in-line filters.  Please see the PLD package insert for additional 
details, and PLD should be administered per the FDA package insert and institutional policies.   
 
5.3.1.4 
Hydration 
There is no required hydration. Any hydration will be determined by the treating investigator. 
 
5.3.1.5 
Special Equipment 
No special equipment is needed for PLD infusion.  
 
5.3.1.6 
Observation period 
There is no stated length of observation for PLD, and should be determined by the treating 
investigator.  
 


 
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5.3.1.7 
Infusion Reactions 
Infusion reactions are described with PLD.  The PLD package insert and standard institutional 
policy should be followed for management of these reactions. Desensitization procedures are 
permitted in participants who experience an allergic reaction to PLD. Patients who have an 
allergic reaction to PLD are allowed to continue on the protocol after a discussion with the 
Overall PI and a consultation with allergy. A desensitization procedure administers the total 
planned dose of PLD over a longer period of time under the guidance of the Investigator and 
Allergist. The duration of the infusion of PLD may vary with each patient’s specific symptoms.   
 
5.3.1.8 
Order of Administration 
If PLD and pembrolizumab infusions do occur on the same day, pembrolizumab should be given 
first, followed by PLD.   
 
5.3.1.9 
Caregiver Precautions 
There are no specific caregiver precautions.  Patients may develop, after PLD infusion, a 
reddish-orange color to their urine and other body fluids.  This non-toxic reaction is due to the 
color of the PLD product and will dissipate as the drug is eliminated.   
 
5.3.2 Pembrolizumab: 
 
5.3.2.1 
Administration and Dosing  
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. The 
drug may be administered +3 days from the scheduled next infusion because of vacations, 
weather, holidays, etc.   Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible.  However, given the variability of infusion pumps from site to site, a 
window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 
min). 
 
5.3.2.2 
Drug, Tubing and Filtration 
No special IV tubing and/or filtration are necessary.  
 
5.3.2.3 
Hydration 
There is no required hydration. Any hydration will be determined by the treating investigator as 
clinically indicated.   
 
5.3.2.4 
Observation period 
Per package insert for pembrolizumab.   
 
5.3.2.5 
Protocol specific procedures 
Vital signs should be taken as per institutional policy.   
 
5.3.2.6 
Infusion Reactions 
Infusion reactions are described with pembrolizumab.  Please see section 6.3. Desensitization 
procedures are permitted in participants who experience an allergic reaction to pembrolizumab. 
Patients who have an allergic reaction to pembrolizumab are allowed to continue on the protocol 
after a discussion with the Overall PI and a consultation with allergy. A desensitization 


 
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procedure administers the total planned dose of pembrolizimab over a longer period of time 
under the guidance of the Investigator and Allergist. The duration of the infusion of 
pembrolizumab may vary with each patient’s specific symptoms.   
 
5.3.2.7 
Order of Administration 
If PLD and pembrolizumab infusions do occur on the same day, pembrolizumab should be given 
first, followed by PLD.   
 
 
5.4 
Definition of Dose-Limiting Toxicity (DLT)  
 
Toxicities that are considered DLT toxicities that occur during the first 4 weeks of treatment will 
be monitored; if 2 out of the first 6 patients develop a DLT, the dose of PLD will be reduced to 
30 mg/m2.  
 
Definition of DLT:  Dose limiting toxicity (DLT) refers to both non-hematologic and 
hematologic toxicities deemed by the treating physician to be related to study treatment 
experienced during the first cycle (i.e. first 4 weeks) of treatment. 
 
A DLT will be defined as any of the following, occurring during Cycle 1: 
 
1. Non-Hematologic Toxicity 
Any Grade 3 or 4 event, excluding: 
 Fatigue 
 Grade 3 nausea and/or vomiting controlled with supportive measures within 24 
hours, 
 Grade 3 constipation controlled with supportive measures within 24 hours, 
 Grade 3 diarrhea controlled with supportive measures within 24 hours, 
 Grade 3 hypophosphatemia,  
 Grade 3 hyponatremia, 
 Grade 3 hypomagnesemia 
 Grade 3 rash that does not resolve to grade 2 or grade 1 within < 5 days  
 
2. Hematologic Toxicity 
 Grade 4 neutropenia of > 7 day’s duration 
 Febrile neutropenia (a disorder characterized by an ANC < 1000/mm3 and a single 
temperature of > 38.3 °C (101 °F) or a sustained temperature of  > 38 °C (100.4 
°F) for more than one hour. 
 Dose delay of greater than 3 weeks (21 days) due to failure to recover counts. 
 Grade 4 thrombocytopenia or bleeding associated with grade 3 thrombocytopenia. 
Any other hematologic toxicities of Grade 4 
Requirement for repeated blood transfusion within 4-6 weeks 
 
3. Any study treatment related death. 
 


 
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5.5 
General Concomitant Medication and Supportive Care Guidelines 
 
5.5.1 Concomitant Medications/Vaccinations (allowed & prohibited) 
 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications or 
vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this with 
the Overall Principal Investigator, who will then contact the Merck Clinical team as needed.  The 
final decision on any supportive therapy or vaccination rests with the Overall Principal 
Investigator and/or the participant's primary physician.  
 
5.5.2  
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and 
fluids.  If changes occur during the trial period, documentation of drug dosage, frequency, route, 
and date may also be included on the CRF. 
All concomitant medications received within 28 days before the first dose of trial treatment and 
30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs and 
ECIs (Events of Clinical Interest) as defined in Section 7.2. 
5.5.3  
Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
       Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed after discussion with the Overall PI..   
 Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine.  


 
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 Systemic glucocorticoids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Overall PI and Sponsor. 
Participants 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.   
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will depend on individual response, evidence of disease progression and 
tolerance. In the absence of treatment delays due to adverse event(s), treatment may continue 
until one of the following criteria applies: 
 
 Disease progression 
 
 Intercurrent illness that prevents further administration of treatment 
 
 Unacceptable adverse event(s) 
 
 Participant decides to withdraw from the protocol therapy 
 
 General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator 
 
 Participant has completed 35 treatments (approximately 2 years) with 
pembrolizumab (Note: participant may continue on study receiving only PLD at 
the discretion of the treating investigator) 
 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
Regarding length of duration of treatment of PLD, investigator should follow the FDA package 
insert for PLD.  
 
Before participants continue on PLD for more than 8 cycles, the treating physician must confer 
with the Overall PI and obtain approval to do so.  
 


 
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If participants are removed from PLD therapy because of PLD toxicities, they are tolerating 
Pembrolizumab, and there is no evidence of RECIST progression, participants may continue on 
Pembrolizumab alone after discussion and approval from the Overall PI.  
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. Other investigative sites will inform the 
Project Manager as soon as a participant is taken off protocol therapy. The Project Manager will 
then make the relevant updates in OnCore. 
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 
In the event of unusual or life-threatening complications, treating investigators must immediately 
notify the Overall PI,  
 
 Ursula Matulonis, M.D. at umatulonis@partners.org. 
 
 
5.7 
Duration of Follow Up 
 
Participants will be followed for 4 weeks after removal from protocol therapy for adverse events.  
Participants will be followed for survival. Follow-up will be reported in 3 month intervals for up 
to two years after removal from study treatment or until death, whichever occurs first. 
Participants removed from protocol therapy for unacceptable adverse event(s) will be followed 
until resolution or stabilization of the adverse event.  
 
5.8 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 Lost to follow-up 
 Withdrawal of consent for data submission 
 Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). 
 
For Centralized Subject Registrations, the research team submits a completed Off Treatment/Off 
Study form to ODQ when a participant comes off study. This form can be found on the ODQ 
website or obtained from the ODQ registration staff. Other investigative sites will inform the 
Project Manager as soon as a participant is taken off study. The Project Manager will then make 
the relevant updates in OnCore. 
 
For Decentralized Subject Registrations, the research team updates the relevant Off 
Treatment/Off Study information in OnCore.  
 


 
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6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Investigators should assess toxicities and make a determination which agent(s) is responsible for 
the toxicity and grade the toxicity.    Dose delays and modifications will be made as indicated in 
the following table(s). The descriptions and grading scales found in the revised NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for dose delays 
and dose modifications. A copy of the CTCAE version 4.0 can be downloaded from the CTEP 
website 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
6.1 
Dose modifications for Pegylated Liposomal Doxorubicin 
 
If patients experience treatment-related toxicities, their PLD dose should be reduced according to 
institutional prescribing and dose-reduction standards per the below tables. 
 
If greater than two dose reductions are required, discussion and approved must be obtained by 
the Overall PI. 
   
Recommended dose reductions for PLD (Doxil) per the FDA package insert:   
 
Hand Foot Syndrome 
Toxicity  
Dose Adjustment  
Hand Foot Syndrome 
 
Grade 1: 
Mild erythema, swelling, or desquamation not 
interfering with daily activities  
 If no previous Grade 3 or 4 HFS, no 
dose adjustment. 
 
 If previous Grade 3 or 4 HFS, delay 
dose up to 2 weeks, then decrease dose 
by 25%.   
Grade 2: 
Erythema, swelling, or desquamation 
interfering with, but not precluding normal 
physical activities; small blisters or ulcerations 
less than 2 cm. in diameter.  
 Delay dosing up to 2 weeks or 
until resolved to grade 0 or 1.   
 Discontinue doxil if no 
resolution after 2 weeks. 
 
 If resolved to grade 0 or 1 within 2 
weeks: and no previous grade 3 or 4 
HFS, continue treatment at previous 
dose  
 
or  
 
And previous Grade 3 or 4 toxicity; 
decrease dose by 25% 
Grade 3:   
Blistering, ulceration, or swelling interfering 
 Delay dosing up to 2 weeks or 
until resolved to grade 0 or 1, 


 
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23 
 
with walking or normal daily activities; cannot 
wear regular clothing.  
then decrease dose by 25% 
 Discontinue doxil if no 
resolution after 2 weeks 
 
Grade 4: 
Diffuse or local process causing infectious 
complications, or a bed ridden state or 
hospitalization.   
 Delay dosing up to 2 weeks or 
until resolved to grade 0 or 1, 
then decrease dose by 25% 
 Discontinue doxil if no 
resolution after 2 weeks 
 
 
Stomatitis 
Toxicity  
Dose Adjustment  
Stomatitis 
 
Grade 1: 
Painless ulcers, erythema, or mild soreness   
 If no previous Grade 3 or 4 toxicity, no 
dose adjustment. 
 
 If previous Grade 3 or 4 toxicity, delay 
dose up to 2 weeks, then decrease dose 
by 25%.   
Grade 2: 
Painful erythema, edema or ulcers but can eat.  
 Delay dosing up to 2 weeks or 
until resolved to grade 0 or 1.   
 Discontinue doxil if no 
resolution after 2 weeks. 
 
 If resolved to grade 0 or 1 within 2 
weeks: 
 
and no previous grade 3 or 4 HFS, 
continue treatment at previous dose  
 
or  
 
And previous Grade 3 or 4 toxicity; 
decrease dose by 25% 
Grade 3:   
Painful erythema, edema or ulcers and cannot 
eat.    
 Delay dosing up to 2 weeks or 
until resolved to grade 0 or 1.  
Decrease dose by 25% and 
return to original dose interval 
 Discontinue doxil if no 
resolution after 2 weeks 
 
Grade 4: 
Diffuse or local process causing infectious 
complications, or a bed ridden state or 
 Delay dosing up to 2 weeks or 
until resolved to grade 0 or 1, 
then decrease dose by 25% and 


 
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24 
 
hospitalization.   
return to original dose interval 
 Discontinue doxil if no 
resolution after 2 weeks 
 
 
 
Neutropenia and Thrombocytopenia 
Toxcity  
Dose Adjustment  
Neutropenia and Thrombocytopenia  
Grade 1 
No dose reduction 
Grade 2 
Delay until ANC ≥ 1500 and plts ≥ 100,000; 
resume treatment at previous dose 
Grade 3 
Delay until ANC ≥ 1500 and plts ≥ 100,000; 
resume treatment at previous dose 
Grade 4 
Delay until ANC ≥ 1500 and plts ≥ 100,000; 
resume at 25% dose reduction or continue 
previous dose with prophylactic granulocyte 
growth factor. 
 
6.2 
Dose Modifications for Pembrolizumab: 
 
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 3 below. See Section 6.3.1 and 
Events of Clinical Interest Guidance Document for supportive care guidelines (Appendix B), 
including use of corticosteroids. 
 
 
Table 3 
Dose Modification Guidelines for Drug-Related Adverse Events (Please also see Appendix B) 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Participant 
Diarrhea/Coli
tis 
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 
T1DM or  
3-4 
Hold pembrolizumab for 
new onset Type 1 diabetes 
mellitus or Grade 3-4 
hyperglycemia associated 
Resume pembrolizumab when patients are 
clinically and metabolically stable. 


 
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25 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Participant 
Hyperglycem
ia 
with evidence of beta cell 
failure.  
 
Hypophysitis 
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 
Hyperthyroid
ism  
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 
Hypothyroidi
sm 
2-4 
Therapy with 
pembrolizumab can be 
continued while treatment 
for the thyroid disorder is 
instituted 
Therapy with pembrolizumab can be 
continued while treatment for the thyroid 
disorder is instituted. 
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.   
 
After discussion and approval from the Overall PI, dosing interruptions are permitted in the case 


 
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26 
 
of medical / surgical events or logistical reasons not related to study therapy (e.g., elective 
surgery, unrelated medical events, patient vacation, and/or holidays).  The reason for interruption 
should be documented in the patient's study record. 
 
6.3 
Rescue Medications & Supportive Care 
 
6.3.1 
Supportive Care Guidelines 
Participants 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 Events of 
Clinical Interest guidance document (Appendix B). 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 6 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. 
 
 Pneumonitis:  
 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. 
 For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
 Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
 
 Diarrhea/Colitis:  
Participants 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).   
 
 All participants 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 


 
DF/HCC Protocol #: 16-257 
 
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27 
 
Grade 2 or higher diarrhea, consider GI consultation and endoscopy to 
confirm or rule out colitis. 
 For Grade 2 diarrhea/colitis that persists greater than 3 days, administer 
oral corticosteroids.  
 For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with 
intravenous steroids followed by high dose oral steroids.   
 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) 
 
 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: 
 
 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. 
 For Grade 3-4 events, treat with an initial dose of IV corticosteroids 
followed by oral corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 
weeks. Replacement of appropriate hormones may be required as the 
steroid dose is tapered. 
 
 Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs and 
symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) 
are suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  


 
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28 
 
 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: 
 For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
 For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours.  
 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: 
 For Grade 2 events, treat with corticosteroids. 
 For Grade 3-4 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.  
 
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 4 below shows treatment guidelines for participants who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant 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 participant 
should be premedicated for the next scheduled 
dose. 
Participant may be premedicated 1.5h (± 30 
minutes) prior to infusion of pembrolizumab 
(MK-3475) with: 
 
Diphenhydramine 50 mg po (or equivalent dose 
of antihistamine). 
 
Acetaminophen 500-1000 mg po (or equivalent 
dose of antipyretic). 


 
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29 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent dosing 
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
referred to allergy after discussion with the PI.
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 participant is deemed 
medically stable in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Participant 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. 
 
 
 
7. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of reported and/or potential AEs (Section 7.1) and the characteristics of an 
observed AE (Section 7.2) will determine whether the event requires expedited reporting in 
addition to routine reporting. For Events of Clinical Interests (ECIs) please see Appendix B 
for reporting guidelines to Merck. 
 
7.1. 
Expected Toxicities 
 
7.1.1 PLD 
The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, 
nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and 
neutropenia, thrombocytopenia and anemia. 
 
Other more rare toxicities include: 
1)  Cardiac toxicity:  Special attention must be given to the risk of myocardial damage from 
cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, 
particularly in patients who have received a total cumulative dosage of doxorubicin exceeding 
the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart 
failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy 
with other potentially cardiotoxic agents such as cyclophosphamide.   Prior use of other 
anthracyclines or anthracenodiones should be included in calculations of total cumulative 
dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of 
anthracycline therapy. Patients with a history of cardiovascular disease should be administered 


 
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30 
 
DOXIL only when the potential benefit of treatment outweighs the risk.   Cardiac function 
should be carefully monitored in patients treated with DOXIL. The most definitive test for 
anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as 
echocardiography or multigated radionuclide scans, have been used to monitor cardiac 
function during anthracycline therapy. Any of these methods should be employed to monitor 
potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible 
cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully 
weighed against the risk of myocardial injury. 
 
2)  Infusion reactions:   Acute infusion-related reactions were reported in 7.1% of patients treated 
with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one 
or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, 
chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, 
cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension.  
 
In most patients, these reactions resolve over the course of several hours to a day once the 
infusion is terminated. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like 
infusion reactions have been reported. Medications to treat such reactions, as well as emergency 
equipment, should be available for immediate use. 
 
The majority of infusion-related events occurred during the first infusion. Similar reactions have 
not been reported with conventional doxorubicin and they presumably represent a reaction to the 
DOXIL liposomes or one of its surface components.  The initial rate of infusion should be 1 
mg/min to help minimize the risk of infusion reactions. 
 
3)  Radiation recall:  can rarely occur. 
 
4)  Fetal mortality:  Most of our patients will not be child-bearing and if they are, eligibility 
requirements require use of contraception.  
 
7.1.2 Pembrolizumab:  
 
The most common adverse reactions (reported in ≥20% of patients) include: Fatigue, cough, 
nausea, pruritus, rash, decreased appetite, constipation, arthralgia, and diarrhea. 
 
Immune-mediated adverse reactions include the following: 
 Immune-mediated pneumonitis 
 Immune-mediated colitis 
 Immune-mediated hepatitis 
 Immune-mediated hypophysitis 
 Immune-mediated nephritis 
 Immune-mediated hyperthyroidism and hypothyroidism 
 Embryofetal toxicity 
 
Other more rare toxicities include: 
1)  Immune-mediated adverse reactions occurred in less than 1% of patients, and include the 


 
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following : exfoliative dermatitis, uveitis, arthritis, myositis, pancreatitis,  hemolytic anemia, 
partial seizures arising in a patient with inflammatory foci in brain parenchyma, andadrenal 
insufficiency.  Across clinical studies with pembrolizumab, in approximately 2000 patients, the 
following additional clinically significant, immune-mediated adverse reactions were reported in 
less than 1% of patients: myasthenic syndrome, optic neuritis, and rhabdomyolysis. 
 
7.2 Adverse Event Characteristics 
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 For expedited reporting purposes only:   
o AEs for the agent(s) that are listed above should be reported only if the adverse 
event varies in nature, intensity or frequency from the expected toxicity 
information which is provided. 
o Other AEs for the protocol that do not require expedited reporting are outlined in 
the next section (Expedited Adverse Event Reporting) under the sub-heading of 
DF/HCC Expedited Reporting Guidelines. 
 
 Attribution of the AE: 
o 
Definite – The AE is clearly related to the study treatment. 
o 
Probable – The AE is likely related to the study treatment. 
o 
Possible – The AE may be related to the study treatment. 
o 
Unlikely – The AE is doubtfully related to the study treatment. 
o 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.3 Expedited Adverse Event Reporting  
 
7.3.1 
Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, or within 30 days of the last 
dose of treatment on the local institutional SAE form.  
 
7.3.2 
For multi-institution studies where a DF/HCC investigator is serving as the Overall 
Principal Investigator, each participating institution must abide by the reporting requirements set 
by the DF/HCC. This applies to any medical event equivalent to an unexpected grade 2 or 3 with 
a possible, probable or definite attribution, both expected (unless listed in the protocol as not 
requiring expedited reporting) and unexpected grade 4 toxicities, and grade 5 (death) regardless 
of study phase or attribution. 
 
7.3.3 
DF/HCC Expedited Reporting Guidelines 
 


 
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32 
 
Investigative sites within DF/HCC and DF/PCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
Other investigative sites will report AEs to their respective IRB according to the local IRB’s 
policies and procedures in reporting adverse events. A copy of the submitted institutional AE 
form should be forwarded to the Overall PI within the timeframes detailed in the table below.   
 
 
 
 
Attribution 
DF/HCC Reportable AEs
Gr. 2 & 3 AE 
Expected 
Gr. 2 & 3 AE 
Unexpected 
Gr. 4 AE Expected
Gr. 4 AE 
Unexpected 
Gr. 5 AE 
Expected or 
Unexpected 
Unrelated 
Unlikely 
Not required 
Not required 
5 calendar days# 
5 calendar days 
24 hours* 
Possible 
Probable 
Definite 
 
Not required 
 
5 calendar days 
 
5 calendar days# 
 
5 calendar days 
 
24 hours* 
# If listed in protocol as expected and not requiring expedited reporting, event does not need to be reported. 
 
* For participants enrolled and actively participating in the study or for AEs occurring within 30 days of the last 
intervention, the AE should be reported within 24 business hours of learning of the event. 
 
 
The Overall PI will submit AE reports from outside institutions to the DFCI OHRS according to 
DFCI IRB policies and procedures in reporting adverse events.  
 
 
7.4 
Expedited Reporting to the Food and Drug Administration (FDA) 
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.5 
Expedited Reporting to Hospital Risk Management 
 
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.6 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 


 
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8. PHARMACEUTICAL INFORMATION 
 
8.1 
Pegylated Liposomal Doxorubicin 
 
8.1.1 
Description 
 
Per the package insert:   PLD or DOXIL (doxorubicin HCl liposome injection) is doxorubicin 
hydrochloride (HCl) encapsulated in STEALTH® liposomes for intravenous administration (PLD 
package insert).  Doxorubicin is an anthracycline topoisomerase inhibitor isolated from 
Streptomyces peucetius var. caesius.  Doxorubicin HCl, which is the established name for 
(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycolyl-7,8,9,10-
tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12-naphthacenedione hydrochloride. The active 
ingredient of DOXIL is doxorubicin HCl. The mechanism of action of doxorubicin HCl is 
thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Cell structure 
studies have demonstrated rapid cell penetration and perinuclear chromatin binding, rapid 
inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and 
chromosomal aberrations. 
 
PLD is doxorubicin HCl encapsulated in long-circulating STEALTH® liposomes.   Liposomes 
are microscopic vesicles composed of a phospholipid bilayer that are capable of encapsulating 
active drugs. The STEALTH® liposomes of DOXIL are formulated with surface-bound 
methoxypolyethylene glycol (MPEG), a process often referred to as pegylation, to protect 
liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood 
circulation time.   STEALTH® liposomes have a half-life of approximately 55 hours in humans. 
They are stable in blood, and direct measurement of liposomal doxorubicin shows that at least 
90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains 
liposome-encapsulated during circulation. It is hypothesized that because of their small size (ca. 
100 nm) and persistence in the circulation, the pegylated DOXIL liposomes are able to penetrate 
the altered and often compromised vasculature of tumors.  
 
8.1.2 
Form 
PLD is a sterile, translucent, red liposomal dispersion for IV administration. PLD is supplied at a 
concentration of 2 mg/mL in 10-mL or 30-mL single-use vials. PLD doses up to 90 mg must be 
diluted in 250 mL of 5% dextrose injection, USP, prior to infusion. PLD doses exceeding 90 mg 
must be diluted in 500 mL of 5% dextrose injection, USP, prior to infusion. Diluted PLD should 
be refrigerated at 2°Cto 8°C (36°Fto 46°F). Each vial and carton will contain a label, either 
single-panel or booklet, affixed to the vial or carton. PLD should not be administered using an 
in-line filter. 
 
8.1.3 
Storage and Stability 
PLD should be stored as per Institutional pharmacy guidelines and the FDA package insert for 
PLD.  Per the package insert, unopened vials of PLD should be refrigerated between 2 and 8 
degrees C and should not be frozen.   
 
8.1.4 
Compatibility 
There are no known compatibility effects between PLD and pembolizumab.   
 


 
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34 
 
8.1.5 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
8.1.6 
Availability 
PLD is available per Institutional pharmacy guidelines since this is an FDA-approved agent for 
recurrent ovarian cancer.   
 
8.1.7 
Preparation 
PLD should be prepared as per Institutional pharmacy guidelines and the FDA package insert for 
PLD.   
 
8.1.8 
Administration 
PLD should be administered as per Institutional pharmacy guidelines and the FDA package 
insert for PLD.  PLD should not be administered as an IV push or bolus. Infusion reactions may 
occur. To attenuate infusion reactions, premedication consisting of acetaminophen (or 
paracetamol), diphenhydramine (or other suitable antihistamine), and a single dose of 
hydrocortisone (e.g., up to 100 mg or an equivalent dose of methylprednisolone) may be 
administered beginning with the first infusion, per standard clinical practice. 
 
 
8.1.9 
Ordering 
Investigative sites will order their own supply of PLD as per institutional guidelines.    
 
8.1.10 
Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent according to institutional guidelines for 
commercial agents.  
 
8.1.11 
Destruction and Return 
Investigative sites will destroy PLD as per institutional guidelines 
 
 
8.2 
Pembrolizumab  
 
8.2.1 
Form 
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD-1 
and its ligands, PD-L1 and PD-L2. Pembrolizumab is an IgG4 kappa immunoglobulin with an 
approximate molecular weight of 149 kDa. 
 
8.2.2 
Storage and Stability    
Pembrolizumab is a sterile, preservative-free, latex free, white to off-white lyophilized powder in 
single-use vials. Each vial is reconstituted and diluted for intravenous infusion. Each 2 mL of 
reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3.1 
mg), polysorbate 80 (0.4 mg), and sucrose (140 mg). May contain hydrochloric acid/sodium 


 
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35 
 
hydroxide to adjust pH to 5.5.    Pembrolizumab is a sterile, preservative-free, latex free, clear to 
slightly opalescent, colorless to slightly yellow solution that requires dilution for intravenous 
infusion. Each vial contains 100 mg of pembrolizumab in 4 mL of solution. Each 1 mL of 
solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1.55 mg), 
polysorbate 80 (0.2 mg), sucrose (70 mg), and Water for Injection, USP. 
 
8.2.3 
Compatibility  
There are no known compatibility effects between PLD and pembolizumab.   
 
8.2.4 
Handling 
Qualified personnel, familiar with procedures that minimize undue exposure to themselves and 
the environment, should undertake the preparation, handling, and safe disposal of the 
chemotherapeutic agent in a self-contained and protective environment.  
 
Store vials under refrigeration at 2°C to 8°C (36°F to 46°F) and should be protected from light.  
Note: vials should be stored in the original box to ensure the drug product is protected from light.  
The vials should not be shaken.  
 
MK-3475 infusion solutions should be prepared in 0.9% Sodium Chloride Injection, 
USP (normal saline) and the final concentration of MK-3475 in the infusion solutions should be 
between 1.0 mg/mL and 10.0 mg/mL. If rounding is necessary, round up to one decimal place.   
Availability  Pembrolizumab will be provided by Merck and will be ordered by the pharmacy of 
each institution.      
 
Pembrolizumab (MK-3475) solutions may be stored at room temperature for a cumulative time 
of up to 6 hours. The 6 hour countdown begins when the vial is pierced, and includes room 
temperature storage of reconstituted drug product solution in vials, room temperature storage of 
admixture solutions in the IV bags and the duration of infusion. (Please note this 6 hour 
timeframe is to provide a microbial control strategy. The microbial clock only starts when the 
product stopper is pierced and not when the vial is removed from the refrigerator.) 
 
In addition, reconstituted vials and/or IV bags may be stored under refrigeration at 2 °C to 8 °C 
(36 °F to 46 °F), total cumulative storage time at room temperature and refrigeration should not 
exceed 24 hours. If refrigerated, allow the vials and/or IV bags to come to room temperature 
prior to use.   
 
8.2.3 
Availability 
Pembrolizumab will be provided by Merck and will be ordered by the pharmacy of each 
institution. 
 
8.2.4 
Preparation 
Aseptic technique must be strictly observed throughout the preparation procedure preferably in a 
biologic safety cabinet or hood since no anti-microbial preservative is present in the solutions.   
Equilibrate required number of MK-3475 vials to room temperature.   Parenteral drug products 
should be inspected visually for particulate matter and discoloration prior to administration. 
Discard vial if opaque or extraneous particulate matter other than proteinaceous particles is 


 
DF/HCC Protocol #: 16-257 
 
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36 
 
observed.      
 
Sites may choose to select an IV bag size based on their institutional practice 
provided that the following conditions are met: 
 Concentration of MK-3475 is between 1.0 mg/mL and 10.0 mg/mL 
 The infusion volume to bag capacity ratio should not be less than 0.3. In other 
words, the bag must be filled to at least 30% of its capacity. Otherwise a lower 
capacity bag must be used to prepare the infusion solution. 
 Choose a suitable infusion bag material from the following list: 
o PVC plasticized with DEHP 
o Non-PVC (polyolefin) 
o EVA (ethylene vinyl acetate) 
o PE lined polyolefin 
*Contact Sponsor for materials not listed above 
 
 
8.2.5 
Administration 
Pembrolizumab (MK-3475) infusions should be administered in 30 minutes, with a window of -5 
and +10 minutes, using an infusion pump. A central catheter is not required for infusion; 
however if a participant has a central venous catheter in place, it is recommended that it be used 
for the infusion. 
 
The following infusion set materials are compatible with MK-3475: 
 PVC Infusion set that is plasticized using DEHP 
 PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
 Polyethylene lined PVC infusion set 
 PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate (DEHT) 
 Polyurethane set 
 
* Contact the Sponsor for materials not listed above.  
 
A sterile, non-pyrogenic, low-protein binding 0.2 to 5 μm in-line filter made of polyethersulfone 
(PES) must be used during administration to remove any adventitious particles. If the infusion 
set does not contain a 0.2 to 5 μm in-line filter, it is recommended to use a 0.2 to 5 μm add-on 
filter which may contain an extension line (the materials of the extension line and filter should be 
as mentioned above). 
 
Attach the infusion line to the pump and prime the line, either with normal saline (at least 25 
mL) or with infusion solution as per local SOP, before starting the infusion.  Infuse MK-3475 
over approximately 30 minutes with a window of -5 and +10 minutes, through a peripheral line 
or indwelling catheter.  Maximum rate of infusion should not exceed 6.7 mL/min. through a 
peripheral line or indwelling catheter. Use 30 mL normal saline to flush the infusion line at the 
end of infusion. If institutional guidelines to not allow the flushing of the infusion line at the 
completion of the infusion, the specific volume of drug/diluent solution should be prepared that 
is required to make up for the volume of the dosing solution lost in the infusion line. 
 


 
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37 
 
8.2.6 
Ordering 
Investigative sites will order their own supply of pembrolizumab.      
 
8.2.7 
Accountability 
The investigator, or a responsible party designated by the investigator, should maintain a careful 
record of the inventory and disposition of the agent using the NCI Drug Accountability Record 
Form (DARF) or another comparable drug accountability form.   
 
8.2.8 
Destruction and Return 
Investigative sites will destroy pembrolizumab as per institutional guidelines 
 
9. BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES 
 
1) DFCI Immuno-oncology program IHC staining of FFPE samples: 
 
To identify different immune cell populations (effector/memory/ CD8 cells, T regulatory 
cells, dendritic cells, tumor associated macrophages, NK cells, TEM) immunohistochemical 
staining will be performed on FFPE tumor slices using the following antibodies:  
CD3, CD4, CD8, CD25, FoxP3, Indoleamine 2,3 deoxygenase-1 (IDO), CD11c, CD83, 
CD86, CD56, CD14, and CD16.  Also included will be IHC staining for PD-L1, PD-L2, 
TIM-3 and LAG-3 through the center for Immuno-oncology Pathology Core (Scott Rodig, 
M.D., Ph.D.). 
 
12 unstained slides that are amenable for IHC will be needed for these studies. 4 µm slice 
thickness is preferred, but 4 -5 µm is acceptable.  
 
 
Tissue can be sent to: 
 
Scott Rodig MD/ Evisa Gjini PhD 
Thorn building, room 603 
Department of Pathology, Brigham & Women’s Hospital 
20 Shattuck Street 
Boston MA 02115 
 
2) Merck PDL1 staining:  5 unstained slides cut from an FFPE tissue block will be needed. See 
section 2.5 and appendix C for details.   
 
3) Nanostring:  For each patient enrolled in the study, 4 unstained slides (4-5 micron sections) 
per sample of FFPE tumor will be sent to Merck at the following address: 
 
Katherine Bohrer 
Merck Sharp and Dohme Corp 
Anatomic Pathology  
Attention:  Tissue Accessioning 
901 South Carolina Ave 
Palo Alto, CA 94304-1104 


 
DF/HCC Protocol #: 16-257 
 
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38 
 
 
10. STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy. 
Baseline labs must be performed within 14 days of treatment initiation. Scans and x-rays must be 
done <4 weeks prior to the start of therapy.  In the event that the participant’s condition is 
deteriorating, laboratory evaluations should be repeated within 48 hours prior to initiation of the 
next cycle of therapy. 
 
Assessments must be performed prior to administration of any study agent. Study assessments 
and agents should be administered within + 3 days of the protocol-specified date, unless 
otherwise noted. 
 
 
Pre- 
Study C1 D1 C1 D8
C1 D15 
C1 D22 C2 D1
C2 D15
C3 D1
C3 D8 
Cycle 4 
and 
beyond f
Off 
Studyc
PLD5  
 
A 
 
 
 
A 
 
A 
 
A 
 
Pembroluzimab5 
 
B 
 
 
B 
 
B 
 
B 
B 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
X---------------------------------------------------------------------------------------------Xf 
 
Physical exam1 
X 
X 
 
 
X 
X 
X 
X 
X 
Xf 
X 
Vital signs2 
X 
X 
 
 
X 
X 
X 
X 
X 
Xf 
X 
Height and weight3 
X 
X 
 
 
X 
X 
X 
X 
X 
Xf 
 
Performance status4 
X 
X 
 
 
X 
X 
X 
X 
X 
Xf 
X 
CA-125 
X 
X 
 
 
 
X 
 
X 
 
X 
 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
Serum chemistrya 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xf 
X 
TSH 
X 
X 
 
 
 
X 
 
 
 
X 
 
EKG (as indicated) 
X 
 
 
 
 
 
 
 
 
 
 
Adverse event 
evaluation 
 
X---------------------------------------------------------------------------------------------Xf 
X 
Tumor measurements 
X 
Tumor measurements are repeated every  [8  weeks ±1 week]   weeks.  
Documentation (radiologic) must be provided for participants removed from study 
for progressive disease.g 
X 
B-HCG 
Xb 
 
 
 
 
 
 
 
 
 
 
FFPE blocks d 
X 
 
 
 
 
 
 
 
 
 
 
ECHO or MUGAe 
X 
 
 
 
 
 
 
 
 
Xe 
 
A: PLD 40 mg/m2 IV every 28 days ±3 days window  
B: 
Pembrolizumab 200 mg IV every 21 days ±3 days window 
1:     Will include skin examination in addition to physical exam 
2:     Including blood pressure, temperature, respiratory rate, heart rate 
3:     Height should be performed at screening and Cycle 1 Day 1 only, weight should be performed at each visit 
4:     ECOG performance status as per Appendix 1.   


 
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39 
 
5:     The schedules for pembrolizumab and doxil can be delayed independently, however, the clock does not stop for each 28 
day cycle regarding the cycle/day. 
a: 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium. 
b: 
Serum pregnancy test (only for women of childbearing potential). 
c: 
Off-study evaluation. Patients will be followed for 4 weeks post treatment for adverse events. Patients will be followed 
for survival every 3 months for two years or until death, whichever occurs first. 
d.     Obtained as part of eligibility criteria and will include PDL1 and nanostring analysis 
e.      Up to a week before cycle 4 of PLD, and subsequent cycles (every 3 cycles).  
f.      Physical exam, vital signs, PS as well as the following labs: CBC with plts, serum chemistry should be performed on a 
treatment day regardless if patients are receiving PLD alone, pembrolizumab alone or both agents.   
g.     Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by potentiating endogenous cancer-
specific immune responses. The response patterns seen with such an approach may extend beyond the typical time 
course of responses seen with cytotoxic agents and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Patients with initial PD will be allowed to stay on trial with a repeat scan 
in 4 weeks. If repeat imaging confirms PD, patients will be discontinued from study therapy. 
 
11. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, participants with measurable disease 
will be assessed by standard criteria.  For the purposes of this study, participants should be re-
evaluated every 8 weeks.   
 
11.1 Antitumor Effect – Solid Tumors 
 
For the purposes of this study, participants should be re-evaluated for response every 8 weeks (± 
1 week).   
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1) 
[Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional measurement) of 
the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the 
RECIST criteria. 
 
11.1.1 Definitions 
 
 Evaluable for Target Disease response.  Only those participants who have 
measurable disease present at baseline, have received at least one cycle of 
therapy, and have had their disease re-evaluated will be considered evaluable for 
target disease response.  These participants will have their response classified 
according to the definitions stated below.  (Note:  Participants who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
 Evaluable Non-Target Disease Response.  Participants who have lesions present 
at baseline that are evaluable but do not meet the definitions of measurable 
disease, have received at least one cycle of therapy, and have had their disease re-
evaluated will be considered evaluable for non-target disease.  The response 
assessment is based on the presence, absence, or unequivocal progression of the 
lesions.  


 
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Protocol Version Date: August 29, 2018 
 
40 
 
 
11.1.2 Disease Parameters 
 
 Measurable disease.  Measurable lesions are defined as those that can be 
accurately measured in at least one dimension (longest diameter to be recorded) as 
≥ 20 mm by chest x-ray or ≥10 mm with CT scan, MRI, or calipers by clinical 
exam.  All tumor measurements must be recorded in millimeters (or decimal 
fractions of centimeters). 
 
 Malignant lymph nodes.  To be considered pathologically enlarged and 
measurable, a lymph node must be ≥15 mm in short axis when assessed by CT 
scan (CT scan slice thickness recommended to be no greater than 5 mm).  At 
baseline and in follow-up, only the short axis will be measured and followed. 
 
 Non-measurable disease.  All other lesions (or sites of disease), including small 
lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 
mm short axis), are considered non-measurable disease.  Bone lesions, 
leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis 
cutis/pulmonitis, inflammatory breast disease, abdominal masses (not followed by 
CT or MRI), and cystic lesions are all considered non-measurable. 
 
Note: Cystic lesions that meet the criteria for radiographically defined simple 
cysts should not be considered as malignant lesions (neither measurable nor non-
measurable) since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if non-cystic lesions are present in the same participant, these are 
preferred for selection as target lesions. 
 
 Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ 
and 5 lesions in total, representative of all involved organs, should be identified as 
target lesions and recorded and measured at baseline.  Target lesions should be 
selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend 
themselves to reproducible repeated measurements. It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in 
which circumstance the next largest lesion which can be measured reproducibly 
should be selected. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions will be calculated and reported as the 
baseline sum diameters. If lymph nodes are to be included in the sum, then only 
the short axis is added into the sum. The baseline sum diameters will be used as 
reference to further characterize any objective tumor regression in the measurable 
dimension of the disease.  
 
 Non-target lesions.  All other lesions (or sites of disease) including any 


 
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41 
 
measurable lesions over and above the 5 target lesions should be identified as 
non-target lesions and should also be recorded at baseline. Measurements of 
these lesions are not required, but the presence, absence, or in rare cases 
unequivocal progression of each should be noted throughout follow up.  
 
 
11.1.3 Methods for Evaluation of Disease 
 
All measurements should be taken and recorded in metric notation using a ruler, calipers, 
or a digital measurement tool.  All baseline evaluations should be performed as closely as 
possible to the beginning of treatment and never more than 4 weeks before the beginning 
of the treatment. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam.  
 
 Clinical lesions. Clinical lesions will only be considered measurable when they 
are superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm in 
diameter as assessed using calipers (e.g., skin nodules).  In the case of skin 
lesions, documentation by color photography, including a ruler to estimate the 
size of the lesion, is recommended.  
 
 Chest x-ray.  Lesions on chest x-ray are acceptable as measurable lesions when 
they are clearly defined and surrounded by aerated lung; however, CT is 
preferable.  
 
 Conventional CT and MRI. This guideline has defined measurability of lesions on 
CT scan based on the assumption that CT thickness is 5mm or less. If CT scans 
have slice thickness greater than 5 mm, the minimum size of a measurable lesion 
should be twice the slice thickness. MRI is also acceptable in certain situations 
(e.g. for body scans).   
 
 Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and 
temporal resolution; however, there are many image acquisition variables 
involved in MRI, which greatly impact image quality, lesion conspicuity, and 
measurement.  Furthermore, the availability of MRI is variable globally.  As with 
CT, if an MRI is performed, the technical specifications of the scanning 
sequences used should be optimized for the evaluation of the type and site of 
disease.  Furthermore, as with CT, the modality used at follow-up should be the 
same as was used at baseline and the lesions should be measured/assessed on the 
same pulse sequence.  It is beyond the scope of the RECIST guidelines to 
prescribe specific MRI pulse sequence parameters for all scanners, body parts, 
and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  


 
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42 
 
Body scans should be performed with breath-hold scanning techniques, if 
possible. 
 
 FDG-PET. While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to 
complement CT scanning in assessment of progression (particularly possible 'new' 
disease).  New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm:  
o Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a 
sign of PD based on a new lesion. 
o No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the 
positive FDG-PET at follow-up corresponds to a new site of disease 
confirmed by CT, this is PD.  If the positive FDG-PET at follow-up is not 
confirmed as a new site of disease on CT, additional follow-up CT  scans 
are needed to determine if there is truly progression occurring at that site 
(if so, the date of PD will be the date of the initial abnormal FDG-PET 
scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic 
images, this is not PD. 
o FDG-PET may be used to upgrade a response to a CR in a manner similar 
to a biopsy in cases where a residual radiographic abnormality is thought 
to represent fibrosis or scarring.  The use of FDG-PET in this 
circumstance should be prospectively described in the protocol and 
supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false 
positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake 
greater than twice that of the surrounding tissue on the attenuation corrected image. 
 
 PET-CT. At present, the low dose or attenuation correction CT portion of a 
combined PET-CT is not always of optimal diagnostic CT quality for use with 
RECIST measurements.  However, if the site can document that the CT 
performed as part of a PET-CT is of identical diagnostic quality to a diagnostic 
CT (with IV and oral contrast), then the CT portion of the PET-CT can be used 
for RECIST measurements and can be used interchangeably with conventional 
CT in accurately measuring cancer lesions over time.  Note, however, that the 
PET portion of the CT introduces additional data which may bias an investigator 
if it is not routinely or serially performed.   
 
 Tumor markers. Tumor markers alone cannot be used to assess response. If 
markers are initially above the upper normal limit, they must normalize for a 
participant to be considered in complete clinical response.  Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer) have been published [JNCI 96:487-488, 2004; J Clin 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
43 
 
Oncol 17, 3461-3467, 1999; J Clin Oncol 26:1148-1159, 2008].  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which 
are to be integrated with objective tumor assessment for use in first-line trials in 
ovarian cancer [JNCI 92:1534-1535, 2000]. 
 
 Cytology, Histology. These techniques can be used to differentiate between 
partial responses (PR) and complete responses (CR) in rare cases (e.g., residual 
lesions in tumor types, such as germ cell tumors, where known residual benign 
tumors can remain). 
 
 The cytological confirmation of the neoplastic origin of any effusion that appears 
or worsens during treatment when the measurable tumor has met criteria for 
response or stable disease is mandatory to differentiate between response or stable 
disease (an effusion may be a side effect of the treatment) and progressive 
disease. 
 
11.1.3.1 
Evaluation of Target Lesions 
 
 Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to 
<10 mm. 
 
 Partial Response (PR):  At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum diameters. 
 
 Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as 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 
progressions). 
 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects 
by potentiating endogenous cancer-specific immune responses. The response 
patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an 
initial increase in tumor burden or even the appearance of new lesions.  
 
Patients with initial PD will be allowed to stay on trial with a repeat scan in 4 
weeks. If repeat imaging confirms PD, patients will be discontinued from study 
therapy. 
 
 Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while 
on study. 
 


 
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44 
 
11.1.3.2 
Evaluation of Non-Target Lesions 
 
 Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological 
in size (<10 mm short axis). 
 
 Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
 Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
 Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of 
overall disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
11.1.3.3 
Evaluation of New Lesions 
 
The finding of a new lesion should be unequivocal (i.e. not due to difference in 
scanning technique, imaging modality, or findings thought to represent something 
other than tumor (for example, some ‘new’ bone lesions may be simply healing or 
flare of pre-existing lesions). However, a lesion identified on a follow-up scan in an 
anatomical location that was not scanned at baseline is considered new and will 
indicate PD. If a new lesion is equivocal (because of small size etc.), follow-up 
evaluation will clarify if it truly represents new disease and if PD is confirmed, 
progression should be declared using the date of the initial scan on which the lesion 
was discovered. 
 
11.1.3.4 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best 
response assignment will depend on the achievement of both measurement and 
confirmation criteria. 
 
For Participants with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
45 
 
CR 
CR 
No 
CR 
>4 wks Confirmation** 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/Non-
PD/not 
evaluated 
No 
SD 
Documented at least once >4 
wks from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**        Only for non-randomized trials with response as primary endpoint. 
***      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
 
Note:  Participants with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Participants with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
 
11.1.4 Duration of Response 
 
 Duration of overall response:  The duration of overall response is measured from 
the time measurement criteria are met for CR or PR (whichever is first recorded) 
until the first date that recurrent or progressive disease is objectively documented 
(taking as reference for progressive disease the smallest measurements recorded 
since the treatment started, or death due to any cause. Participants without events 
reported are censored at the last disease evaluation). 
 


 
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46 
 
 Duration of overall complete response: The duration of overall CR is measured 
from the time measurement criteria are first met for CR until the first date that 
progressive disease is objectively documented, or death due to any cause. 
Participants without events reported are censored at the last disease evaluation.
 
 
 Duration of stable disease:  Stable disease is measured from the start of the 
treatment until the criteria for progression are met, taking as reference the 
smallest measurements recorded since the treatment started, including the baseline 
measurements.  
 
11.1.5 Progression-Free Survival, Overall Survival and Time to Progression: 
 
 Overall Survival: Overall Survival (OS) is defined as the time from randomization 
(or registration) to death due to any cause, or censored at date last known alive. 
 
 Progression-Free Survival: Progression-Free Survival (PFS) is defined as the time 
from randomization (or registration) to the earlier of progression or death due to 
any cause. Participants alive without disease progression are censored at date of 
last disease evaluation. 
 
 Time to Progression: Time to Progression (TTP) is defined as the time from 
randomization (or registration) to progression, or censored at date of last disease 
evaluation for those without progression reported. 
 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
 
12.1 Data Reporting 
 
12.1.1 Method 
The ODQ will collect, manage, and perform quality checks on the data for this study. 
 
12.1.2 Responsibility for Data Submission 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or data 
forms to ODQ according to the schedule set by the ODQ. 
 
 
12.2 Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of clinical specialists with 
experience in oncology and who have no direct relationship with the study. Information that 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
47 
 
raises any questions about participant safety will be addressed with the Overall PI and study 
team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; DLT information; all grade 2 or higher 
unexpected adverse events that have been reported; summary of all deaths occurring with 30 
days of intervention for Phase I or II protocols; for gene therapy protocols, summary of all deaths 
while being treated and during active follow-up; any response information; audit results, and a 
summary provided by the study team. Other information (e.g. scans, laboratory values) will be 
provided upon request.  
 
12.3 Multicenter Guidelines 
 
This protocol will adhere to the policies and requirements of the DF/HCC Multi-Center Data and 
Safety Monitoring Plan.  The specific responsibilities of the Overall PI, Coordinating Center, and 
Participating Institutions and the procedures for auditing are presented in Appendix D. 
 The Overall PI/Coordinating Center is responsible for distributing all IND Action 
Letters or Safety Reports to all participating institutions for submission to their 
individual IRBs for action as required. 
 
 Mechanisms will be in place to ensure quality assurance, protocol compliance, 
and adverse event reporting at each site. 
 
 Except in very unusual circumstances, each participating institution will order the 
study agent(s) directly from supplier.  A participating site may order the agent(s) 
only after the initial IRB approval for the site has been forwarded to the 
Coordinating Center. 
 
 
13. STATISTICAL CONSIDERATIONS 
 
This is a non-randomized single-arm phase II study designed to evaluate the safety and efficacy 
of pegylated liposomal doxorubicin (PLD) and pembrolizumab for the treatment of platinum 
resistant recurrent ovarian, fallopian tube or peritoneal cancer. A six patient safety lead will be 
performed of these 2 drugs given in combination at their recommended phase II doses, 
respectively.  If 2 out of the first 6 patients develop a DLT, the dose of PLD will be reduced to 
30 mg/m2. If no more than 1 patient of the first 6 patients has evidence of dose limiting 
toxicities, the dose level will be considered the maximum tolerated dose (MTD), an additional 20 
patients will be enrolled to complete the phase II study. 
 
13.1 
Study Design/Endpoints 
  
Primary safety endpoint: 


 
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Protocol Version Date: August 29, 2018 
 
48 
 
• 
Dose limiting toxicity that occur during the first 4 weeks of treatment, as defined in Section 
5.4 
 
For the safety run-in using cohorts of 6 patients at any dose level, the following table gives the 
probability of continuing to the phase II portion of the study under varying true rates of dose-
limiting toxicity. 
 
 
Acceptable dosage using 6 subjects 
True DLT rate 
 0.1         0.2          0.3         0.4          0.5        0.6        0.7  
Probability  
 89%       66%       42%       23%       11%       4%        1% 
 
Primary efficacy endpoint: 
• 
Clinical benefit rate (CR + PR + SD ≥ 24 weeks) 
 
Secondary endpoints include: 
 Toxicity by CTCAE version 4.0 
 Objective response by RECIST 1.1.  
 Progression-free survival 
 Overall survival 
 Time to progression 
 Duration of response  
 
Patients who withdraw study consent before receiving any study treatment will be replaced. 
Patients who are receive study treatment, but who go off-treatment or off-study in cycle 1 and 
are not evaluable for DLT will be replaced for the safety run-in, but will be considered as non-
responders in the final efficacy analysis.         
 
13.2 
Sample Size, Accrual Rate and Study Duration 
 
Because of the possibility that both objective response and prolongment of progression –free 
intervals are enhanced when chemotherapy and immune checkpoint blockade inhibitors are 
combined, the primary endpoint of this study is clinical benefit rate, using an interval of at least 
24 weeks of stable disease.  Pujade-Lauraine et al reported a 12% objective response rate in 
control arm to the AURELIA of single-agent chemotherapy for platinum-resistant ovarian 
cancer; the probability of being progression-free at 6 months was approximately 20%.   
 
Therefore, a true clinical benefit rate of 25% or less would not be of clinical interest, and is the 
null hypothesis to a binomial test for a single-stage A’Hern design.   A true clinical benefit rate 
of 50% would be considered a clinically meaningful level of response. Sample size was chosen 
to have high power (≥90%) to declare the combination effective at this rate, while controlling the 
one-sided Type I error at no more than 10% under the null (exact alpha = 0.091) 
 


 
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Protocol Version Date: August 29, 2018 
 
49 
 
13.3 
Interim Monitoring Plan 
 
During the safety run-in, the first 6 patients within a dosing cohort need to complete at least one 
cycle of treatment, and safety data will be reviewed before enrolling additional patients. 
 
13.4 
Analysis of Primary Endpoints 
 
Under the exact binomial test, if clinical benefit is seen at least 10 of 26 patients (38%), the null 
hypothesis will be rejected and the regimen will be considered worthy of further study.  The 
observed clinical benefit rate will be reported with a two-sided 90% exact confidence interval. 
 
13.5 
Analysis of Secondary Endpoints 
 
Treatment-related toxicities will be summarized by maximum grade and by term using CTCAE 
v4.0 in all patients treated at the MTD.  
 
Best overall response will be evaluated using RECIST 1.1 and objective response requiring 
confirmation will be reported in all patients who receive at least one dose of treatment at the 
MTD.    
 
PFS, OS, TTP and duration of response as defined in section 11.1.5 and 11.1.4, will be described 
using the method of Kaplan-Meier, and summarized as median PFS, OS, TTP and duration of 
response as well as estimates of PFS and OS at landmark time points.  
 
All secondary endpoints will be reported with 95% confidence intervals. 
 
14. PUBLICATION PLAN 
 
The results will be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  


 
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Protocol Version Date: August 29, 2018 
 
50 
 
 
REFERENCES 
1)  Siegel R, Ma J, Zou Z, Jemal A.  Cancer Statistics 2014.  CA Cancer J Clin. 2014;64:9-29.  
 
2) Jemal A, Bray F, Center MM,Ferlay J, Ward E, Forman D. Global cancer statistics. CA 
Cancer J Clin 2011;61:69–90. 
 
3)  Buys SS, Partridge E, Black A, Johnson CC, Lamerato L, Issacs C, et al.  Effect of screening 
on ovarian cancer mortality: the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer 
Screening Randomized Controlled trial. JAMA 2011;305:2295–303. 
 
4)  McGuire WP, Hoskins WJ, Brady MF et al.  Cyclophosphamide and cisplatin compared with 
paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer.  New Engl Journal 
of Medicine 1996;334:1-6. 
  
5)   Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, et al. Intraperitoneal 
cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34–43. 
 
6)  Katsumata N, Yasuda M, Isonishi S, Takahashi F, Michimae H, Kimura E, et al. Long-term 
results of dose-dense paclitaxel and carboplatin versus conventional paclitaxel and carboplatin 
for treatment of advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer 
(JGOG 3016): a randomised, controlled, open-label trial. Lancet Oncol 2013;14:1020–6. 
 
7)  Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant 
chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 
2010;363:943–53. 
 
8)  Bookman MA, Gilks CB, Kohn EC, Kaplan KO, Huntsman D, Aghajanian C, et al. Better 
therapeutic trials in ovarian cancer. J Natl Cancer Inst 2014;106;dju029. 
 
 9) Burger RA, Brady MF, Bookman MA, Fleming GF, Monk BJ, Huang H, et al. Incorporation 
of bevacizumab in the primary treatment of ovarian cancer. N Engl J Med 2011;365:2473–83. 
 
10)  Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG et al.    OCEANS:  A 
randomized, double-blind, placebo-controlled phase III study of chemotherapy with or without 
bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or 
fallopian tube cancer.   Journal of Clinical Oncology 2012;30:2039-2045. 
 
11)  Pujade-Lauraine E, Hilpert F, Weber B, Reuss A, Poveda A, Kristensen G, et al. 
Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the 
AURELIA open-label randomized phase III trial. J Clin Oncol 2014;32:1302–8. 
 
12)  Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME and Lacave AJ.  Recurrent 
epithelial ovarian carcinoma:  a randomized phase III trial of pegylated liposomal doxorubicin 
versus topotecan.  JCO 2001;19:3312-3322. 
 


 
DF/HCC Protocol #: 16-257 
 
Protocol Version Date: August 29, 2018 
 
51 
 
13)  Colombo N, Kutarska E, Dimopoulos M, Bae D-S, Rzepka-Gorska I et al.  Randomized, 
open label, phase III study comparing patupilone (EPO906) with pegylated liposomal 
doxorubicin in platinum refractory or resistant patients with recurrent epithelial ovarian, 
fallopian tube or peritoneal cancer.  JCO 2012;30:3841-3847 
 
14)  Genentech press release for the Aurelia study, November 14, 2014.  
http://www.gene.com/media/press-releases/14578/2014-11-14/fda-approves-genentechs-avastin-
bevacizu 
 
15)  www.nccn.org (ovarian cancer treatment guidelines)   
16)  Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, et al.  Programmed cell death 1 
ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian 
cancer.  Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3360-5.  
17)   Abiko K, Mandai M, Hamanishi J, Yoshioka Y, Matsumura N, et al.  PD-L1 on tumor cells 
is induced in ascites and promotes peritoneal dissemination of ovarian cancer through CTL 
dysfunction  Clin Cancer Res. 2013 Mar 15;19(6):1363-74.  
18)   Dalgleish AG. Rationale for combining chemotherapy with immunotherapy.  
Immunotherapy. 2015;7(3):309-16. 
 
19)  Apetoh L, Ladoire S, Coukos G, Ghiringhelli F. Combining immunotherapy and anti-cancer 
agents:  the right path to achieve cancer cure?  Ann Oncol. 2015 Apr 28. pii: mdv209. [Epub 
ahead of print]  
 
20)  Drake CG.  Combination immunotherapy approaches.  Annals of Oncology 23 (Supplement 
8): viii41–viii46, 2012.   
 
 
 
 
 
 
 
 
 


 
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Protocol Version Date: August 29, 2018 
 
52 
 
APPENDIX A: 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work.
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 


 
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53 
 
 
APPENDIX B:  EVENTS OF CLINICAL INTEREST GUIDANCE DOCUMENT 
 
  
 
 
 
 
 
 
 
 
PEMBROLIZUMAB PROGRAM 
(MK-3475) 
  
 
 
 
 
 
 
EVENT OF CLINICAL INTEREST 
GUIDANCE DOCUMENT 
  
 
Version 5.0


Final 18-Dec-2014 
Version 5.0 
5
 
Pembrolizumab Event of Clinical Interest Guidance Document 
 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
 
 
 
 
1. OVERVIEW ............................................................................................................................... 6 
2. ECI REPORTING GUIDELINES .............................................................................................. 8 
3. ECI CATEGORIES AND TERMS ............................................................................................ 8 
3.1 Pneumonitis .......................................................................................................................... 9 
3.2 Colitis .................................................................................................................................. 10 
3.3 Endocrine ............................................................................................................................ 12 
3.4 Hematologic ........................................................................................................................ 15 
3.5 Hepatic ................................................................................................................................ 16 
3.6 Neurologic........................................................................................................................... 18 
3.7 Ocular.................................................................................................................................. 19 
3.8 Renal ................................................................................................................................... 20 
3.9 Skin ..................................................................................................................................... 21 
3.9.1. Immediate Evaluation for Potential Skin ECIs ........................................................... 22 
3.10 Other ................................................................................................................................. 23 
3.11 Infusion Reactions ............................................................................................................ 24 
3.12 Follow-up to Resolution ................................................................................................... 26 
4. REFERENCES ......................................................................................................................... 27 
APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table ...................................... 28 
APPENDIX 2 – Past Medical History Related to Dermatologic Event ................................... 29 
APPENDIX 3 – Presentation of the Dermatologic Event ........................................................ 30 
APPENDIX 4 – Focused Skin Examination............................................................................. 32


Pembrolizumab Event of Clinical Interest Guidance Document
Final 18-Dec-2014 
Version 5.0 
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1. OVERVIEW 
  
The purpose of this document is to provide study sites with guidance on the identification and management of 
Events of Clinical Interest for the MK-3475 (also known as pembrolizumab) program. 
 
Based on the literature review [1-11], and consideration of mechanism of action of pembrolizumab, potential 
immune-related adverse events (irAEs) are the primary Event of Clinical Interest (ECI). Immune-related AEs 
are adverse events associated with the treatment of patients with immunotherapy treatments that appear to be 
associated with the immune therapy’s mechanism of action. Based on these potential irAEs, the sponsor has 
defined a list of specific adverse event terms (ECIs) that are selected adverse experiences that must be 
reported to Merck within 24 hours to Merck Global Safety (Attn: Worldwide Product Safety; FAX 
215 993-1220)from the time the Investigator/physician is aware of such an occurrence, regardless of whether 
or not the investigator/physician considers the event to be related to study drug(s). In addition, these ECIs 
require additional detailed information to be collected and entered in the study database. ECIs may be 
identified through spontaneous patient report and / or upon review of subject data. Table 1 provides the list of 
terms and reporting requirements for AEs that must be reported as ECIs for MK-3475 protocols.  Of note, the 
requirement for reporting of ECIs applies to all arms, including comparators, of MK- 
3475 clinical trials 
 
Given that our current list of events of clinical interest is not comprehensive for all potential immune-related 
events, it is possible that AEs other than those listed in this document may be observed in patients receiving 
pembrolizumab. Therefore any  Grade  3  or  higher  event  that  the  investigator/physician considers  to  be 
immune-related should be reported as an ECI regardless of whether the specific event term is in Table 1 and 
reported to Merck within 24 hours to Merck Global Safety (Attn: Worldwide Product Safety; FAX 215 
993-1220) from the time the Investigator/physician is aware of such an occurrence. Adverse events that are 
both an SAE and an ECI should be reported one time as an SAE only, however the event must be 
appropriately identified as an ECI as well in in the database.


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Pneumonitis (reported as ECI if  ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the
AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if  ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 
 
Table 1: Events of Clinical Interest


Pembrolizumab Event of Clinical Interest Guidance Document
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Each of the events above is described within this guidance document, along with site requirements for 
reporting these events to the Sponsor.  The information collected should be entered into the narrative field(s) 
of the Adverse Event module in the database (please note, if narrative entry into the database is not available, 
please use the narrative text box on the 1727/AER Form).   If additional Medical History or Concomitant 
Medications are reported, the Medical History and Concomitant Medication modules in the database must be 
updated. 
 
In addition, the guidelines include recommendations on the management of these ECIs. These guidelines are 
intended to be applied when the physician determines the events to be related to pembrolizumab. Note: if after 
the evaluation the event is determined not to be related, the physician is instructed to follow the ECI reporting 
guidance but does not need to follow the treatment guidance (below). Therefore, these recommendations 
should be seen as guidelines and the treating physician should exercise individual clinical judgment based on 
the patient.  For any question of dose modification or other treatment options, the specific language in the 
protocol should be followed.  Any questions pertaining to the collection of this information or management of 
ECIs should be directed to your local Sponsor contact. 
 
Dose Modification/Discontinuation 
 
The treatment guidance provides specific direction when to hold and/or discontinue pembrolizumab for each 
immune related adverse event.  Of note, when the guidance states to “discontinue” pembrolizumab this is the 
permanent discontinuation of treatment with pembrolizumab. “Hold” means to stop treating with 
pembrolizumab but resumption of treatment may be considered assuming the patient meets the criteria for 
resumption of treatment. 
 
 
2. ECI REPORTING GUIDELINES 
ECIs are selected non-serious and serious adverse experiences that must be reported to Merck  within 24 hours 
regardless of attribution to study treatment.  The AEs listed in this document and any event that meets the ECI 
criteria (as noted) in Table 1 or in the respective protocol (event term and Grade) must be reported regardless 
of physician-determined causality with study medication and whether or not considered immune-related by the 
physician (unless otherwise specified).   Physicians/study coordinators/designated site personnel are required 
to record these experiences as ECIs on the Adverse Experience electronic Case Report Forms (eCRFs) (or on 
paper) and to provide supplemental information (such as medical history, concomitant medications, 
investigations, etc.) about the event. 
 
–    Please refer to the Data Entry Guidelines (DEGs) for your protocol (Section 12.1). 
–    Please refer to protocol for details on reporting timelines and reporting of Overdose and Drug Induced 
Liver Injury (DILI) (Section 7.0). 
 
3. ECI CATEGORIES AND TERMS 
This section describes the ECI  categories and  outlines subject management guidelines when an  ECI  is 
reported.


Pembrolizumab Event of Clinical Interest Guidance Document
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3.1 Pneumonitis 
  
The following AE terms, if considered ≥ Grade 2, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
–    Pneumonitis 
–    Interstitial lung disease 
–    Acute interstitial pneumonitis 
 
If symptoms indicate possible new or worsening cardiac abnormalities additional testing and/or a cardiology 
consultation should be considered. 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or viral infection.  It 
is important that patients with a suspected diagnosis of pneumonitis be managed as per the guidance 
below until treatment-related pneumonitis is excluded. Treatment of both a potential infectious etiology 
and pneumonitis in parallel may be warranted. Management of the treatment of suspected pneumonitis 
with steroid treatment should not be delayed for a therapeutic trial of antibiotics.   If an alternative 
diagnosis is established, the patient does not require management as below; however the AE should be 
reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
–    Report as ECI 
–    Hold pembrolizumab. 
–    Consider pulmonary consultation with bronchoscopy and biopsy/BAL. 
–    Consider ID consult 
–    Conduct an in person evaluation approximately twice per week 
–    Consider frequent Chest X-ray as part of monitoring 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg/day prednisone or equivalent.  When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
– Second episode of pneumonitis – discontinue pembrolizumab if upon re-challenge the patient develops 
a second episode of Grade 2 or higher pneumonitis. 
 
Grade 3 and 4 events: 
–    Report as ECI 
–    Discontinue pembrolizumab. 
–    Hospitalize patient 
–    Bronchoscopy with biopsy and/or BAL is recommended. 
– Immediately  treat  with  intravenous  steroids  (methylprednisolone 125  mg  IV).  When  symptoms 
improve to Grade 1 or less, a high dose oral steroid (prednisone 1 to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 hours) taper should be started and continued over no less than 4 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 
hours, treat with additional anti-inflammatory measures. Discontinue additional anti-inflammatory 
measures upon symptom relief and initiate a prolonged steroid taper over 45 to 60 days. If symptoms 
worsen during steroid reduction, initiate a retapering of steroids starting at a higher dose of 80 or 100 
mg followed by a more prolonged taper and administer additional anti-inflammatory measures, as 
needed 
–    Add prophylactic antibiotics for opportunistic infections.


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Pembrolizumab Event of Clinical Interest Guidance Document
 
 
 
3.2 Colitis 
  
The following AE terms, if considered ≥ Grade 2 or resulting in dose modification or use of systemic steroids 
to treat the AE, are considered ECIs and should be reported to the Sponsor within 24 hours of the event: 
 
–    Colitis 
–    Colitis microscopic 
–    Enterocolitis 
–    Enterocolitis hemorrhagic 
–    Gastrointestinal perforation 
–    Intestinal obstruction 
–    Necrotizing colitis 
–    Diarrhea 
 
All attempts should be made to rule out other causes such as metastatic disease, bacterial or parasitic infection, 
viral gastroenteritis, or the first manifestation of an inflammatory bowel disease by examination for stool 
leukocytes, stool cultures, a Clostridium difficile titer and endoscopy.   However the AE should be reported 
regardless of etiology. 
 
Course of Action 
 
Grade 2 Diarrhea/Colitis (4-6 stools/day over baseline, dehydration requiring IV fluids < 24 hours, abdominal 
pain, mucus or blood in stool): 
–    Report as ECI 
–    Hold pembrolizumab. 
–    Symptomatic Treatment 
–    For Grade 2 diarrhea that persists for greater than 3 days, and for diarrhea with blood and/or mucus, 
o Consider GI consultation and endoscopy to confirm or rule out colitis 
o Administer oral corticosteroids (prednisone 1-2 mg/kg QD or equivalent) 
–    When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
–    If symptoms worsen or persist > 3 days treat as Grade 3 
 
Grade 3 Diarrhea/Colitis (or Grade 2 diarrhea that persists for > 1 week): 
–    Report as ECI 
–    Hold pembrolizumab. 
–    Rule out bowel perforation. Imaging with plain films or CT can be useful. 
–    Recommend consultation with Gastroenterologist and confirmation biopsy with endoscopy. 
– Treat with intravenous steroids (methylprednisolone 125 mg) followed by high dose oral steroids 
(prednisone 1 to 2 mg/kg once per day or dexamethasone 4 mg every 4 hours)   When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Taper over 6 to 8 weeks in patients with diffuse and severe ulceration and/or bleeding. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
– If IV steroids followed by high dose oral steroids does not reduce initial symptoms within 48 to 72 
hours, consider treatment with additional anti-inflammatory measures as described in the literature [5]. 
Discontinue additional anti-inflammatory measures upon symptom relief and initiate a prolonged 
steroid taper over 45 to 60 days. If symptoms worsen during steroid reduction, initiate a retapering of 
steroids starting at a higher dose of 80 or 100 mg followed by a more prolonged taper and administer 
additional anti-inflammatory measures as needed.


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Grade 4 events: 
–    Report as ECI 
–    Permanently discontinue pembrolizumab. 
–    Manage as per Grade 3.


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3.3 Endocrine 
  
The following AE terms, if considered ≥Grade 3 or if ≥Grade 2 and require holding/discontinuation/ 
modification of pembrolizumab dosing, are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
 
–    Adrenal insufficiency 
–    Hyperthyroidism 
–    Hypophysitis 
–    Hypopituitarism 
–    Hypothyroidism 
–    Thyroid disorder 
–    Thyroiditis 
 
All attempts should be made to rule out other causes such as brain metastases, sepsis and/or infection. 
However the AE should be reported regardless of etiology. 
 
Hypophysitis or other symptomatic endocrinopathy other than hypo- or hyperthyroidism 
 
Grade 2-3 events: 
–    Report as ECI if appropriate 
–    Hold pembrolizumab 
–    Rule out infection and sepsis with appropriate cultures and imaging. 
– Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until 
returned to baseline values. 
– Pituitary gland  imaging should be  considered (MRIs with  gadolinium and  selective cuts  of  the 
pituitary can show enlargement or heterogeneity and confirm the diagnosis). 
– Treat with prednisone 40 mg p.o. or equivalent per day.  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. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
– Hypophysitis  with  clinically  significant  adrenal  insufficiency  and  hypotension, dehydration, and 
electrolyte abnormalities (such as hyponatremia and hyperkalemia) constitutes adrenal crisis. 
–    Consultation with an endocrinologist may be considered.


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Hyperthyroidism and 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. 
 
Grade 2 hyperthyroidism, Grade 2-4 hypothyroidism events: 
–    Report as ECI if appropriate (see Table 1) 
– Monitor thyroid function or other hormonal level tests and serum chemistries more frequently until 
returned to baseline values. 
–    Thyroid hormone and/or steroid replacement therapy to manage adrenal insufficiency. 
–    Therapy with pembrolizumab can be continued while treatment for the thyroid disorder is instituted. 
–    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. 
–    Consultation with an endocrinologist may be considered. 
 
Grade 3 hyperthyroidism events: 
–    Report as ECI 
–    Hold pembrolizumab. 
–    Rule out infection and sepsis with appropriate cultures and imaging. 
– Treat with an initial dose of methylprednisolone 1 to 2 mg/kg intravenously followed by oral 
prednisone 1 to 2 mg/kg per day. 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. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 hyperthyroidism events: 
–    Report as ECI 
–    Discontinue pembrolizumab. 
–    Manage as per Grade 3


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Type 1 diabetes mellitus (if new onset) and ≥ Grade 3 Hyperglycemia 
 
The following AE terms are considered ECIs and should be reported to the Sponsor within 24 hours of the 
event: 
 
–    Type I diabetes mellitus (T1DM), if new onset, including diabetic ketoacidosis (DKA) 
–    Grade 3 or higher hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA). 
 
Immune-mediated diabetes may present as new onset of Type 1 diabetes or an abrupt worsening of pre- 
existing diabetes associated with laboratorial evidence of beta cell failure. All attempts should be made to rule 
out other causes such as type 2 diabetes mellitus (T2DM), T2DM decompensation, steroid-induced diabetes, 
physiologic stress-induced diabetes, or poorly controlled pre-existing diabetes (either T1DM or T2DM), but 
events meeting the above criteria should be reported as ECIs regardless of etiology. The patients may present 
with hyperglycemia (abrupt onset or abrupt decompensation) with clinical evidence of diabetic ketoacidosis or 
laboratory evidence of insulin deficiency, such as ketonuria, laboratory evidence of metabolic acidosis, or low 
or undetected c-peptide. 
  
 
Course of Action 
 
T1DM should be immediately treated with insulin. 
 
T1DM or Grade 3-4 Hyperglycemia events: 
-     Report as ECI if appropriate (see Table 1) 
- 
Hold pembrolizumab for new onset Type 1 diabetes mellitus or Grade 3-4 hyperglycemia associated 
with  evidence of  beta  cell  failure, and  resume  pembrolizumab when  patients are  clinically and 
metabolically stable. 
- 
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. 
-     Consultation with an Endocrinologist is recommended. 
- 
Consider local testing for islet cell antibodies and antibodies to GAD, IA-2, ZnT8, and insulin may be 
obtained.


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3.4 Hematologic 
  
The following AE term, if considered Grade ≥3 or requiring dose modification or use of systemic steroids to 
treat the AE, are considered an ECI and should be reported to the Sponsor within 24 hours of the event: 
 
–    Autoimmune hemolytic anemia 
–    Aplastic anemia 
–    Disseminated Intravascular Coagulation (DIC) 
–    Haemolytic Uraemic Syndrome (HUS) 
–    Idiopathic (or immune) Thrombocytopenia Purpura (ITP) 
–    Thrombotic Thrombocytopenic Purpura (TTP) 
–    Any Grade 4 anemia regardless of underlying mechanism 
 
All attempts should be made to rule out other causes such as metastases, sepsis and/or infection.    Relevant 
diagnostic studies such as peripheral blood smear, reticulocyte count, LDH, haptoglobin, bone marrow biopsy 
or Coomb’s test, etc., should be considered to confirm the diagnosis. However the AE should be reported 
regardless of etiology. 
  
 
Course of Action 
 
Grade 2 events: 
–    Report as ECI 
–    Hold pembrolizumab 
–    Prednisone 1-2 mg/kg daily may be indicated 
–    Consider Hematology consultation. 
Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 3 events: 
–    Report as ECI 
–    Hematology consultation. 
–    Hold pembrolizumab  Discontinuation should be considered as per specific protocol guidance. 
–    Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 events: 
–    Report as ECI 
–    Hematology consultation 
– Discontinue pembrolizumab for all solid tumor indications; refer to protocol for hematologic 
malignancies. 
–    Treat with methylprednisolone 125 mg iv or prednisone 1-2 mg/kg p.o. (or equivalent) as appropriate


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3.5 Hepatic 
  
The following AE terms, if considered ≥ Grade 2 or greater (or any grade with dose modification or use of 
systemic steroids to treat the AE), are considered ECIs and should be reported to the Sponsor within 24 hours 
of the event: 
 
–    Autoimmune hepatitis 
–    Hepatitis 
–    Transaminase elevations 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other hepatic 
diseases. However the AE should be reported regardless of etiology. 
 
Drug Induced Liver Injury (DILI) 
 
In addition, the event must be reported as a Drug Induced Liver Injury (DILI) ECI, if the patient meets the 
laboratory criteria for potential DILI defined as: 
 
An elevated alanine transaminase (ALT) or aspartate transaminase (AST) lab value that is greater than 
or equal to three times (3X) the upper limit of normal (ULN) and 
    An elevated total bilirubin lab value that is greater than or equal to two times (2X) ULN and 
    At the same time, an alkaline phosphatase (ALP) lab value that is less than 2X ULN, 
    As a result of within-protocol-specific testing or unscheduled testing. 
 
Note that any hepatic immune ECI meeting DILI criteria should only be reported once as a DILI event. 
 
Course of Action 
 
Grade 2 events: 
–    Report as ECI 
–    Hold pembrolizumab when AST or ALT >3.0 to 5.0 times ULN and/or total bilirubin >1.5 to 3.0 times 
ULN. 
–    Monitor liver function tests more frequently until returned to baseline values (consider weekly). 
o Treat with 0.5-1 mg/kg/day methylprednisolone or oral equivalent and when LFT returns to 
grade 1 or baseline, taper steroids over at least 1 month, consider prophylactic antibiotics for 
opportunistic infections, and resume pembrolizumab per protocol 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
–    Permanently discontinue pembrolizumab for patients with liver metastasis who begin treatment with 
Grade 2 elevation of AST or ALT, and AST or ALT increases ≥50% relative to baseline and lasts ≥1 
week. 
 
Grade 3 events: 
–    Report as ECI 
–    Discontinue pembrolizumab when AST or ALT >5.0 times ULN and/or total bilirubin >3.0 times 
ULN. 
–    Consider appropriate consultation and liver biopsy to establish etiology of hepatic injury, if necessary 
– Treat with high-dose intravenous glucocorticosteroids for 24 to 48 hours. When symptoms improve to 
Grade 1 or less, a steroid taper with dexamethasone 4 mg every 4 hours or prednisone at 1 to 2 mg/kg 
should be started and continued over no less than 4 weeks. 
– If serum transaminase levels do not decrease 48 hours after initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg every 12 hours may be given. Infliximab is not recommended due to 
its 
potential 
for 
hepatotoxicity.


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– Several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose 
is decreased. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 events: 
–    Report as ECI 
–    Permanently discontinue pembrolizumab 
–    Manage patient as per Grade 3 above


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3.6 Neurologic 
  
The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
 
–    Autoimmune neuropathy 
–    Demyelinating polyneuropathy 
–    Guillain-Barre syndrome 
–    Myasthenic syndrome 
 
All attempts should be made to rule out other causes such as metastatic disease, other medications or infectious 
causes. However the AE should be reported regardless of etiology. 
  
 
Course of Action 
 
Grade 2 events: 
–    Report as ECI 
–    Moderate (Grade 2) – consider withholding pembrolizumab. 
–    Consider treatment with prednisone 1-2 mg/kg p.o. daily as appropriate 
–    Consider Neurology consultation. Consider biopsy for confirmation of diagnosis. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 3 and 4 events: 
–    Report as ECI 
–    Discontinue pembrolizumab 
–    Obtain neurology consultation. Consider biopsy for confirmation of diagnosis 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. If 
condition worsens consider IVIG or other immunosuppressive therapies as per local guidelines 
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.


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3.7 Ocular 
  
The following AE terms, if considered Grade ≥2 or requiring dose modification or use of systemic steroids to 
treat the AE, is considered an ECI and should be reported to the Sponsor within 24 hours of the event: 
 
–    Uveitis 
–    Iritis 
 
All attempts should be made to rule out other causes such as metastatic disease, infection or other ocular 
disease (e.g. glaucoma or cataracts). However the AE should be reported regardless of etiology. 
  
 
Course of Action 
 
Grade 2 events: 
–    Evaluation by an ophthalmologist is strongly recommended. 
–    Treat with topical steroids such as 1% prednisolone acetate suspension and iridocyclitics. 
– Discontinue  pembrolizumab  as  per  protocol  if  symptoms  persist  despite  treatment  with  topical 
immunosuppressive therapy. 
 
Grade 3 events: 
–    Evaluation by an ophthalmologist is strongly recommended 
–    Hold pembrolizumab and consider permanent discontinuation as per specific protocol guidance. 
– Treat with systemic corticosteroids such as prednisone at a dose of 1 to 2 mg/kg per day.   When 
symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
  
 
Grade 4 events: 
–    Evaluation by an ophthalmologist is strongly recommended 
–    Permanently discontinue pembrolizumab. 
–    Treat with corticosteroids as per Grade 3 above


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3.8 Renal 
  
The following AEs if ≥ Grade 2 are considered ECIs and should be reported to the Sponsor within 24 hours of 
the event: 
 
–    Nephritis 
–    Nephritis autoimmune 
–    Renal failure 
–    Renal failure acute 
 
Creatinine elevations ≥ Grade 3 or any grade with dose modification or use of systemic steroids to treat the 
AE. 
  
 
All attempts should be made to rule out other causes such as obstructive uropathy, progression of disease, or 
injury due to other chemotherapy agents.  A renal consultation is recommended. However the AE should be 
reported regardless of etiology. 
  
 
Course of Action 
  
 
Grade 2 events: 
–    Hold pembrolizumab 
–    Treatment with prednisone 1-2 mg/kg p.o. daily. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 3-4 events: 
–    Discontinue pembrolizumab 
–    Renal consultation with consideration of ultrasound and/or biopsy as appropriate 
– Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone IV or equivalent once per 
day. 
  
 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less than 4 
weeks.


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3.9 Skin 
  
Rash and Pruritus 
 
The following AEs should be considered as ECIs, if ≥ Grade 3 and should be reported to the Sponsor within 
24 hours of the event: 
 
–    Pruritus 
–    Rash 
–    Rash generalized 
–    Rash maculo-papular 
– In addition to CTCAE Grade 3 rash, any rash that is considered clinically significant, in the physician's 
judgment, should be treated as an ECI. Clinical significance is left to the physician to determine, and 
could possibly include rashes such as the following: 
o rash with a duration >2 weeks; OR 
o rash that is >10% body surface area; OR 
o rash that causes significant discomfort not relieved by topical medication or temporary cessation 
of study drug. 
 
Other Skin ECIs 
 
The following AEs should always be reported as ECIs, regardless of grade, and should be reported to the 
Sponsor within 24 hours of the event: 
 
–    Dermatitis exfoliative 
–    Erythema multiforme 
–    Steven’s Johnson syndrome 
–    Toxic epidermal necrolysis 
 
Please note, the AE should be reported regardless of etiology. 
 
Course of Action 
 
Grade 2 events: 
–    Symptomatic treatment should be given such as topical glucocorticosteroids (e.g., betamethasone 
0.1% cream or hydrocortisone 1%) or urea-containing creams in combination with oral anti-pruritics 
(e.g., diphenhydramine HCl or hydroxyzine HCl). 
–    Treatment with oral steroids is at physician’s discretion for Grade 2 events. 
 
Grade 3 events: 
–    Hold pembrolizumab. 
–    Consider Dermatology Consultation and biopsy for confirmation of diagnosis. 
– Treatment with oral steroids is recommended, starting with 1 mg/kg prednisone or equivalent once per 
day or dexamethasone 4 mg four times orally daily.  When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. 
 
Grade 4 events: 
–    Permanently discontinue pembrolizumab. 
–    Dermatology consultation and consideration of biopsy and clinical dermatology photograph. 
– Initiate steroids at 1 to 2 mg/kg prednisone or equivalent.  When symptoms improve to Grade 1 or 
less, 
steroid 
taper 
should 
be 
started 
and 
continued 
over 
no 
less 
than 
4 
weeks.


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3.9.1. Immediate Evaluation for Potential Skin ECIs 
 
A. Photographs: 
Every attempt should be made to get a photograph of the actual ECI skin lesion or rash as soon as possible. 
Obtain appropriate consent for subject photographs if a consent form addendum is required by your 
IRB/ERC. 
–    Take digital photographs of: 
o the head (to assess mucosal or eye involvement), 
o the trunk and extremities, and 
o a close-up of the skin lesion/rash. 
 
– 
If possible, a ruler should be placed alongside the site of a skin occurrence as a fixed marker of 
distance. 
–    The time/date stamp should be set in the 'ON' position for documentation purposes. 
–    Photographs should be stored with the subject’s study records. 
– 
The Sponsor may request copies of photographs. The local study contact (e.g., CRA) will provide 
guidance to the site, if needed. 
 
B. Past Medical History: 
Collect past medical history relevant to the event, using the questions in Appendix 2 (Past Medical History 
Related to Dermatologic Event) as a guide. Any preexisting conditions not previously reported (e.g., drug 
allergy) should be entered into the Medical History eCRF. 
 
C. Presentation of the Event: 
Collect information on clinical presentation and potential contributing factors using the questions in Appendix 
3 (Presentation of the Dermatologic Event) as a guide. This information should be summarized and entered in 
narrative format in the AE eCRF. Please use the available free-text fields, such as Signs and Symptoms. Note 
pertinent negatives where applicable to reflect that the information was collected. Any treatments administered 
should be entered on the Concomitant Medication eCRF. 
 
D. Vitals Signs and Standard Laboratory Tests: 
Measure vital signs (pulse, sitting BP, oral temperature, and respiratory rate) and record on the Vital Signs 
eCRF.  Perform standard laboratory tests (CBC with manual differential and serum chemistry panel, including 
LFTs). 
 
E. Focused Skin Examination: 
Perform a focused skin examination using the questions in Appendix 4 (Focused Skin Examination) as a 
guide. Information should be summarized and entered on the Adverse Experience eCRF as part of the 
narrative. 
 
F. Dermatology Consult 
Refer the subject to a dermatologist as soon as possible. 
–    For a “severe rash”, the subject must be seen within 1-2 days of reporting the event. 
–    For clinically significant rash, the subject should be seen within 3-5 days. 
 
The  dermatologist  should  submit  a  biopsy  sample  to  a  certified  dermatopathology  laboratory  or  to  a 
pathologist experienced in reviewing skin specimens. 
 
The  site  should  provide  the  dermatologist  with  all  relevant  case  history,  including  copies  of  clinical 
photographs 
and 
laboratory 
test 
results.


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3.10 Other 
  
The following AEs, regardless of grade, are considered ECIs and should be reported to the Sponsor within 24 
hours of the event: 
 
–    Myocarditis 
–    Pericarditis 
–    Pancreatitis 
–    Any additional Grade 3 or higher event which the physician considers to be immune related 
 
All  attempts  should be  made  to  rule  out  other  causes.    Therapeutic specialists should be  consulted as 
appropriate. However the AE should be reported regardless of etiology. 
  
 
Course of Action 
 
Grade 2 events or Grade 1 events that do not improve with symptomatic treatment: 
–    Withhold pembrolizumab. 
–    Systemic corticosteroids may be indicated. 
–    Consider biopsy for confirmation of diagnosis. 
–    If pembrolizumab held and corticosteroid required, manage as per grade 3 below. 
 
Grade 3 events: 
–    Hold pembrolizumab 
–    Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. 
– When symptoms improve to Grade 1 or less, steroid taper should be started and continued over no less 
than 4 weeks. 
– Permanently discontinue for inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks. Otherwise, pembrolizumab treatment may be restarted and the 
dose modified as specified in the protocol 
 
Grade 4 events: 
–    Treat with systemic corticosteroids at a dose of 1 to 2 mg/kg prednisone or equivalent once per day. 
–    Discontinue pembrolizumab


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3.11 Infusion Reactions 
  
The following AE terms, regardless of grade, are considered ECIs and should be reported to the Sponsor 
within 24 hours of the event: 
–    Allergic reaction 
–    Anaphylaxis 
–    Cytokine release syndrome 
–    Serum sickness 
–    Infusion reactions 
–    Infusion-like reactions 
 
Please note, the AE should be reported regardless of etiology. 
  
 
Course of Action 
 
Refer to infusion reaction table in the protocol and below.


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Infusion Reactions 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
None
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator. 
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original infusion 
rate (e.g. from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until 
symptoms resolve and the subject should 
be premedicated for the next scheduled 
dose. 
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration. 
Subject may be premedicated
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
 
Diphenhydramine 50 mg p.o. 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500-1000 mg 
p.o. (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. 
For Further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 


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3.12 Follow-up to Resolution 
  
Subjects should be followed to resolution. The Adverse Experience eCRF should be updated with information 
regarding duration and clinical course of the event. Information obtained from the consulting specialist, 
including diagnosis, should be recorded in the appropriate AE fields. Free-text fields should be used to record 
narrative information: 
 
–    Clinical course of the event 
–    Course of treatment 
–    Evidence supporting recovery 
–    Follow-up to the clinical course 
 
Any treatments administered for the event should also be entered in the Concomitant Medication eCRF.


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4. REFERENCES 
  
1.   Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy.  Nature Reviews Cancer 
2012; 12:252-264. 
 
2.   Weber JS Practical Management of Immune-Related Adverse Events from Immune Checkpoint Protein 
Antibodies for the Oncologist. American Society of Clinical Oncology 2012; 1092-9118/10/1-10. 
 
3.   Weber JS, Ka¨hler KC, and Hauschild A. Management of Immune-Related Adverse Events and Kinetics 
of 
Response           With           Ipilimumab.           J           Clin           Oncol           30.           2012. 
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.41.6750. 
 
4.   Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, et al. Improved Survival with Ipilimumab in 
Patients with Metastatic Melanoma. N Engl J Med 363:711-723, 2010. 
 
5.   Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, Activity, and 
Immune Correlates of Anti-PD-1 Antibody in Cancer. N Engl J Med 2012; 366:2443-2454. 
 
6.   Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, et al. Safety and Activity of Anti–PD-L1 Antibody in 
Patients with Advanced Cancer. N Engl J Med 2012; 366:2455-2465. 
 
7.   Weber J, Thompson JA, Hamid O, et al: A randomized, double-blind, placebo-controlled, phase II study 
comparing the tolerability and efficacy of ipilimumab administered with or without prophylactic 
budesonide in patients with unresectable stage III or IV melanoma. Clin Cancer Res 15:5591-5598, 2009. 
 
8.   Lemech C and Arkenau HT. Novel Treatments for Metastatic Cutaneous Melanoma and the Management 
of Emergent Toxicities. Clinical Medicine Insights: Oncology 2012:6 53–66. 
 
9.   Phan GQ, Weber JS, and Sondak VK.  CTLA-4 Blockade with Monoclonal Antibodies in Patients with 
Metastatic Cancer: Surgical Issues. Annals of Surgical Oncology 15(11):3014–3021. 
 
10. Bristol-Myers Squibb: YERVOY (ipilimumab): Serious and fatal immune-mediated adverse reactions— 
YERVOY Risk Evaluation and Mitigation Strategy (REMS). http://www.yervoy.com/hcp/rems.aspx 
 
11. Bristol-Myers   Squibb:   YERVOY   (ipilimumab)   prescribing   information   revised   March   2011. 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/125377s0000lbl.pdf


Pembrolizumab Event of Clinical Interest Guidance Document
Final 18-Dec-2014 
Version 5.0 
28
 
 
 
 
APPENDIX 1 –Events of Clinical Interest (ECI) – Reference Table 
 
Pneumonitis (reported as ECI if  ≥ Grade 2) 
Acute interstitial pneumonitis 
Interstitial lung disease 
Pneumonitis 
Colitis (reported as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Intestinal Obstruction 
Colitis 
Colitis microscopic 
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotizing colitis 
Diarrhea 
 
Endocrine (reported as ECI if  ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of systemic steroids to treat 
the AE) 
Adrenal Insufficiency 
Hyperthyroidism 
Hypophysitis 
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or metabolic acidosis (DKA) 
Endocrine (reported as ECI) 
Type 1 diabetes mellitus (if new onset) 
 
 
Hematologic (reported as ECI if  ≥ Grade 3 or any grade resulting in dose modification or use of systemic steroids to treat the
AE) 
Autoimmune hemolytic anemia 
Aplastic anemia 
Thrombotic Thrombocytopenic Purpura
(TTP) 
Idiopathic (or immune) Thrombocytopenia 
Purpura  (ITP) 
Disseminated Intravascular Coagulation
(DIC) 
Haemolytic Uraemic Syndrome (HUS) 
Any Grade 4 anemia regardless of underlying mechanism 
Hepatic (reported as ECI if  ≥ Grade 2, or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Hepatitis 
Autoimmune hepatitis 
Transaminase elevations (ALT and/or AST) 
Infusion Reactions (reported as ECI for any grade) 
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic (reported as ECI for any grade) 
Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome 
 
 
Ocular (report as ECI if  ≥ Grade 2 or any grade resulting in dose modification or use of systemic steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal (reported as ECI if  ≥ Grade 2) 
Nephritis 
Nephritis autoimmune 
Renal Failure 
 
Renal failure acute 
Creatinine elevations (report as ECI if ≥Grade 3 or any grade resulting in dose 
modification or use of systemic steroids to treat the AE) 
Skin (reported as ECI for any grade) 
Dermatitis exfoliative 
Erythema multiforme 
Stevens-Johnson syndrome 
Toxic epidermal necrolysis 
 
 
Skin (reported as ECI if ≥ Grade 3) 
Pruritus 
Rash 
Rash generalized 
Rash maculo-papular 
 
 
Any rash considered clinically significant in the physician’s judgment 
Other (reported as ECI for any grade) 
Myocarditis 
Pancreatitis 
Pericarditis 
Any other Grade 3 event which is considered immune-related by the physician 


Pembrolizumab Event of Clinical Interest Guidance Document
Final 18-Dec-2014 
Version 5.0 
29
 
 
 
 
 
APPENDIX 2 – Past Medical History Related to Dermatologic Event 
  
Past Medical History: 
Any preexisting conditions not previously reported (e.g., drug allergy) should be entered into the Medical 
History eCRF. 
 
1. Does the subject have any allergies? □ Yes □ No 
 
If yes, please obtain the following information: 
 
a. Any allergy to drugs (including topical or ophthalmic drugs)? □ Yes □ No 
 
List the drug name(s) and describe the type of allergic response (e.g. rash, anaphylaxis, etc): 
  
 
 
b. Any allergy to external agents, such as laundry detergents, soaps, poison ivy, nickel, etc.? □ Yes □ 
No 
 
Describe the agent and type of allergic response:   
 
 
 
c. Any allergy to food? □ Yes □ No 
 
Describe the food and type of allergic response:   
 
 
 
d. Any allergy to animals, insects? □ Yes □ No 
 
Describe the allergen and type of allergic response:   
 
 
 
e. Any other allergy? □ Yes □ No 
 
Describe the allergen and type of allergic response:   
 
 
 
2. Does the subject have any other history of skin reactions, skin eruptions, or rashes? □ Yes □ No 
 
If so what kind?   
 
 
3. Has the subject ever been treated for a skin condition? □ Yes □ No 
 
If so what kind?   
 
 
4. Is the current finding similar to a past experience? □ Yes □ No


Pembrolizumab Event of Clinical Interest Guidance Document
Final 18-Dec-2014 
Version 5.0 
30
 
 
  
 
 
APPENDIX 3 – Presentation of the Dermatologic Event 
  
Presentation of the event: 
Collect information on clinical presentation and potential contributing factors. Key information should be 
summarized and entered on the Adverse Experience eCRF. Any treatments administered should be entered on 
the Concomitant Medication eCRF. 
 
1. What is the onset time of the skin reaction, skin eruption, or rash relative to dose of study drug? 
 
 
2. Has the subject contacted any known allergens? □ Yes □ No 
 
If so what kind?   
 
 
3. Has the subject contacted new, special, or unusual substances (e.g., new laundry detergents, soap, personal 
care product, poison ivy, etc.)? □ Yes □ No 
 
If so what kind?   
 
 
4. Has the subject taken any other medication (over the counter, prescription, vitamins, and supplement)? 
□ Yes □ No 
 
If so what kind?   
 
 
5. Has the subject consumed unaccustomed, special or unusual foods? □ Yes □ No 
 
If so what kind?   
 
 
6. Does the subject have or had in the last few days any illness? □ Yes □ No 
 
If so what kind?   
 
 
7. Has the subject come into contact with any family or house members who are ill? □ Yes □ No 
 
If so who and what?   
 
 
8. Has the subject recently been near children who have a skin reaction, skin eruption, or rash (e.g. Molluscum 
Contagiosum)? □ Yes □ No


Pembrolizumab Event of Clinical Interest Guidance Document
Final 18-Dec-2014 
Version 5.0 
31
 
 
 
 
9. Has the subject had recent sun exposure? □ Yes □ No 
  
 
10. For the current rash, have there been any systemic clinical signs? □ Yes □ No 
 
If so what kind?   
 
 
i. Anaphylaxis? □ Yes □ No 
ii. Signs of hypotension? □ Yes □ No 
iii. Signs of dyspnea? □ Yes □ No 
iv. Fever, night sweats, chills? □ Yes □ No 
 
11. For the current rash, has the subject needed subcutaneous epinephrine or other systemic catecholamine 
therapy? □ Yes □ No 
 
If so what kind?   
 
 
12. For the current rash, has the subject used any other medication, such as inhaled bronchodilators, 
antihistaminic medication, topical corticosteroid, and/or systemic corticosteroid? □ Yes □ No 
 
List medication(s) and dose(s):   
 
 
 
13. Is the rash pruritic (itchy)? □ Yes □ No 


Pembrolizumab Event of Clinical Interest Guidance Document
Final 18-Dec-2014 
Version 5.0 
32
 
 
 
APPENDIX 4 – Focused Skin Examination 
  
Focused Skin Examination: 
Key information should be summarized and entered on the Adverse Experience eCRF. 
 
Primary Skin Lesions Description 
Color:   
 
 
General description: 
  
 
 
Describe the distribution of skin reaction, skin eruption, or rash on the body: 
  
 
 
Is skin reaction, skin eruption, or rash resolving or continuing to spread? 
  
 
 
Any associated signs on physical examination? 


DF/HCC Protocol #: 16-257 
Protocol Version Date: August 29, 2018  
 
53 
 
APPENDIX C: 
BIOASSAY TEMPLATES 
 
 
 
 
 
MISP Sample Handling Manual 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QualTek Molecular Laboratories
300 Pheasant Run 
Newtown, PA 18940 
Phone: 215.504.7402 
Fax: 805.830.6379 
Email: MISPsamples@qmlabs.com 


 
54 
 
 
Table of Contents 
Page 
1. Introduction 
3 
2. Protocol Requirements 
3-4 
3. Sectioning of Tissue onto ProbeOn Plus Slides From Formalin‐Fixed, 
Paraffin‐Embedded (FFPE) Block(s) 
5 
4. Packaging Instructions for Formalin-Fixed Paraffin Embedded Slides  
6-7 
5. Investigator Studies Supply List for FFPE Sectioned Slides Shipping to 
QualTek (Supplies Provided by QualTek) 
8-9 
6. Example of Site Supply Inventory  
10 


 
55 
 
Introduction 
 
Here we describe the collection of sectioned slides from tumor samples for the purpose of 
immunohistochemical (IHC) analysis. Sectioned slides from formalin‐fixed, paraffin‐embedded 
(FFPE) samples will be stained for the biomarker(s) of interest, and then evaluated by a 
pathologist for review of biomarker staining expression levels. 
 
Protocol Requirements  
 
1. For patient samples, the provided positively charged ProbeOn Plus slides (Fisher 
ProbeOn Plus Catalog Number 22‐230‐900) are strongly recommended for tissue 
sections. If a sample has existing sections already cut, slide measurements should be 
75mm x 25mm x 1mm (other slide sizes may not be able to be accommodated ‐ please 
contact QualTek to discuss further).  
 
2. Tumor tissue for biomarker analysis should be provided as five (5) unstained slides cut 
from an FFPE tissue block. Three (3) sectioned slides per sample are necessary for H&E, 
PD‐L1, and isotype control staining. The 4th and 5th sections are for a repeat staining if 
needed.  
a. Existing H&E slides may be provided along with 2 unstained slides if less tissue is 
available (assumes H&E stained section is fairly close to section level of 
unstained slides sent for analysis). A PD‐L1 and isotype control stain will be 
performed. Isotype control will only be run if first section staining for PD‐L1 is 
successful otherwise a second attempt will be made for PD‐L1 staining. 
b. If no H&E is available and only 2 unstained sections are sent, then an H&E and a 
PD‐L1 stain will be performed.  
3. If additional markers beyond PD‐L1 are requested to be tested as per the service 
contract established between QualTek and the Investigator Site, 2 additional sections 
per marker are the minimum to allow staining for the additional marker and the isotype 
control, however 4 sections will allow for repeat staining if needed. 
4. Samples may be held as blocks indefinitely at the site and then cut in batches. Slides 
should be shipped to QualTek as immediately as possible after sectioning.  
5. As per Merck protocol requirements, sectioned slides should be shipped cold (2‐8°C) 
and in the dark using the shipping materials provided by QualTek pages 8‐9. Be advised 
that slides received that do not meet these conditions may affect PD‐L1 staining. 
6. Sectioned slides provided should contain tumor specimen sufficient for pathology 
review and analysis of the tumor sample. If available, greater than 50% tumor content is 


 
56 
preferred. At least fifty viable neoplastic cells overall or at least five viable, PD‐L1‐
staining neoplastic cells are necessary to be scored by the pathologist. 
 
7. Non‐acceptable sample types for IHC analysis include brushing, bone metastases, lavage 
specimen, frozen sample, plastic embedded sample, or formalin fixed sample that was 
frozen at any point.  
 
8. Needle core biopsies or endo‐bronchial ultrasound (EBUS) preps that are formalin‐fixed 
and paraffin‐embedded are acceptable. Fine‐needle aspiration (FNA) or cell pellet from 
pleural effusion samples that are formalin‐fixed and paraffin‐embedded will be 
accepted for testing with the following caveats: 
 
a. The PD‐L1 IHC assay is not validated for FNA or cell pellet from pleural effusion 
samples. However, on a research basis QualTek has successfully PD‐L1 stained 
FNA samples. 
b. The scoring parameter for assessing stromal interface (presence/ absence) will 
not be provided for FNAs or cell pellets from pleural effusion due to the nature 
of the sample. 
 


 
57 
Sectioning of Tissue onto ProbeOn Plus Slides from Formalin‐Fixed, Paraffin‐
Embedded (FFPE) Block(s)  
1. Prepare freshly‐cut serial sections at 4 micron thickness onto the provided Fisher 
ProbeOn Plus Slides, Cat Number 22‐230‐900. Sections must be placed on the 
painted/textured side of the slide. 
 No adhesives should be used in the water bath since the slides are positively‐
charged.  
2. Ensure that the sample has the institutional block ID clearly marked on 
each slide as well as the slide section levels, if possible. 
 Ensure that the block ID is referenced on the manifest 
 Note that the sample must be labeled with 2 patient identifiers 
(Refer to the label provided for the slide holder)  
3. When placing the sections onto the slides, ensure that the tissue is 
towards the bottom third of the slide as pictured at right. 
 Ensure tissue sections are oriented the same direction on all slides. 
 No adhesive labels directly on slides. Slide / patient identifiers must be hand 
written with indelible / chemical proof ink. 
 Number the slides sequentially (serially), one section per slide. 
4. DO NOT OVEN DRY SLIDES. Air dry until completely dry (12‐24 hours). 
5. Complete an electronic Sample Manifest for each shipment (Excel Spreadsheet provided 
by QualTek to the Site Contact at study initiation). 
 Email the completed electronic manifest prior to shipment to: 
MISPsamples@qmlabs.com 
 Make a copy of the manifest to include with the shipment of the sample(s) 
 Retain the original at the site for your records 
6. Email or enclose a de‐identified (redacted) pathology report(s) if available. Write the 
block ID on the top of each page of the pathology report 
7. Prepare samples for shipping as detailed on pages 6‐7.  


 
58 
 
Packaging Instructions for Formalin-Fixed Paraffin Embedded Slides  
1. Affix and complete the label provided for the slide holder with Unique Patient ID 
number, Site Number/Identifier and Sectioning Date using indelible ink. Ensuring that 
the patient identifiers on the slide holder match the patient slides. 
Top line of the label are the Study Identifiers 
and will be pre-printed for the specific study 
Left - Investigator Study Number 
Center – Merck Protocol Number 
Right – QualTek Project Number 
 
2. Place the newly sectioned slides (air dried until completely dry (12‐24 hours), into the 
labeled slide holder.  Ensure only one patient per slide holder and no more than 5 slides 
per slide holder. 
3. Place the piece of small foam between the top of the slides and the holder’s lid to 
prevent the slides from breaking. Tape the lid closed. 
4. Insert the slide holders into the Amber UV bag labeled as “Biohazard” and seal the bag. 
5. Place the Amber UV bag into a bubble wrap bag, or wrap in a sheet of bubble wrap. 
6. More than one shipping box size may have been provided, choose the appropriate size 
as follows: 
 If shipping 1 patient slide holder: 
Use a 9x12 Insulated Shipping mailer.  Place 1 freezer pack in the cooler liner, 
place the bubble wrap bag containing slides on top of the freezer pack. 
 If shipping between 2 and 10 patient slide holders: 
Use a 10x10x10 Shipping box and cooler box liner.  Place 1 freezer pack on the 
bottom of the cooler liner, place the bubble wrap bag containing slides on top of 
the freezer pack and include 1 freezer pack on top of the bubble wrap bag.  
 If shipping between 11 and 20 patient slides holders: 
Use a 12x12x12 shipping box and cooler box liner.  Place 2 freezer packs on the 
bottom of the cooler liner place the bubble wrap bag containing the slides on 
top of the freezer pack and include 2 freezer packs on top of the bubble wrap 
bag.  
7. Fill remaining space with appropriate cushioning, i.e. additional bubble wrap or other 
packing material. For extreme temperature conditions additional ice packs may be 
required. Samples should be shipped cold (2‐8°C) and in the dark. 


 
59 
8. Enclose the de‐identified (redacted) pathology report and the Sample Manifest, ensure 
that an electronic copy of the Manifest has been emailed to MISPsamples@qmlabs.com 
9. Seal the mailer/box to ensure it will not open during shipping. Package & ship to 
QualTek. 
10. Complete the pre‐printed air bill provided by QualTek with sender information. 
11. Verify correct shipping address as:    
QualTek Molecular Laboratories 
MISP Receiving 
300 Pheasant Run 
Newtown, PA USA 18940 
12. Adhere the pre‐printed air bill to the top of the shipping mailer/box. 
13. For all U.S. domestic shipments, ship Standard Overnight Monday through Thursday, do 
not ship Friday, Saturday or Sunday. 


 
60 
Investigator Studies Supply List for FFPE Sectioned Slides Shipping to QualTek 
The following supplies, or their equivalent, will be provided by QualTek: 
 
1. Positively charged microscope slides used for 
sectioning of slides (5 per patient) 
 
Fisher ProbeOn Plus 25mm x 75mm x 1mm 
Capillary Gap Microscope Slides catalog 22‐
230‐900  
 
http://www.fishersci.com  
2. Plastic slide holders (1 per patient, each hold 
maximum of 5 slides) 
 Catalog 12‐587‐17B 
 http://www.fishersci.com 
3. Paraffin embedding cassette sponge to 
cushion slides in the plastic slide holder 
during shipping 
 “square” biopsy foam pad sized 1 7/8” 
x 1” x 1/16” (catalog 60872‐492) 
 http://us.vwr.com  
 
 
4. Amber UV bags with biohazard sticker (to 
keep the slides in dark) 
 Amber UV bag (6x8 Inches) – catalog 
89005‐326 
 http://us.vwr.com  
 Biohazard Sticker – catalog ML1022 
 
http://www.marketlab.com   
5. Shippers 
 9x12 (Mailer) For shipping 1 sample 
holder – catalog S18306 
(http://www.uline.com) 
 10x10x10 (Small) For shipping between 
2 to 10 patient slide holders – catalog 
s4105 (http://www.uline.com)  
 12x12x12 (Large) For bulk shipments, 
between 11 to 20 patient slide holders – 
catalog s18283 (http://www.uline.com) 
 Insulated shippers – catalog s18282 
(http://www.uline.com) 
 


 
61 
6. Cold Packs (12 oz. Ice Packs, 1 for the Mailer, 
2 for the Small Shipper, 4 for the Large 
Shipper) 
 
Catalog s7889  
 
http://www.uline.com 
 
7. Bubble wrap  
 Catalog s‐683 
 http://www.uline.com 
 
8. Miscellaneous  
 Labels for the slide holders 
 FedEx Pre‐Printed Air bills 
 Site Supply Inventory 
 Sample Manifest Template (Excel 
Spreadsheet provided electronically 
to site contact) 
 
 
 


 
62 
 
(EXAMPLE) Site Supply Inventory 
 
Date  
QualTek Project #  
Investigator Study 
# 
 
Merck Protocol #  
Site Name  
Site Address  
Address 
Continued 
 
 
 
Quantity 
Description 
Quantity
Description 
X 
Positively Charged Capillary Gap 
(ProbeOn Plus) Microscope 
Slides 
X 
Freezer Packs 
X 
Plastic Five (5) Slide Holder (with 
small Foam Pad) 
X 
Fed-Ex Pre-Printed Air bill(s) 
X 
Labels for Slide Holder 
X 
10x10x10 Shipping Box with Cooler Box 
Liner 
X 
Amber UV Bags (labeled Biohazard) 
X 
12x12x12 Shipping Box with Cooler Box 
Liner 
X 
Bubble Wrap Bags 
X 
Other (If Applicable) 
 
Unpacking Instructions 
 
1. Confirm material counts and check for breakage. 
2. Remove freezer packs and place in freezer as soon as possible. 
3. Retain all other materials for return of samples to QualTek Molecular Labs. 
4. When ready to section, remove Positively Charged Capillary Gap (ProbeOn Plus) Microscope 
Slides from slide holder and use these slides for sectioning. Retain foam pad for repackaging. 


DF/HCC Protocol #: 16-257 
Protocol Version Date: August 29, 2018  
 
63 
 
 
APPENDIX D: DATA SAFETY MONITORING PLAN 
 
 
 
 
 
 
 
 
 
 
 
 
 
DFCI IRB Protocol #: 16-257 
 
 
 
 
 
APPENDIX D 
 
Dana-Farber/Harvard Cancer Center 
Multi-Center Data and Safety Monitoring Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
64 
 
TABLE OF CONTENTS 
 
1. 
INTRODUCTION .............................................................................................................65 
1.1 
Purpose ...................................................................................................................65 
1.2 
Multi-Center Data and Safety Monitoring Plan Definitions ..................................65 
2. 
GENERAL ROLES AND RESPONSIBILITIES .............................................................66 
2.1 
DF/HCC Sponsor ...................................................................................................66 
2.2 
Coordinating Center ...............................................................................................67 
2.3 
Participating Institution ..........................................................................................67 
3. 
DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS..............................68 
3.1 
Protocol Distribution ..............................................................................................68 
3.2 
Protocol Revisions and Closures ...........................................................................68 
3.3 
Informed Consent Requirements ...........................................................................69 
3.4 
IRB Documentation ...............................................................................................69 
3.5 
IRB Re-Approval ...................................................................................................69 
3.6 
Participant Confidentiality and Authorization Statement ......................................69 
3.7 
DF/HCC Multi-Center Protocol Registration Policy .............................................70 
3.8 
DF/HCC Protocol Case Number ............................................................................70 
3.9 
Safety Assessments and Toxicity Monitoring .......................................................72 
3.10 
Data Management ..................................................................................................73 
4. 
REQUISITIONING INVESTIGATIONAL DRUG..........................................................73 
5. 
MONITORING: QUALITY CONTROL ..........................................................................73 
5.1 
Ongoing Monitoring of Protocol Compliance .......................................................73 
5.2 
Monitoring Reports ................................................................................................74 
5.3 
Accrual Monitoring ................................................................................................75 
6. 
AUDITING: QUALITY ASSURANCE ...........................................................................75 
6.1 
DF/HCC Internal Audits ........................................................................................75 
6.2 
Audit Notifications .................................................................................................75 
6.3 
Audit Reports .........................................................................................................75 
6.4 
Participating Institution Performance ....................................................................75 
 


 
65 
 
1. INTRODUCTION 
 
The Dana-Farber/Harvard Cancer Center Multi-Center Data and Safety Monitoring Plan 
(DF/HCC DSMP) outlines the procedures for conducting a DF/HCC Multi-Center research 
protocol. The DF/HCC DSMP serves as a reference for any sites external to DF/HCC that 
are participating in a DF/HCC clinical trial. 
 
1.1 Purpose 
 
To establish standards that will ensure that a Dana-Farber/Harvard Cancer Center Multi-
Center protocol will comply with Federal Regulations, Health Insurance Portability and 
Accountability Act (HIPAA) requirements and applicable DF/HCC Standard Operating 
Procedures.        
 
1.2 Multi-Center Data and Safety Monitoring Plan Definitions 
 
DF/HCC Multi-Center Protocol:  A research protocol in which one  or more outside 
institutions are collaborating with Dana-Farber/Harvard Cancer Center where  a DF/HCC 
investigator is the sponsor. DF/HCC includes Dana-Farber/Partners Cancer Care (DF/PCC) 
Network Clinical Trial Affiliates.  
 
Lead Institution:  One of the Dana-Farber/Harvard Cancer Center consortium members 
(Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH), Beth 
Israel Deaconess Medical Center (BIDMC), Boston Children’s Hospital (BCH), Brigham 
and Women’s Hospital (BWH) responsible for the coordination, development, 
submission, and approval of a protocol as well as its subsequent amendments per the 
DFCI IRB and applicable regulatory guidelines (CTEP, Food and Drug Administration 
(FDA), Office of Biotechnology Activities (OBA) etc.).  The Lead Institution is typically 
the home of the DF/HCC Sponsor. The Lead Institution also typically serves as the 
Coordinating Center for the DF/HCC Multi-Center Protocol.   
 
DF/HCC Sponsor:  The person sponsoring the submitted Multi-Center protocol who 
takes responsibility for initiation, management and conduct of the protocol at all research 
locations. In applicable protocols, the DF/HCC Sponsor will serve as the single liaison 
with any regulatory agencies (i.e. FDA, etc.). The DF/HCC Sponsor has ultimate authority 
over the protocol and is responsible for the conduct of the study at DF/HCC and all 
Participating Institutions. In most cases the DF/HCC Sponsor is the same person as the 
DF/HCC Overall Principal Investigator; however, both roles can be filled by two different 
people.  
 
Participating Institution:  An institution that is outside the DF/HCC and DF/PCC 
consortium that is collaborating with DF/HCC on a protocol where the sponsor is a 
DF/HCC Investigator.  The Participating Institution acknowledges the DF/HCC Sponsor 
as having the ultimate authority and responsibility for the overall conduct of the study.    
Coordinating Center: The entity (i.e. Lead Institution, Medical Monitor, Contract 
Research Organization (CRO), etc) that provides administrative support to the DF/HCC 
Sponsor in order that he/she may fulfill the responsibilities outlined in the protocol 


 
66 
document and DSMP, and as specified in applicable regulatory guidelines (i.e. CTEP 
Multi-Center Guidelines). In general, the Lead Institution is the Coordinating Center for 
the DF/HCC Multi-Center Protocol.  
 
DF/HCC Office of Data Quality (ODQ): A group within DF/HCC responsible ensuring 
high-quality standards are used for data collection and the ongoing management of clinical 
trials, auditing, and data and safety monitoring. ODQ also coordinates quality assurance 
efforts related to multi-center clinical research. 
 
DF/HCC Clinical Trials Research Informatics Office (CTRIO): A group within 
DF/HCC responsible for providing a comprehensive data management platform for 
managing clinical trial data. 
 
2. GENERAL ROLES AND RESPONSIBILITIES 
For DF/HCC Multi-Center Protocols, the DF/HCC Sponsor, the Coordinating Center, and 
the Participating Institutions are expected to adhere to the following general 
responsibilities:  
 
2.1 DF/HCC Sponsor 
 
The DF/HCC Sponsor, Ursula Matulonis, M.D., will accept responsibility for all aspects 
of conducting a DF/HCC Multi-Center protocol which includes but is not limited to:  
 Oversee the coordination, development, submission, and approval of the protocol 
as well as subsequent amendments.  
 Ensure that the investigators, study team members, and Participating Institutions 
are qualified and appropriately resourced to conduct the protocol.   
 Include the Multi-Center Data and Safety Monitoring Plan as an appendix to the 
protocol. 
 Ensure all Participating Institutions are using the correct version of the protocol. 
 Ensure that each participating investigator and study team member receives 
adequate protocol training (and/or a Site Initiation Visit prior to enrolling 
participants) and throughout trial’s conduct as needed. 
 Ensure the protocol will be provided to each participating site in a language 
understandable to all applicable site personnel when English is not the primary 
language.  
 Monitor progress and overall conduct of the study at all Participating Institutions.  
 Ensure all DFCI Institutional Review Board (IRB), DF/HCC and other applicable 
(i.e. FDA) reporting requirements are met.  
 Review data and maintain timely submission of data for study analysis.  
 Act as the single liaison with FDA (investigator-held IND trials), as applicable. 
 Ensure compliance with all requirements as set forth in the Code of Federal 
Regulations, applicable DF/HCC requirements, HIPAA requirements, and the 
approved protocol. 
 Commit to the provision that the protocol will not be rewritten or modified by 
anyone other than the DF/HCC Sponsor. 
 Identify and qualify Participating Institutions and obtain accrual commitments 
prior to extending the protocol to that site. 


 
67 
 Monitor accrual and address Participating Institutions that are not meeting their 
accrual requirements.  
 
2.2 Coordinating Center  
 
The general responsibilities of the Coordinating Center may include but are not limited to: 
 Assist in protocol development.  
 Maintain FDA correspondence, as applicable. 
 Review registration materials for eligibility and register participants from 
Participating Institutions in the DF/HCC clinical trial management system 
(CTMS). 
 Distribute protocol and informed consent document updates to Participating 
Institutions as needed. 
 Oversee the data collection process from Participating Institutions. 
 Maintain documentation of Serious Adverse Event (SAE) reports and 
deviations/violation submitted by Participating Institutions and provide to the 
DF/HCC Sponsor for timely review and submission to the DFCI IRB, as 
necessary.  
 Distribute serious adverse events reported to the DF/HCC Sponsor that fall under 
the DFCI IRB Adverse Event Reporting Policy to all Participating Institutions. 
 Provide 
Participating 
Institutions 
with 
information 
regarding 
DF/HCC 
requirements that they will be expected to comply with. 
 
 Carry out plan to monitor Participating Institutions either by on-site or remote 
monitoring.  
 Maintain Regulatory documents of all Participating Institutions which includes but 
is not limited to the following: local IRB approvals/notifications from all 
Participating Institutions, confirmation of Federalwide Assurances (FWAs) for all 
sites,  all SAE submissions, Screening Logs for all sites, IRB approved consents 
for all sites 
 Conduct regular communications with all Participating Institutions (conference 
calls, emails, etc) and maintain documentation all relevant communications. 
 
2.3 Participating Institution 
 
Each Participating Institution is expected to comply with all applicable federal regulations 
and DF/HCC requirements, the protocol and HIPAA requirements.  
 
The general responsibilities for each Participating Institution may include but are not 
limited to: 
 Document the delegation of research specific activities to study personnel. 
 Commit to the accrual of participants to the protocol. 
 Submit protocol and/or amendments to their local IRB. 
 Maintain regulatory files as per sponsor requirements. 
 Provide the Coordinating Center with regulatory documents or source documents 
as requested. 
 Participate in protocol training prior to enrolling participants and throughout the 
trial as required (i.e. teleconferences). 


 
68 
 Update Coordinating Center with research staff changes on a timely basis. 
 Register participants through the Coordinating Center prior to beginning research 
related activities.  
 Submit Serious Adverse Event (SAE) reports to local IRB per institutional 
requirements and to the Coordinating Center, in accordance with DF/HCC 
requirements.  
 Submit protocol deviations and violations to local IRB per institutional 
requirements and to the DF/HCC Sponsor in accordance with DF/HCC 
requirements. 
 Order, store and dispense investigational agents and/or other protocol mandated 
drugs per federal guidelines and protocol requirements. 
 Have office space, office equipment, and internet access that meet HIPAA 
standards. 
 Participate in any quality assurance activities and meet with monitors or auditors at 
the conclusion of a visit to review findings. 
 Promptly provide follow-up and/or corrective action plans for any monitoring 
queries or audit findings. 
 
3. DF/HCC REQUIREMENTS FOR MULTI-CENTER PROTOCOLS 
The following section will clarify DF/HCC Requirements and further detail the expectations 
for participating in a DF/HCC Multi-Center protocol.  
 
3.1 Protocol Distribution 
 
The Coordinating Center will distribute the final DFCI IRB approved protocol and any 
subsequent amended protocols to all Participating Institutions.    
 
3.2 Protocol Revisions and Closures 
 
The Participating Institutions will receive notification of protocol revisions and closures 
from the Coordinating Center.  It is the individual Participating Institution’s responsibility 
to notify its IRB of these revisions. 
 
 Non life-threatening revisions: Participating Institutions will receive written 
notification of protocol revisions regarding non life-threatening events from the 
Coordinating Center. Non-life-threatening protocol revisions must be IRB 
approved and implemented within 90 days from receipt of the notification. 
 
 Revisions for life-threatening causes: Participating Institutions will receive 
immediate notification from the Coordinating Center concerning protocol revisions 
required to protect lives with follow-up by fax, mail, e-mail, etc.  Life-threatening 
protocol revisions will be implemented immediately followed by IRB request for 
approval. 
 
 Protocol closures and temporary holds: Participating Institutions will receive 
notification of protocol closures and temporary holds from the Coordinating 
Center. Closures and holds will be effective immediately.  In addition, the 


 
69 
Coordinating Center, will update the Participating Institutions on an ongoing basis 
about protocol accrual data so that they will be aware of imminent protocol 
closures. 
 
3.3 Informed Consent Requirements 
 
The DF/HCC approved informed consent document will serve as a template for the 
informed consent for Participating Institutions. The Participating Institution consent form 
must follow the consent template as closely as possible and should adhere to specifications 
outlined in the DF/HCC Guidance Document on Model Consent Language for PI-Initiated 
Multi-Center Protocols.  This document will be provided separately to each Participating 
Institution upon request. 
 
Participating Institutions are to send their version of the informed consent document and 
HIPAA authorization, if a separate document, to the Coordinating Center for review and 
approval prior to submission to their local IRB. The approved consent form must also be 
submitted to the Coordinating Center after approval by the local IRB for all consent 
versions. 
 
The Principal Investigator (PI) at each Participating Institution will identify the physician 
members of the study team who will be obtaining consent and signing the consent form 
for therapeutic protocols. Participating institutions must follow the DF/HCC requirement 
that only attending physicians obtain informed consent and re-consent for all 
interventional drug, biologic, or device research.   
 
3.4 IRB Documentation 
 
The following must be on file with the Coordinating Center: 
 Initial approval letter of the Participating Institution's IRB.  
 Copy of the Informed Consent Form(s) approved by the Participating Institution’s 
IRB.  
 Participating Institution’s IRB approval for all amendments. 
 Annual approval letters by the Participating Institution's IRB. 
 
3.5 IRB Re-Approval 
 
Verification of IRB re-approval from the Participating Institutions is required in order to 
continue research activities.  There is no grace period for continuing approvals. 
 
The Coordinating Center will not register participants if a re-approval letter is not received 
from the Participating Institution on or before the anniversary of the previous approval 
date.   
 
 
3.6 Participant Confidentiality and Authorization Statement 
 
In 1996, congress passed the first federal law covering the privacy of health information 
known as the Health Insurance Portability and Accountability Act (HIPPA). Any 


 
70 
information, related to the physical or mental health of an individual is called Protected 
Health Information (PHI). HIPAA outlines how and under what circumstances PHI can be 
used or disclosed.  
 
In order for covered entities to use or disclose protected health information during the 
course of a study, the study participant must sign an authorization statement.  This 
authorization statement may or may not be separate from the informed consent document.  
The Coordinating Center, with the approval from the DFCI IRB, will provide a consent 
template, with information regarding authorization for the disclosure of protected health 
information.  
 
The DF/HCC Sponsor will use all efforts to limit its use of protected health information in 
its trials. However, because of the nature of these trials, certain protected health 
information must be collected. DF/HCC has chosen to use authorizations, signed by the 
participant in the trial, rather than limited data sets with data use agreements. 
 
3.6.1  DF/HCC Multi-Center Protocol Confidentiality 
 
All documents, investigative reports, or information relating to the participant are strictly 
confidential. Whenever reasonably feasible, any participant specific reports (i.e. Pathology 
Reports, MRI Reports, Operative Reports, etc.) submitted to the Coordinating Center 
should be de-identified. It is recommended that the assigned protocol case number (as 
described below) be used for all participant specific documents. Participant initials may be 
included or retained for cross verification of identification.  
 
3.7 DF/HCC Multi-Center Protocol Registration Policy 
 
3.7.1  Participant Registration and Randomization  
Please see section 4 of the protocol. 
 
3.7.2  Initiation of Therapy 
 
Participants must be registered with the DF/HCC CTMS before the initiation of treatment 
or other protocol-specific interventions. Treatment and other protocol-specific 
interventions may not be initiated until the Participating Institution receives confirmation 
of the participant’s registration from the Coordinating Center. The DF/HCC Sponsor and 
DFCI IRB must be notified of any violations to this policy. 
 
3.7.3  Eligibility Exceptions 
 
No exceptions to the eligibility requirements for a protocol without DFCI IRB approval 
will be permitted. All Participating Institutions are required to fully comply with this 
requirement. The process for requesting an eligibility exception is defined below. 
 
3.8 DF/HCC Protocol Case Number 
 
At the time of registration, the following identifiers are required for all subjects: initials, 
date of birth, gender, race and ethnicity. Once eligibility has been established and the 


 
71 
participant successfully registered, the participant is assigned a unique protocol case 
number. 
Participating 
Institutions 
should 
submit 
all 
de-identified 
subsequent 
communication and documents to the Coordinating Center, using this case number to 
identify the subject.   
 
3.8.1 Protocol Deviations, Exceptions and Violations 
 
Federal Regulations require an IRB to review proposed changes in a research activity to 
ensure that researchers do not initiate changes in approved research without IRB review 
and approval, except when necessary to eliminate apparent immediate hazards to the 
participant. DF/HCC requires all departures from the defined procedures set forth in the 
IRB approved protocol to be reported to the DF/HCC Sponsor, who in turn is responsible 
for reporting to the DFCI IRB. 
 
 
For reporting purposes, DF/HCC uses the terms “violation”, “deviation” and “exception” 
to describe departures from a protocol. All Participating Institutions must adhere to these 
requirements for reporting to the DF/HCC Sponsor and will follow their institutional 
policy for reporting to their local IRB. 
 
3.8.2  Definitions 
 
Protocol Deviation: Any departure from the defined procedures set forth in the IRB-
approved protocol which is prospectively approved prior to its implementation. 
 
Protocol Exception:  Any protocol deviation that relates to the eligibility criteria, e.g. 
enrollment of a participant who does not meet all inclusion/exclusion criteria. 
 
 
 
Protocol Violation: Any protocol departure that was not prospectively approved by the 
IRB prior to its initiation or implementation.  
 
 
3.8.3  Reporting Procedures 
 
DF/HCC Sponsor: is responsible for ensuring that clear documentation is available in the 
medical record and/or regulatory documents to describe all protocol exceptions, deviations 
and violations. The DF/HCC Sponsor will also be responsible for ensuring that all 
protocol violations/deviations are promptly reported per DFCI IRB guidelines.  
 
Participating Institutions: Protocol deviations require prospective approval from the DFCI 
IRB. The Participating Institution must submit the deviation request to the Coordinating 
Center who will then submit the deviation request to the DFCI IRB. Upon DFCI IRB 
approval the deviation is submitted to the Participating Institution IRB, per institutional 
policy. A copy of the Participating Institution’s IRB report and determination will be 
forwarded to the Coordinating Center within 10 business days after the original 
submission.  The deviation may not be implemented without all required approvals. 
 
All protocol violations must be sent to the Coordinating Center in a timely manner. The 
Coordinating Center will provide training for the requirements for the reporting of 
violations.  


 
72 
 
Coordinating Center:  Upon receipt of the violation/deviation report from the Participating 
Institution, the Coordinating Center will submit the report to the DF/HCC Sponsor for 
review. Subsequently, the Participating Institution’s IRB violation/deviation report will be 
submitted to the DFCI IRB for review per DFCI IRB reporting guidelines. DF/HCC will 
forward all violation reports to CTEP via an internal DF/HCC process, as applicable. 
 
3.9 Safety Assessments and Toxicity Monitoring 
 
The study teams at all participating institutions are responsible for protecting the safety, 
rights and well-being of study participants. Recording and reporting of adverse events that 
occur during the course of a study help ensure the continuing safety of study participants.  
 
All participants receiving investigational agents and/or other protocol mandated therapy 
will be evaluated for safety. The safety parameters include all laboratory tests and 
hematological abnormalities, physical examination findings, and spontaneous reports of 
adverse events reported by participants.  All toxicities encountered during the study will 
be evaluated according to the NCI criteria specified in the protocol. Life-threatening 
toxicities must be reported immediately to the DF/HCC Sponsor via the Coordinating 
Center.  
 
Additional safety assessments and toxicity monitoring will be outlined in the protocol. 
 
3.9.1 Guidelines for Reporting Serious Adverse Events  
 
Guidelines for reporting Adverse Events (AEs) and Serious Adverse Events (SAEs) are 
detailed in protocol section 7. 
 
 
 
 
 
 
Participating Institutions must report the SAEs to the DF/HCC Sponsor and the 
Coordinating Center following the DFCI IRB Adverse Event Reporting Policy.  
 
The Coordinating Center will maintain documentation of all Participating Institution 
Adverse Event reports and be responsible for communicating to all participating 
investigators, any observations reportable under the DFCI IRB Reporting Requirements.  
Participating Institutions will review and submit to their IRB according to their 
institutional policies and procedures 
 
 
3.9.2 Guidelines for Processing IND Safety Reports  
 
The DF/HCC Sponsor will review all IND Safety Reports and ensure that all IND Safety 
Reports are distributed to the Participating Institutions. Participating Institutions will 
review/submit to their IRB according to their institutional policies and procedures. 
 
 
 
 


 
73 
3.10 Data Management 
DF/HCC CTRIO develops case report forms (CRF/eCRFs), for use with the protocol.  
These forms are designed to collect data for each study. DF/HCC CTRIO provides a web 
based training for all eCRF users. 
   
3.10.1 Data Forms Review 
 
Data submissions are monitored for timeliness and completeness of submission. If study 
forms are received with missing or questionable data, the submitting institution will 
receive a written or electronic query from the DF/HCC Office of Data Quality, 
Coordinating Center, or designee.  
 
Responses to all queries should be completed and submitted within 14 calendar days.   
 
Responses may be returned on the written query or on an amended paper case report form, 
or in the case of electronic queries, within the electronic data capture (eDC) system. In the 
case of a written query for data submitted on a paper case report form, the query must be 
attached to the specific data being re-submitted in response.   
 
If study forms are not submitted on schedule, the Participating Institution will periodically 
receive a Missing Form Report from the Coordinating Center noting the missing forms.  
 
4. REQUISITIONING INVESTIGATIONAL DRUG 
 
 
The ordering of investigational agent is specified in the protocol section 8. 
 
Participating Institutions should order their own agent regardless of the supplier. (i.e., NCI 
or a pharmaceutical company.)  
 
If the agent is commercially available, check with the local Director of Pharmacy and/or 
the Research Pharmacy to ensure that the agent is in stock. If the agent is not stocked, 
ensure that the agent can be ordered once the protocol is approved by the local IRB.  
 
If the agent is investigational, ensure that the pharmacy will be able to receive and store the 
agent according to state and federal requirements. The local IRB should be kept informed 
of who will supply the agent (i.e., NCI or a pharmaceutical company) so that any 
regulatory responsibilities can be met in a timely fashion.  
 
5. MONITORING: QUALITY CONTROL 
 
The quality control process for a clinical trial requires verification of protocol compliance 
and data accuracy. The Coordinating Center, with the aid of the DF/HCC Office of Data 
Quality, provides quality control oversight for the protocol. 
 
5.1 Ongoing Monitoring of Protocol Compliance 
 


 
74 
The Participating Institutions may be required to submit participant source documents to 
the Coordinating Center for monitoring. Participating Institution may also be subject to 
on-site monitoring conducted by the Coordinating Center.  
 
The Coordinating Center will implement ongoing monitoring activities to ensure that 
Participating Institutions are complying with regulatory and protocol requirements, data 
quality, and participant safety. At a minimum, the DF/HCC Lead Institute, or designee, 
will monitor each participating site twice a year while patients are receiving treatment. 
Should a Participating Institution be monitored once and then not accrue any additional 
patients or participant visits, then a second monitoring visit may not be necessary. 
Additional monitoring practices may include but are not limited to; source verification, 
review and analysis of the following: eligibility requirements of all participants, informed 
consent procedures, adverse events and all associated documentation, study drug 
administration/treatment, regulatory files, protocol departures, pharmacy records, response 
assessments, and data management. 
 
Participating institutions will be required to participate in Coordinating Center initiated 
teleconferences, as scheduled. The Coordinating Center will keep in close touch with the 
Participating Institutions via email and phone. Source documents from Participating 
Institutions, will be collected at specific data points that support the primary and or 
secondary endpoints. 
 
On-Site Monitoring: On-site monitoring will occur on an as-needed basis. Participating 
Institutions will be required to provide access to participants’ complete medical record and 
source documents for source documentation verification during the on-site visit. In 
addition, upon request from a monitor or auditor, Participating Institutions should provide 
access to regulatory documents, pharmacy records, local policies related to the conduct of 
research, and any other trial-related documentation maintained by the participating site. If 
there are concerns for protocol compliance, issues that impact subject safety or the 
integrity of the study are found, or trends identified based on areas of need, additional 
monitoring visits may be scheduled. On site monitoring visits can be supplemented with 
virtual monitoring assessments, provided that the minimum monitoring frequencies are 
adhered to. 
 
Remote Monitoring: The Coordinating Center will request source documentation from 
Participating Institutions as needed to complete monitoring activities. Participating 
Institutions will be asked to forward de-identified copies of participants’ medical record 
and source documents to the Coordinating Center to aid in source documentation 
verification. 
 
5.2 Monitoring Reports 
 
The DF/HCC Sponsor will review all monitoring reports to ensure protocol compliance. 
The DF/HCC Sponsor may increase the monitoring activities at Participating Institutions 
that are unable to comply with the protocol, DF/HCC Sponsor requirements or federal and 
local regulations.  
 


 
75 
5.3 Accrual Monitoring 
 
Prior to extending a protocol to an external site, the DF/HCC Sponsor will establish 
accrual requirements for each participating institution. Accrual will be monitored for each 
participating institution by the DF/HCC Sponsor or designee. Sites that are not meeting 
their accrual expectations may be subject to termination. 
 
6. AUDITING: QUALITY ASSURANCE 
 
Auditing is a method of Quality Assurance and involves the systematic and independent 
examination of all trial related activities and documents.  Audits determine if evaluated 
activities were appropriately conducted and whether data was generated, recorded and 
analyzed, and accurately reported per the protocol, applicable Standard Operating 
Procedures (SOPs), and the Code of Federal Regulations (CFR). 
 
 
6.1 DF/HCC Internal Audits 
  
 All Participating Institutions are subject to audit by the DF/HCC Office of Data Quality 
(ODQ). Typically, approximately 3-4 participants would be audited at the site over a 2 day 
period. If violations which impact participant safety or the integrity of the study are found, 
more participant records may be audited.  
 
6.2 Audit Notifications 
 
It is the Participating Institution’s responsibility to notify the Coordinating Center of all 
scheduled audit dates (internal or NCI) and re-audit dates (if applicable), which involve 
this protocol. All institutions will forward a copy of final audit and/or re-audit reports and 
corrective action plans (if applicable) to the Coordinating Center, within 12 weeks after 
the audit date.  
 
6.3 Audit Reports  
 
The DF/HCC Sponsor will review all final audit reports and corrective action plans, if 
applicable. The Coordinating Center, must forward any reports to the DF/HCC ODQ per 
DF/HCC policy for review by the DF/HCC Audit Committee. For unacceptable audits, the 
DF/HCC Audit Committee would forward the final audit report and corrective action plan 
to the DFCI IRB as applicable. 
 
6.4 Participating Institution Performance 
 
The DF/HCC Sponsor and DFCI IRB is charged with considering the totality of an 
institution’s performance in considering institutional participation in the protocol. 
 
Participating Institutions that fail to meet the performance goals of accrual, submission of 
timely and accurate data, adherence to protocol requirements, and compliance with state 
and federal regulations, may be recommended for a six-month probation period. Such 
institutions must respond with a corrective action plan and must demonstrate during the 


 
76 
probation period that deficiencies have been corrected, as evidenced by the improved 
performance measures. Participating Institutions that fail to demonstrate significant 
improvement will be considered by the DF/HCC Sponsor for revocation of participation. 
A DF/HCC Sponsor and/or the DFCI IRB may terminate a site’s participation if it is 
determined that a site is not fulfilling its responsibilities as described above. 
 
 
 
 
 
 
 


Protocol #16-257: Drafted (06/29/16)(CSC)/Approved (08/02/16)(CW) 
 
DANA-FARBER CANCER INSTITUTE 
Nursing Protocol Education Sheet 
Protocol Number: 
16-257 
Protocol Name: 
A Phase II Study of Pembrolizumab combined with pegylated liposomal doxorubicin (PLD) 
for recurrent platinum resistant ovarian, fallopian tube, or peritoneal cancer.  
DFCI Site PI: 
Ursula Matulonis 
DFCI Research Nurse: 
Stephanie Morrissey, Cate Cavanaugh, Brittany Bowes, Christin Whalen  
Page the DFCI research nurse or DFCI site PI if there are any questions/concerns about the protocol.   
Please also refer to ONC 15: Oncology Nursing Protocol Education Policy 
*** Remember to check the ALERT PAGE*** 
              SPECIAL NURSING CONSIDERATIONS UNIQUE TO THIS PROTOCOL 
Study Design 
 
 
PLD is an approved drug in the U.S., Canada, and Europe for use in ovarian cancer following progression of 
cancer after platinum-based chemotherapy. 
 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 
 
The Study Design is in Section 1.1 
 
The Study Rationale is in Section 2.4 
 
A cycle is defined as 28 days (Section 5.1). 
Dose 
Calc. 
 
PLD is dosed in mg/m2 IV every 28 days (Section 5.3.1).  
 
Pembrolizumab will be flat dosed every 21 days (Section 5.3.2.1) 
 
PLD will be dosed according institutional standard (Section 5.3.1.2).  
Study Drug  
Administration 
Agent Administration Guidelines are found in Section 5.3.1 and 5.3.2 
 
PLD administration should be at a range of 1mg/min per the FDA package insert. If no infusion reaction occurs, 
the infusion can be increased to complete drug in 1 hour (Section 5.3.1.1) 
 
Pembrolizumab will be administered IV over 30 minutes and has a -5/+10minute infusion window (Section 
5.3.2.1) 
 
Pembrolizumab should be administered before PLD on days where both are indicated (5.3.2.7) 
 
Criteria to treat for C1D1 must meet eligibility criteria in section 3.1  
 
Criteria to treat for subsequent cycles, Day 1 is in Section 5.2.2. 
 
There is no required hydration for PLD or Pembro. (Section 5.3.1.4 & Section 5.3.2.3) 
 
There is a +/- 3day window for infusions (Section 5.3.1.2 & Section 10). 
 
Dose  
Mods & 
Toxicity 
Dose Modifications/Dosing Delay for Toxicity are outlined in Section 6. 
 
This protocol uses NCI CTCAE criteria, version 4.0 (Section 6). 
 
The definition of a DLT is found in Section 5.4. 
Con 
Meds 
Concomitant Therapy Guidelines are in Section 5.5. 
 
Please review the cited sections for permitted, prohibited, and “use with caution” medications/therapies/foods 
 
No live vaccines are allowed while participating in the trial (Section 5.5.3). 
Required  
Data  
Study Calendar and Assessment Required data are outlined in Section 10. 
 
The study calendar is in Section 10 
 
Vital signs: The time points are in Section 5.3.2.5 & Section 10. 
 
ECGs:  The time points are in Section 10. 
 
Charting Tips 
All study drugs require documentation of exact administration time. 
Please be sure to DOCUMENT study medication actual UP/DOWN times in medical record (e.g. LMR, eMAR, 
nursing notes). Edit eMAR as needed to match the exact time given. 
 If there is a discrepancy in the infusion time, delay in administration, or the infusion takes longer than is 
permitted by the guidelines of the protocol, please document the reason for the discrepancy in the medical 
record.   
Please be sure to also DOCUMENT any required observation periods, any additional vital signs, routes of 
administration, injection sites, and exact time of PK collections. 
 


Protocol #16-257: Drafted (06/29/16)(CSC)/Approved (08/02/16)(CW) 
 
 


Institutional Conflict of Interest Information Sheet 
A Phase II Study of Pembrolizumab combined with pegylated liposomal doxorubicin (PLD) for 
recurrent platinum resistant ovarian, fallopian tube or peritoneal cancer  
Protocol #16‐257 
 
You are invited to take part in a clinical trial, a type of research study.  This research study is studying a 
targeted therapy as a possible treatment for this diagnosis.  Merck is supporting this research study by 
providing the study drug, Pembrolizumab.  You are receiving this Information Sheet because Dana‐
Farber Cancer Institute has a financial interest in Pembrolizumab, which may be affected by the 
outcome of this research. This is known as a potential “institutional conflict of interest.”  
 
Pembrolizumab is considered an investigational drug in this research, which means that the intervention 
is being studied and has not been approved for your type of cancer by the FDA (U.S. Food and Drug 
Administration). It is possible that, as the result of this clinical trial and other clinical trials involving this 
drug that may follow, this investigational drug could be approved by the FDA, and become widely 
available for sale. Specifically, the drug being investigated involves a technology that was discovered 
through research conducted at DFCI.  As a result, a concern exists that DFCI could be biased because it 
stands to benefit financially from the outcome of clinical trials involving this drug.   
Dana‐Farber Cancer Institute (“DFCI”) is committed to ensuring that all of its research and clinical 
activities are conducted with integrity.  As part of this commitment, DFCI fully discloses the existence of 
all actual or potential conflicts of interest to research participants, sponsors, and regulatory bodies. Also, 
we have made sure that appropriate steps have been taken to ensure the safety of research participants 
and the reliability of research results.   
First, DFCI will disclose the existence and nature of its financial interest to all research participants. 
Second, DFCI will disclose the existence and nature of its financial interest to all research collaborators 
and in all public presentations and publications of data related to this research. 
Finally, and most importantly, we want to be certain that all research participants are fully informed 
about the financial interest, and are able to consider this information in deciding whether to participate 
in this trial. To that end, if you have additional questions about DFCI’s financial interests and their 
potential impact upon this clinical trial, or any of the steps taken by DFCI to safeguard the integrity of 
this research, please contact: 
 
Roberta Driscoll, JD 
Director, Office of Research Integrity 
Dana‐Farber Cancer Institute 
450 Brookline Avenue, BP333 
Boston, MA  02215‐5450 
617‐632‐4557 
Roberta_Driscoll@dfci.harvard.edu