Clinical trial NCT02520154
Conditions: Stage III Fallopian Tube Cancer AJCC v7 Stage III Ovarian Cancer AJCC v6 and v7 Stage III Primary Peritoneal Cancer AJCC v7 Stage IIIA Fallopian Tube Cancer AJCC v7 Stage IIIA Ovarian Cancer AJCC v6 and v7 Stage IIIA Primary Peritoneal Cancer AJCC v7 Stage IIIB Fallopian Tube Cancer AJCC v7 Stage IIIB Ovarian Cancer AJCC v6 and v7 Stage IIIB Primary Peritoneal Cancer AJCC v7 Stage IIIC Fallopian Tube Cancer AJCC v7 Stage IIIC Ovarian Cancer AJCC v6 and v7 Stage IIIC Primary Peritoneal Cancer AJCC v7 Stage IV Fallopian Tube Cancer AJCC v6 and v7 Stage IV Ovarian Cancer AJCC v6 and v7 Stage IV Primary Peritoneal Cancer AJCC v7
Sponsor: M.D. Anderson Cancer Center
Start date: 2016-07-05; Completion date: 2025-05-22
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase II trial studies how well pembrolizumab works when given in combination with carboplatin and paclitaxel in treating patients with stage III-IV ovarian, primary peritoneal, or fallopian tube cancer. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab in combination with carboplatin and paclitaxel may be a better treatment for ovarian, primary peritoneal, or fallopian tube cancer.

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate progression-free survival of paclitaxel/carboplatin and pembrolizumab in patients with advanced stage, metastatic ovarian cancer undergoing neoadjuvant chemotherapy (NACT).

SECONDARY OBJECTIVES:

I. To describe the feasibility of combination therapy with pembrolizumab in this population.

II. To evaluate the safety of combination and maintenance pembrolizumab. III. To report overall survival.

EXPLORATORY OBJECTIVES:

I. To describe the sequential effects of chemotherapy on immune response and PD-1 expression and receptor occupancy.

II. To evaluate circulating lymphoid populations (subsets). III. To determine tissue PD-L1 expression and T-cell infiltration.

OUTLINE:

NACT: Patients receive paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.

ADJUVANT THERAPY: Beginning 3-6 weeks after surgery, paclitaxel IV over 1 hour on days 1, 8, and 15, patients receive carboplatin IV over 1 hour on day 1, and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 20 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Arms: arm 1: NACT: Patients receive paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgery.

ADJUVANT THERAPY: Beginning 3-6 weeks after surgery, paclitaxel IV over 1 hour on days 1, 8, and 15, patients receive carboplatin IV over 1 hour on day 1, and pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity.

MAINTENANCE THERAPY: Patients receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 20 cycles in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Carboplatin intervention 2: Laboratory Biomarker Analysis intervention 3: Paclitaxel intervention 4: Pembrolizumab intervention 5: Pharmacological Study
Intervention descriptions: intervention 1: Given IV intervention 2: Correlative studies intervention 3: Given IV intervention 4: Given IV intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2014-0662 
Protocol Title 
Matched 
Paired 
Pharmacodynamics 
and 
Feasibility 
Study 
of 
Pembrolizumab in Combination with Chemotherapy in Frontline Ovarian 
Cancer 
Protocol Version 
15 
Version Date 
03/10/2020 
Protocol PI 
Amir Jazaeri 
Department 
Gynecologic Oncology and Reproductive Medicine 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
125866 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 2 of 77 
 
Matched Paired Pharmacodynamics and Feasibility Study of Pembrolizumab in Combination with 
Chemotherapy in Frontline Ovarian Cancer 
 
Sponsor: UT MD Anderson Cancer Center  
Supporting Company: Merck 
IND Number: 125866  
 
 
 
Study Chair:  Amir Jazaeri, M.D. 
 
 
Professor 
Department of Gynecologic Oncology and Reproductive Medicine 
The University of Texas MD Anderson Cancer Center 
1155 Herman Pressler Drive, Unit 1362 
Houston, TX 77030 
(713) 745-1613 tel. 
(713) 792-7586 fax. 
aajazaeri@mdanderson.org 
 
Collaborators:  
 
Anil K. Sood, M.D. 
Professor, Department of Gynecologic Oncology and Reproductive Medicine 
The University of Texas MD Anderson Cancer Center 
 
Nicole Fleming, MD 
Assistant Professor 
Phone: 281-566-1900 
Email: nfleming@mdanderson.org 
 
MD Anderson in Sugar Land 
1327 Lake Pointe Parkway 
Sugar Land, TX 77478 
 
MD Anderson in Katy 
19770 Kingsland Blvd. 
Houston, TX 77094 
 
 
 
 
 
 
MD Anderson in The Woodlands  
Medical Arts Center I & III 
17198/17450 St. Luke’s Way 
The Woodlands, TX 77384 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 3 of 77 
 
 
MD Anderson in the Bay Area 
18100 St. John Dr. 
Nassau Bay, TX 77058 
 
Statistician: 
 
 
 
Ying Yuan, PhD 
 
 
Department of Biostatistics, Unit 1411 
 
 
MD Anderson Cancer Center 
 
 
1400 Hermann Pressler 
 
 
Houston, TX 77030 
 
 
Phone: 713-563-4271 
 
 
yyuan@mdanderson.org 
 
External Collaborator: 
 
 
 
Gordon Mills, MD, PhD 
Director of Precision Oncology - OHSU Knight Cancer Institute 
Professor – Cell, Developmental & Cancer Biology 
Knight Cancer Institute | Oregon Health & Science University 
2730 SW Moody Ave, Portland, OR 97201 
Phone: 503-346-4660 
millsg@ohsu.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 4 of 77 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 5 of 77 
 
 
TABLE OF CONTENTS 
1.0 
STUDY SUMMARY ................................................................................................. 11 
2.0 
OBJECTIVE(S) & HYPOTHESIS (ES) ................................................................. 11 
2.1 
Primary Objective(s) & Hypothesis (es) ............................................................. 11 
2.2 
Secondary Objective(s) & Hypothesis (es) .......................................................... 11 
2.3 
Exploratory Objective .......................................................................................... 11 
3.0 
BACKGROUND & RATIONALE .......................................................................... 12 
3.1 
Background ........................................................................................................... 12 
3.1.1 Pharmaceutical and Therapeutic Background..................................................... 14 
3.1.2 Preclinical and Clinical Study Data .................................................................... 14 
3.2 
Rationale…………………………………………………………………………15 
3.2.1 Rationale for the Study and Selected Subject Population ................................... 15 
3.2.2 Rationale for Dose Selection/Regimen/Modification ......................................... 16 
3.2.3 Rationale for Endpoints ...................................................................................... 17 
4.0 
Study Design .............................................................................................................. 17 
4.1 
Study Diagram ...................................................................................................... 17 
4.2 
Eligibility Criteria ................................................................................................. 17 
4.2.1 Inclusion Criteria ................................................................................................ 17 
4.2.2 Exclusion Criteria ............................................................................................... 19 
4.3 
Subject Withdrawal/Discontinuation Criteria ................................................... 21 
4.4 
Clinical Criteria for Early Study Termination .................................................. 22 
5.0 
Investigational Products ........................................................................................... 22 
5.1 
Pembrolizumab ..................................................................................................... 22 
5.1.1 Formulation/packaging/storage ........................................................................... 22 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 6 of 77 
 
5.1.2 Doses and treatment regimen .............................................................................. 23 
5.1.3 Study drug preparation ........................................................................................ 23 
5.1.4 Dose administration ............................................................................................ 23 
5.1.5 Monitoring of dose administration ...................................................................... 23 
5.1.6 Accountability and dispensation ......................................................................... 24 
5.1.7 Disposal of unused investigational study drug ................................................... 24 
5.2 
Paclitaxel 24 
5.2.1 Formulation/packaging/storage ........................................................................... 24 
5.2.2 Doses and treatment regimen .............................................................................. 24 
5.2.3 Product preparation ............................................................................................. 24 
5.2.4 Dose administration ............................................................................................ 24 
5.2.5 Monitoring of dose administration ...................................................................... 24 
5.2.6 Disposal of unused product ................................................................................. 24 
5.3 
Carboplatin ............................................................................................................ 25 
5.3.1 Formulation/packaging/storage ........................................................................... 25 
5.3.2 Doses and treatment regimen .............................................................................. 25 
5.3.3 Product preparation ............................................................................................. 25 
5.3.4 Dose administration ............................................................................................ 25 
5.3.5 Monitoring of dose administration ...................................................................... 25 
5.3.6 Disposal of unused product ................................................................................. 25 
6.0 
Treatment Plan.......................................................................................................... 25 
Table 1 Study Treatment...................................................................................................... 26 
6.1 
Study description .................................................................................................. 27 
6.2 
Subject recruitment and enrollment ................................................................... 27 
6.2.1 Subjects who qualify for preoperative laparoscopic assessment ........................ 28 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 7 of 77 
 
6.2.2 Subjects who do not undergo preoperative laparoscopic assessment ................. 28 
6.2.3 Subjects who have had previous NACT treatment ............................................. 28 
6.2.4 Subjects who have had interval debulking surgery. ............................................ 28 
6.3 
Dose Selection/Modification ................................................................................. 28 
6.3.1 Dose Selection .................................................................................................... 28 
6.3.2 Dose Modification .............................................................................................. 29 
Table 2: Dose modification guidelines for drug-related adverse events. ......................... 29 
Table 3: Criteria for treatment modifications and management of toxicities ................. 32 
6.4 
Timing of Dose Administration ........................................................................... 36 
6.4.1 Dosing of Pembrolizumab .................................................................................. 36 
6.4.2 Dosing of Paclitaxel ............................................................................................ 36 
6.4.3 Dosing of Carboplatin ......................................................................................... 37 
6.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 37 
6.5.1 Acceptable Concomitant Medications ................................................................ 38 
6.5.2 Prohibited Concomitant Medications ................................................................. 38 
6.6 
Rescue Medications & Supportive Care ............................................................. 39 
6.6.1 Supportive Care Guidelines ................................................................................ 39 
Table 4 Infusion Reaction Treatment Guidelines .............................................................. 43 
6.6.2 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) ...................................................................................... 44 
Table 5 GENERAL Approach to Handling irAEs ............................................................ 44 
6.7 
Diet/Activity/Other Considerations ..................................................................... 45 
6.7.1 Diet ...................................................................................................................... 45 
6.7.2 Contraception ...................................................................................................... 45 
6.7.3 Use in Pregnancy ................................................................................................ 45 
6.7.4 Use in Nursing Women ....................................................................................... 46 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 8 of 77 
 
7.0 
Study Procedures ...................................................................................................... 46 
7.1 
Schedule of Assessments and Segments .............................................................. 47 
7.1.1 Schedule of Assessments .................................................................................... 47 
7.1.2 Screening Phase .................................................................................................. 50 
7.1.3 Treatment Phase .................................................................................................. 50 
7.1.4 Safety Follow-Up Visit ....................................................................................... 51 
7.1.5 Follow-up Visits .................................................................................................. 51 
7.1.6 Survival Follow-up ............................................................................................. 51 
7.1.7 Withdrawal/Discontinuation ............................................................................... 51 
7.2 
Description of study procedures .......................................................................... 52 
7.2.1 Medical history and physical exam ..................................................................... 52 
7.2.2 Laboratory Procedures/Assessments................................................................... 52 
7.3 
Pharmacodynamics Sampling ............................................................................. 52 
7.3.1 Collection, Storage, and Handling of Specimen (s) ............................................ 52 
7.3.2 Pharmacodynamics Procedures (PD) .................................................................. 53 
7.3.3 Analyses and Processes for Ovarian Cancer Moon Shot Program ..................... 53 
7.3.4 Analyses and Process for QualTek Molecular Laboratories ............................... 54 
7.4 
Withdrawal of informed consent for donated biological samples .................... 54 
8.0 
Disease Evaluation and Methods ............................................................................. 55 
8.1 
Tumor Imaging and Assessment of Disease (RECIST v1.1) ............................. 55 
8.1.1 Physical examination .......................................................................................... 55 
8.1.2 Radiological Imaging Guidelines/Procedures ..................................................... 55 
8.2 
Measurability of Tumor Lesions ......................................................................... 55 
8.3 
Response Criteria .................................................................................................. 56 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 9 of 77 
 
8.3.1 Evaluation of Target Lesions .............................................................................. 56 
8.3.2 Evaluation of Non-target Lesions ....................................................................... 57 
8.3.3 Appearance of New Lesions ............................................................................... 57 
8.3.4 Evaluation of Overall Response with Modifications .......................................... 57 
Table 6. Evaluation of Overall Response ............................................................................ 58 
Table 7. Evaluation of Overall Response ............................................................................ 58 
8.4 
MRI Scans ............................................................................................................. 59 
8.4.1 Measurability of Tumor Lesions   .................................................................... 59 
8.4.2 Tumor lesions are categorized as follows: .......................................................... 59 
8.4.3 Response Criteria ................................................................................................ 60 
9.0 
Safety Assessments .................................................................................................... 61 
9.1 
Assessing and Recording Adverse Events .......................................................... 61 
9.1.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
MDACC and to Merck ........................................................................................ 63 
9.1.2 Reporting of Pregnancy and Lactation to the MDACC and to Merck................ 63 
9.1.3 Immediate Reporting of Adverse Events to the MDACC and to Merck ............ 63 
9.1.4 Evaluating Adverse Events ................................................................................. 67 
9.1.5 Attribution of Adverse Events ............................................................................ 67 
9.1.6 MDACC Responsibility for Reporting Adverse Events ..................................... 67 
10.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 68 
10.1 
Statistical Analysis Plan Summary ..................................................................... 68 
11.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 71 
11.1 
Investigational Product ........................................................................................ 71 
12.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 72 
12.1 
Confidentiality ....................................................................................................... 72 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 10 of 77 
 
12.2 
Compliance with Financial Disclosure Requirements ....................................... 72 
12.3 
Compliance with Law, Audit and Debarment ................................................... 72 
12.4 
Compliance with Study Registration and Results Posting Requirements ....... 73 
12.5 
Quality Management System ............................................................................... 73 
12.6 
Data Management ................................................................................................. 73 
13.0 
REFERENCES .......................................................................................................... 74 
 
 
 
 
 
 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 11 of 77 
 
1.0 STUDY SUMMARY 
Abbreviated Title 
Pembrolizumab with Chemotherapy in Frontline Ovarian Cancer 
Study Phase 
II 
Clinical Indication 
Primary Ovarian, Peritoneal, or Fallopian Tube Cancer 
Study Type 
Feasibility Study 
Type of control 
NACT patient population 
Route of administration 
IV 
Treatment Groups  
Pembrolizumab 
+ 
paclitaxel/carboplatin; 
Pembrolizumab 
maintenance 
Number of Study subjects 
30 
Estimated duration of Study 36 months 
Duration of Participation 
14 months 
 
 
 
 
2.0 OBJECTIVE(S) & HYPOTHESIS (ES) 
2.1 
Primary Objective(s) & Hypothesis (es) 
(1) Objective:  To evaluate progression-free survival of paclitaxel/carboplatin and pembrolizumab in 
patients with advanced stage, metastatic ovarian cancer undergoing NACT. 
Hypothesis: The treatment program will be associated with prolonged PFS relative to contemporary 
controls treated with standard care chemotherapy 
2.2 
Secondary Objective(s) & Hypothesis (es) 
(1) Objectives:  
a. To describe the feasibility of combination therapy and maintenance pembrolizumab in this 
population 
b. To evaluate the safety of combination and maintenance pembrolizumab 
c. To report overall survival 
2.3 
Exploratory Objective 
(1) 
Objectives: 
i. To describe the sequential effects of chemotherapy on immune response and PD-
1 expression and receptor occupancy 
ii. To evaluate circulating lymphoid populations (subsets) 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 12 of 77 
 
iii. To determine tissue PD-L1 expression and T-cell infiltration 
3.0 BACKGROUND & RATIONALE 
3.1 
Background 
Ovarian Cancer: Primary epithelial ovarian cancer is an orphan disease for which little substantive 
progress has been made over the last 30 years. Nevertheless prevalence is increasing (currently nearing 
200,000 affected women), due to 
several intrinsic and extrinsic 
factors such as better and more 
aggressive 
surgical 
and 
supportive medical care, as well 
as, an increasing cache of active 
agents, 
used 
alone, 
in 
combination, and sequentially in 
these patients over a long 
duration 
of 
time. 
Median 
survival for the collective is 
approaching 5 years despite 
there 
being 
no 
measurable 
increase in cure rates.1 Ovarian 
Cancer Moonshot: Both of 
these elements in care are the 
focus of the M. D. Anderson 
Ovarian Cancer Moonshot. This ambitious program, the goal of which is to reduce mortality in these 
diseases, combines high grade serous ovarian cancer with triple negative breast cancer due to high fidelity 
genomic homology and opportunity to share surgical and medical strategy to accomplish its mission.2 As 
part of the ovarian cancer Flagship surgical project most patients with suspected primary ovarian cancer 
undergo a preoperative laparoscopic assessment to accomplish the following: diagnosis, metastatic disease 
burden score (modified Fagotti score), tissue acquisition.3 Confirming a primary in the ovary, fallopian tube 
and peritoneum, the disease burden score is used to triage primary cytoreduction or use of neoadjuvant 
chemotherapy followed by interval cytoreduction. The tissue sampling (along with blood and urine) is 
integral to the program and is directed in nature. That is, all patients have tissue collection from the primary 
(ovary or fallopian tube), the omentum, and at least 2 metastatic peritoneal sites. Additional reservoirs in 
the pelvic peritoneum (in the absence of adnexa or adnexal disease) and intestinal mesentery may be taken. 
Triage to surgical approach is made based on the likelihood of leaving residual disease (non-R0 resection). 
Our laparoscopic triage is accomplished by scoring made by two independent and blinded surgeons; those 
patients scored <10 undergo primary cytoreduction (with up to a 2 week interval). Those with scores ≥10 
undergo neoadjuvant chemotherapy (NACT, 3 cycles) followed by interval surgery followed by 3 cycles 
of chemotherapy (± maintenance therapy). Prior to April 1, 2018, patients with scores <8 underwent 
primary cytoreduction (with up to a 2 week interval), and patients with scores ≥8 underwent neoadjuvant 
chemotherapy (3 cycles) followed by interval surgery followed by 3 cycles of chemotherapy (± 
maintenance therapy).  
Our previous laparoscopic scoring algorithm used from April 1, 2013 until March 31, 2018 was based on 
initial laparoscopic scoring algorithm published by Fagotti et al. which identified a predictive index value 
(PIV) cutoff of 8 to avoid a suboptimal primary tumor reductive surgery and these patients being 
Figure 1 describes the general algorithm of laparoscopic triage in MS.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 13 of 77 
 
dispositioned to neoadjuvant chemotherapy. This laparoscopic model has been revised based on additional 
data presented by the Fagotti group in 2015, which revealed when excluding those patients that had 
mesenteric retraction and miliary carcinomatosis on the small bowel by laparoscopic assessment, a 
predictive index value cutoff of 10 could be used to avoid a suboptimal primary tumor cytoreduction and 
these patients being dispositioned to neoadjuvant chemotherapy. Thus, at our institution we implemented a 
change to our laparoscopic scoring algorithm on April 1, 2018, in which patients scoring PIV <10 without 
mesenteric retraction or small bowel miliary carcinomatosis will be dispositioned to primary tumor 
reductive surgery, and patients scoring PIV ≥ 10 will receive neoadjuvant chemotherapy.  
At surgery, repeated tissue, blood and urine are collected. All tissue is fresh frozen and stored, and 
annotated. This strategy has been accomplished in nearly 80 consecutive patients (~10/month) with 
compliance over 95%. Tissue pairing is available in nearly 50 patients treated with standard 
paclitaxel/carboplatin (predominately dose dense paclitaxel). Optimal (R0) resection has improved to 
greater than 90% in both surgical strata, which represents a substantial improvement over historical rates. 
Novel Therapeutics: Often quoted survival data from clinical study experience suggests primary ovarian 
cancer is a chemo-sensitive disease with measurable responses occurring in up to 70% of patients with 50% 
of these being complete responses. However, pathological complete response after induction NACT is rare 
(4-6%) and recurrence after clinical CR (after 6-8 cycles) is observed in nearly 75% of patients at a median 
of 10 months (suboptimal) to 28 months (R0).4-7 This highlights the need for better frontline therapy, since 
recurrent disease is seldom curable. Several novel biological agents have been, or are being, investigated 
in front-line phase III studies including bevacizumab (GOG-218, ICON-7), nintedanib (LUME-1), 
trebananib (TRINOVA-3), and veliparib. Of the three anti-angiogenesis studies completed, none has 
improved overall survival, and impact on PFS has been modest. It is largely appreciated that immune 
evasion and suppression is a central feature of the ovarian cancer microenvironment. Immune abrogation 
has also been linked to primary and adaptive chemoresistance and angiogenesis.8 Thus, prolonged 
immunocompetence represents the most promising intervention to achieve lasting tumor suppression 
promoting survival. Despite its promise and significant attention over the last 35 years, little progress has 
been made with various immunotherapeutic approaches, including peptide-based vaccination, poxviral 
vectors, carbohydrate based vaccines, dendritic cell-based vaccination, lymphocyte-based vaccination, and 
most recently immunotherapy.9 Governance of T-cell activation in the tumor microenvironment occurs via 
an intricate network of regulatory pathways. Negative regulatory pathways are controlled through CTLA4, 
B7-H1, and B7-H4 (among others), and positive regulatory pathways are controlled through CD28, B7 
family members, tumor necrosis factor and tumor necrosis factor receptor family members (e.g., CD40), 
and inducible T-cell costimulator. Undesired autoimmunity against cancer in the microenvironment is 
promoted under conditions of chronic T-cell exposure to tumor-associated antigens. Cytotoxic T-
lymphocyte antigen 4 (CTLA-4) and PD-1 function normally to counteract T-cell activation to self-
antigens. However, they serve as one of several mechanisms leveraged by tumors to promote immune 
escape to normal surveillance. CTLA-4 and PD-1 signaling contribute to CD4+ CD25+ regulatory T cell 
(Treg) activation with decreases antigen presenting cell function and effector T-cell proliferation.10 Further, 
PD-1 contributes to T-cell exhaustion in peripheral tissues. Clinical experience with agents targeting PD-
1/PD-L1 and CTLA-4 are limited but responses to both classes of agents have been observed among ovarian 
cancer patients enrolled in phase I studies of solid tumors.  
Strategy: To better inform primary therapy strategies with sequential and combined chemotherapy and 
Pembrolizumab. Safety of paclitaxel/carboplatin/Pembrolizumab has been shown in NSCLC. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 14 of 77 
 
3.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has 
been known for decades [1]. Accumulating evidence shows a correlation between tumor-infiltrating 
lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies [2; 3; 4; 5; 6]. 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) [7; 8]. The structure of murine PD-1 has been resolved [9]. 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 CD3, PKC and ZAP70 which are involved in 
the CD3 T-cell signaling cascade [7; 10; 11; 12]. 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 [13; 14]. 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 [15; 16]. Expression has also been shown 
during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17]. 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 [18; 19; 20; 13]. 
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 [13]. Although 
healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in 
subjects with melanoma (MEL) [21]. 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 (previously known as SCH 900475) 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.  
3.1.2 Preclinical and Clinical Study Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 


 
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3.2 
Rationale 
3.2.1 Rationale for the Study and Selected Subject Population 
Often quoted survival data from clinical study experience suggests primary ovarian cancer is a chemo-
sensitive disease with measurable responses occurring in up to 70% of patients with 50% of these being 
complete responses. However, pathological complete response after induction NACT is rare (4-6%) and 
recurrence after clinical CR (after 6-8 cycles) is observed in nearly 75% of patients at a median of 10 months 
(suboptimal) to 28 months (R0).4-7 This highlights the need for better frontline therapy, since recurrent 
disease is seldom curable. Several novel biological agents have been, or are being, investigated in front-
line phase III studies including bevacizumab (GOG-218, ICON-7), nintedanib (LUME-1), Trebananib 
(TRINOVA-3), and veliparib. Of the three anti-angiogenesis studies completed, none has improved overall 
survival, and impact on PFS has been modest. It is largely appreciated that immune evasion and suppression 
is a central feature of the ovarian cancer microenvironment. Immune abrogation has also been linked to 
primary and adaptive chemoresistance and angiogenesis.8 Thus, prolonged immunocompetence represents 
the most promising intervention to achieve lasting tumor suppression promoting survival. Despite its 
promise and significant attention over the last 35 years, little progress has been made with various 
immunotherapeutic approaches, including peptide-based vaccination, poxviral vectors, carbohydrate based 
vaccines, dendritic cell-based vaccination, lymphocyte-based vaccination, and most recently 
immunotherapy.9 Governance of T-cell activation in the tumor microenvironment occurs via an intricate 
network of regulatory pathways. Negative regulatory pathways are controlled through CTLA4, B7-H1, and 
B7-H4 (among others), and positive regulatory pathways are controlled through CD28, B7 family members, 
tumor necrosis factor and tumor necrosis factor receptor family members (e.g., CD40), and inducible T-
cell costimulator. Undesired autoimmunity against cancer in the microenvironment is promoted under 
conditions of chronic T-cell exposure to tumor-associated antigens. Cytotoxic T-lymphocyte antigen 4 
(CTLA-4) and PD-1 function normally to counteract T-cell activation to self-antigens. However, they serve 
as one of several mechanisms leveraged by tumors to promote immune escape to normal surveillance. 
CTLA-4 and PD-1 signaling contribute to CD4+ CD25+ regulatory T cell (Treg) activation with decreases 
antigen presenting cell function and effector T-cell proliferation.10 Further, PD-1 contributes to T-cell 
exhaustion in peripheral tissues. Clinical experience with agents targeting PD-1/PD-L1 and CTLA-4 are 
limited but responses to both classes of agents have been observed among ovarian cancer patients enrolled 
in phase I studies of solid tumors. To better inform primary therapy strategies with sequential and combined 
chemotherapy and Pembrolizumab. Safety of paclitaxel/carboplatin/Pembrolizumab has been shown in 
NSCLC. 
The selected subject population are women with advanced stage, metastatic ovarian cancer. Although our 
goal is to triage patients with suspected ovarian cancer by following the Ovarian Cancer Moon Shot 
algorithm described above, patients may still be considered eligible to participate on this trial even if they 
do not undergo a preoperative laparoscopic evaluation at MD Anderson as long as they have already 
received no more than four cycles of prior neoadjuvant chemotherapy or have a disposition to neoadjuvant 
chemotherapy with planned interval tumor reductive surgery. For instance, some patients may have 
undergone a laparoscopic evaluation at another hospital, they may be found to have extensive disease via 
other imaging, or they may have been diagnosed with primary ovarian cancer at another hospital. In each 
of these instances the preoperative laparoscopy would not be necessary. In cases where a preoperative 


 
Investigational Drug  
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laparoscopy will not be performed, adequate tissue from a diagnostic or research biopsy will be required to 
meet the primary objective of this study. 
3.2.2 Rationale for Dose Selection/Regimen/Modification  
The dose regimen of 200 mg Q3W of pembrolizumab is planned for all urothelial cancer trials. Available 
PK results in subjects with melanoma, NSCLC, and other solid tumor types support a lack of meaningful 
difference in PK exposures obtained at a given dose among tumor types. An open-label Phase 1 trial 
(PN001) in melanoma subjects is being conducted to evaluate the safety and clinical activity of single agent 
pembrolizumab. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 
10 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumors. All three dose levels 
were well tolerated and no dose-limiting toxicities were observed. This first in human study of 
pembrolizumab 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 maximum tolerated dose (MTD) has been 
identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma subjects receiving pembrolizumab at 
a dose of 2 mg/kg versus 10 mg/kg Q3W have been completed. The clinical efficacy and safety data 
demonstrate a lack of clinically important differences in efficacy response or safety profile at these doses. 
For example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab therapy were 
randomized to receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W. The overall response rate (ORR) 
was 26% (21/81) in the 2mg/kg group and 26% (25/79) in the 10 mg/kg group (full analysis set (FAS)). 
The proportion of subjects with drug-related adverse events (AEs), grade 3-5 drug-related AEs, serious 
drug-related AEs, death or discontinuation due to an AE was comparable between groups or lower in the 
10 mg/kg group.  
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor types support 
a lack of meaningful difference in pharmacokinetic exposures obtained at a given dose among tumor types. 
Population PK analysis has been performed and has confirmed the expectation that intrinsic factors do not 
affect exposure to pembrolizumab to a clinically meaningful extent. Taken together, these data support the 
use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid tumor indications. 2 mg/kg Q3W 
is being evaluated in NSCLC in PN001, Cohort F30 and PN010, and 200 mg Q3W is being evaluated in 
head and neck cancer in PN012, which are expected to provide additional data supporting the dose selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on simulation results 
indicating that 200 mg will provide exposures that are reasonably consistent with those obtained with 2 
mg/kg dose and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response. A population PK model, which 
characterized the influence of body weight and other patient covariates on exposure, has been developed 
using available data from 476 subjects from PN001. The distribution of exposures from the 200 mg fixed 
dose are predicted to considerably overlap those obtained with the 2 mg/kg dose, with some tendency for 
individual values to range slightly higher with the 200 mg fixed dose. The slight increase in PK variability 
predicted for the fixed dose relative to weight-based dosing is not expected to be clinically important given 
that the range of individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety. 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 tumor types and indication settings.  


 
Investigational Drug  
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3.2.3 Rationale for Endpoints 
3.2.3.1 Efficacy Endpoints: The primary endpoint for this trial is progression-free 
survival with secondary endpoints of safety, tolerability, overall survival, and 
translational endpoints of immune response elements in blood and tumor tissue. The trial 
is powered for efficacy against a contemporarily evaluated cohort defined by primary 
inoperability (discussed above). Our provision of the estimated PFS in this population 
is based on historical data of NACT trials and our own patient population similarly 
defined. This is outlined in detail in the Statistical Analysis Plan, Section 10.0)  
3.2.3.2 Biomarker Research: There is the potential that certain immune markers may 
predict response to immunotherapy agents including pembrolizumab. PD-L1 
overexpression correlates with malignancy and immune regulation in ovarian cancer.11 
PD-L1 has been suggested to predict anti-PD-1 responses (Antonia S, 2013 abst). In a 
phase 1 trial of pembrolizumab, pretreatment tumor PD-L1 expression by 
immunohistochemistry (IHC) was a statistically significant predictor of response 
(Garon E, 2013 abst.). We will also examine these geographically paired tissues for 
cellular DNA, RNA, proteins and PD-1 expression, and tumor tissue expression of PD-
L1 (+/- other markers i.e. IDO, LAG-3, TIM-3, ICOS, etc.). See Section 7.3 for details 
 
4.0 STUDY DESIGN 
This is a non-randomized, phase II study to assess progression-free survival of paclitaxel/carboplatin 
and Pembrolizumab for women with advanced stage, metastatic ovarian cancer undergoing 
neoadjuvant chemotherapy. 
 
4.1 
Study Diagram 
 
4.2 
Eligibility Criteria 
Newly diagnosed advanced stage, ovarian, fallopian tube, or primary peritoneal cancer. 
4.2.1 Inclusion Criteria 
In order to be eligible for participation in this study, the subject must have: 


 
Investigational Drug  
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1. Signed, written Informed Consent 
2. Women 18 years of age or older 
3. Histology showing high-grade epithelial non-mucinous ovarian, primary peritoneal, or fallopian 
tube cancer 
4. No more than 4 prior cycles of chemotherapy treatment for primary advanced (Stage III or IV) 
epithelial ovarian, primary peritoneal, or fallopian tube carcinoma. 
5. No prior treatment involving irradiation, hormonal therapy, immunotherapy, investigational therapy, 
and/or other concurrent agents or therapies for ovarian cancer. 
6. A disposition to neoadjuvant chemotherapy with planned interval tumor reductive surgery after 4 
complete cycles of treatment 
7. Planned dose-dense chemotherapy with combination carboplatin and paclitaxel given intravenously  
8. Have measurable disease based on RECIST 1.1.  
a. Measurable disease is defined at least one lesion that can be accurately measured in at least 
one dimension (longest dimension to be recorded). Each “target” lesion must be >20 mm 
when measured by conventional techniques, including palpation, plain x-ray, CT, and MRI, 
or >10 mm when measured by spiral CT. 
b. Patients with non-measurable but evaluable solid tumors may be deemed eligible 
contingent upon PI review. 
9. Peripheral neuropathy Grade 0 or 1 by NCI CTCAE version 4.0 
10. Tissue from an archival tissue sample or fresh tissue obtained from a core or excisional biopsy of a 
tumor lesion. 
11. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
12. Adequate organ function as determined by the following laboratory values: 
a. ANC ≥1,500 /mcL  
b. Platelets ≥100,000 / mcL 
c. Hgb ≥9 g/dL or ≥5.6 mmol/L 
d. Creatinine Clearance ≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 
e. Total Bilirubin ≤ 1.5 X ULN  
OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN 
f. AST (SGOT) and ALT (SGPT) ≤ 2.5 X ULN  
OR ≤ 5 X ULN for subjects with liver metastases 
g. INR/PT 
≤1.5 
X 
ULN 
(unless 
subject 
is 
receiving 
anticoagulant 
therapy 
as long as PT or PTT is within therapeutic range of intended use of anticoagulants) 


 
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h. PTT ≤1.5 X ULN (unless subject is receiving anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use of anticoagulants  
13. Women of child-bearing potential (intact uterus) should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication. Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free from menses for > 
1 year. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.  
14. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be 
surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days 
after the last dose of study medication (Reference Section 6.7.2). Subjects of childbearing potential 
are those who have not been surgically sterilized or have not been free from menses for > 1 year. 
Should a woman become pregnant or suspect she is pregnant while participating in this study, she 
should inform her treating physician immediately. 
15. Pre-treatment fresh frozen tissue if available for research purposes. This tissue can be collected 
from preoperative laparoscopy, other diagnostic biopsy, or a research-specific biopsy. 
16. Signed informed consent on protocol LAB02-188. 
4.2.2 Exclusion Criteria 
The subject must be excluded from participating in the study if the subject: 
1. Is currently participating in or has participated in a study of an investigational agent or using an 
investigational device within 4 weeks of the first dose of treatment. 
2. Histology showing mucinous or low grade epithelial carcinoma 
3. History of another primary malignancy except for: 
• 
Malignancy treated with curative intent and with no known active disease >5 years before 
the first dose of study drug and or low potential risk for recurrence 
• 
Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of 
disease 
• 
Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in 
situ 
• 
Concomitant Stage 1A/B, Grade 1-2 endometrioid endometrial cancer as allowable 
contemporary tumor 
4. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. 
Subjects 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 Study treatment 
and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging 
brain metastases, and are not using steroids for at least 7 days prior to Study treatment.  


 
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5. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-
Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any 
other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). 
6. Patients with ovarian cancer not medically fit for diagnostic laparoscopy prior to initiation of 
therapy 
7. Patients with any evidence of severe or uncontrolled systemic disease (e.g. severe hepatic 
impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease], uncontrolled 
chronic renal disease [glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular 
acidosis]), or current unstable or uncompensated respiratory or cardiac conditions, or uncontrolled 
hypertension blood pressure >140/90, active bleeding diatheses or active infection. 
8. 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 study treatment. 
 
9. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not recovered 
(i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks 
earlier.  
10. 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. 
• 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify 
for the study. 
• 
Note: If subject received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting therapy.  
11. No active autoimmune disease that has required systemic treatment in past two years (i.e. with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy 
(e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
12. Has evidence of interstitial lung disease or active, non-infectious pneumonitis. 
13. Has an active infection requiring systemic therapy. 
14. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might 
confound the results of the study, interfere with the subject’s participation for the full duration of 
the study, or is not in the best interest of the subject to participate, in the opinion of the treating 
investigator.  
15. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the 
requirements of the study. 


 
Investigational Drug  
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16. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected 
duration of the study, starting with the pre-screening or screening visit through 120 days after the 
last dose of study treatment. 
17. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
18. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] 
is detected). 
19. Has received a live vaccine within 30 days prior to the first dose of study treatment.  
20. Patients with tuberculosis. 
21. Patients with known hypersensitivity to pembrolizumab or any of its excipients 
22. Patients receiving concurrent additional biologic therapy 
23. History of allergic reactions attributed to compounds of similar chemical or biologic composition 
to carboplatin, paclitaxel not responsive to traditional desensitization procedures. 
24. Patient that is not able to understand or to comply with the study instructions and requirements or 
has a history of non-compliance to the medical regimen. 
4.3 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the Study at the discretion 
of the investigator should any untoward effect occur. In addition, a subject may be withdrawn by the 
investigator or the MDACC if enrollment into the Study is inappropriate, the Study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding discontinuation or withdrawal are 
provided in Section 7.1.7. 
A subject must be discontinued from the Study for any of the following reasons: 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws consent. 
• 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 8.1.1 
Note: A subject may be granted an exception to continue on treatment with confirmed 
radiographic progression if clinically stable or clinically improved, please see Section 8.1.1 
• 
Unacceptable adverse experiences as described in Section 9.1.3 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 


 
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• 
Noncompliance with Study treatment or procedure requirements 
• 
The subject is lost to follow-up 
• 
Completed 23 total cycles of treatment with Pembrolizumab 
Note: 23 cycles of study medication is calculated from the date of first dose. Subjects who stop 
Pembrolizumab after 23 cycles may be eligible for up to one year of additional study treatment if 
they progress after stopping study treatment provided they meet the requirements detailed in 
Section 6.3.2.1. 
• 
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 7.1 Schedule of Assessments. 
After the end of treatment, each subject will be followed for 30 days for adverse event monitoring (serious 
adverse events will be collected for 90 days after the end of treatment as described in Section 9.1.3. Subjects 
who discontinue for reasons other than progressive disease will have post-treatment follow-up for disease 
status until disease progression, initiating a non-study cancer treatment, withdrawing consent or becoming 
lost to follow-up. After documented disease progression each subject will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end of the study, whichever occurs first. 
4.4 
Clinical Criteria for Early Study Termination 
Early Study termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard 
to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be provided so that 
appropriate adjustments to subject treatment can be made. 
5.0 INVESTIGATIONAL PRODUCTS 
5.1 
Pembrolizumab 
Pembrolizumab will be supplied to the investigator as a powder to be reconstituted for infusion by Merck 
and Co pharmaceutical company. 
5.1.1 Formulation/packaging/storage 
Two Drug Product (DP) dosage forms are available for MK-3475: a white to off-white lyophilized powder, 
50 mg/vial, and a liquid, DP 100 mg/vial, both in Type I glass vials intended for single use only. 


 
Investigational Drug  
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Study Number: 
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5.1.2 Doses and treatment regimen 
Pembrolizumab will be administered in the out-patient setting with paclitaxel and carboplatin. 
Pembrolizumab infusion solution will be administered at a fixed dose of 200 mg IV infusion on day 1 of a 
cycle, every 21 days for 3 cycles (cycle length = 3 weeks) and during maintenance therapy. 
Maintenance therapy will be administered until progression (approximately 10 months) with 
Pembrolizumab 200 mg IV on Day 1 every 21 days. 
Pembrolizumab will be infused prior to paclitaxel and carboplatin. 
5.1.3 Study drug preparation 
The preparation of infusion bags should be done under aseptic conditions by trained personnel; it should 
not be prepared on the ward.  
• 
MK-3475 Powder for Solution for Infusion, 50 mg/vial (manufactured using the partially 
formulated DS), is reconstituted with sterile water for injection prior to use. MK-3475 DP is 
formulated with L-histidine as buffering agent, polysorbate 80 as surfactant, sucrose as 
stabilizer/tonicity modifier, and hydrochloric acid (HCl) and/or sodium hydroxide (NaOH) for pH 
adjustment (if necessary). 
• 
MK-3475 Solution for Infusion 100 mg/vial is a liquid DP (manufactured using the fully formulated 
DS), and has the identical formulation as that of the reconstituted lyophilized vial. 
5.1.4 Dose administration 
Study treatment should be administered on Day 1 of each cycle after all procedures/assessments have been 
completed as detailed in the Schedule of Assessments (Section 7.1). Study treatment may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All Study treatments will be administered on an outpatient basis. Pembrolizumab will be administered first 
and as a 30 minute IV infusion (treatment cycle intervals may be increased due to toxicity as described in 
Section 6.3.2.1). 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). 
Appendix I contains specific instructions for Pembrolizumab dose reconstitution, preparation of the 
infusion fluid, and administration. 
5.1.5 Monitoring of dose administration 
Subjects will be monitored during and after the infusion with assessment of vital signs at the times specified 
in the Schedule of Assessments (see Section 7.1) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent an 
immunologic etiology. The adverse events may occur shortly after the first dose or several months after the 
last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table 2 in Section 6.3.2.1.  


 
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5.1.6 Accountability and dispensation 
The investigator, or a responsible party designated by the investigator, must maintain a careful record of 
the inventory and disposition of the agent using the NCI Drug Accountability Record Form (DARF). See 
the CTEP home page at http://ctep.cancer.gov for the Procedures for Drug Accountability and Storage or 
to obtain a copy of the DARF. 
5.1.7 Disposal of unused investigational study drug 
Standard institutional pharmacy procedures will be followed. 
5.2 
Paclitaxel 
Paclitaxel will be obtained from the institutional pharmacy through standard mechanisms. 
5.2.1 Formulation/packaging/storage 
Per manufacturer’s guidelines. 
5.2.2 Doses and treatment regimen 
Subjects will be administered paclitaxel in line with normal clinical practice, with a dose and schedule of 
80mg/m2 intravenously every week. It is expected that subjects will receive between 3 and 6 cycles of 
paclitaxel. 
5.2.3 Product preparation 
Per manufacturer’s guidelines. 
5.2.4 Dose administration 
Paclitaxel will be dosed at 80 mg/m2 infused according to institutional standards on day 1, 8 and 15 every 
21 days followed by carboplatin. 
Paclitaxel doses should be calculated prior to each course of therapy. Dosing of paclitaxel will be based on 
the subject’s BSA in m2. Paclitaxel dose will be capped at a body surface area (BSA) of 2.0.the 
manufacturer’s guidelines.  
Details of dose preparation and administration is in section 6.4, Timing of Dose Administration, of the 
protocol. 
5.2.5 Monitoring of dose administration 
Per manufacturer’s guidelines. 
5.2.6 Disposal of unused product 
Standard institutional pharmacy procedures will be followed. 


 
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5.3 
Carboplatin 
Carboplatin will be obtained from the institutional pharmacy through standard mechanisms. 
5.3.1 Formulation/packaging/storage 
Per manufacturer’s guidelines. 
5.3.2 Doses and treatment regimen 
Subjects will be administered carboplatin in line with normal clinical practice, with a dose and schedule of 
AUC 6 given intravenously. It is expected that subjects will receive between 3 and 6 cycles of carboplatin. 
5.3.3 Product preparation 
Per manufacturer’s guidelines. 
5.3.4 Dose administration 
Carboplatin will be administered based on the subject’s creatinine clearance and target AUC of 6.  
Carboplatin doses should be calculated prior to each course of therapy. 
Details of dose preparation and administration is in section 6.4., Timing of Dose Administration, of the 
protocol. 
5.3.5 Monitoring of dose administration 
Per manufacturer’s guidelines. 
5.3.6 Disposal of unused product 
Standard institutional pharmacy procedures will be followed. 
6.0 TREATMENT PLAN 
Patients will undergo tissue acquisition followed by neoadjuvant chemotherapy (NACT) during the 
induction phase. Initial clinical measurement of disease will include the following: physical exam, CA125 
and CT imaging. All patients felt to be appropriate surgical candidates will proceed with diagnostic 
laparoscopy for peritoneal disease assessment with issuance of a score by 2 independent blinded surgeons. 
Those patients who score > 8 will be offered NACT per protocol. All patients will undergo repeat clinical 
assessment after 3 cycles of NACT. As part of standard of care this includes physical exam, CA125 and 
CT imaging. It will not include laparoscopy as the scoring system is not validated for use after initiation of 
chemotherapy. Progression after NACT will be defined by RECIST criteria.  
 
 NACT consisting of paclitaxel/carboplatin will be administered at 80mg/ m2 and AUC 6 respectively for a 
total of three cycles followed by interval debulking surgery. A cycle will consist of 21 days. The 
chemotherapy regimen may be administered in an outpatient setting. Patients will be assigned to receive 
treatment every 3 weeks as follows: 


 
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Day 1: Carboplatin at AUC=6 followed by Paclitaxel 80 mg/m2  
Day 8: Paclitaxel 80 mg/m2 
Day 15: Paclitaxel 80 mg/m2 
Day 22: Repeat the cycle- this is Day 1 of the next cycle 
The carboplatin dose is calculated as follows (using a modified Calvert formula): Total 
dose (mg) =Target AUC x (Creatinine clearance + 25) 
Paclitaxel dose will be capped at a body surface area (BSA) of 2.0 
The experimental treatment to be used in this study is outlined below in Table 1 and will be administered 
in combination with carboplatin and paclitaxel following interval cytoreductive surgery. 
 
 
 
 
 
TABLE 1 STUDY TREATMENT 
REGIMEN DESCRIPTION 
 
Agent 
 
Pre-medications; 
Precautions 
 
Dose 
 
Route 
 
Schedule 
 
Cycle 
Length  
Pembrolizumab* 
 
200 mg 
IV 
Day 1 q 
21 days 
 
 


 
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Carboplatin 
1. Pre-medicate 
with Zofran 8 mg 
in 50cc 
  
 NS IVPB 30 min. 
prior to 
Carboplatin 
infusion. 
 
2. Needles or IV 
sets containing 
aluminum that 
may contact the 
drug must not be 
used. 
AUC 6 
reconstituted in 
250cc. 
IV 
 short infusion 
after completion 
of Paclitaxel 
through separate 
IV line 
Day 1 q 21 
days  
 
3 weeks 
(21 
days) 
 
 
 
 
 
 
 
 
Paclitaxel 
Pre-medicate with 
Dexamethasone, 
Diphenhydramine 
and Famotidine 30 
minutes prior to 
Paclitaxel. 
 
80 mg/m2 in 500 
cc in D5W 
IV  
according to 
institutional 
standards 
 before 
Carboplatin 
Day 1, 8 
and 15 
q 21 days 
*Pembrolizumab will be administered prior to paclitaxel and carboplatin. During this phase there will be 3 
infusions before re-imaging at completion 
The Pembrolizumab dosing interval may be increased due to toxicity as described in Section 6.3.2.1. 
 
Maintenance therapy will be administered for up to 20 cycles or until progression with Pembrolizumab 200 
mg IV D1 q 21 days. 
Study treatment should begin as close as possible to the date on which treatment is allocated/assigned. 
6.1 
Study description 
This is a non-randomized, phase II study to assess progression-free survival of paclitaxel/carboplatin 
and Pembrolizumab for women with advanced stage, metastatic ovarian cancer undergoing 
neoadjuvant chemotherapy (NACT). 
6.2 
Subject recruitment and enrollment 
Patients will be recruited from the Department of Gynecologic Oncology and Reproductive Medicine at 
The University of Texas MD Anderson Cancer Center. All new patients with the potential diagnosis of 
advanced stage high grade serous ovarian, primary peritoneal, or fallopian tube cancers will be screened by 
the designated research nurse and/or study investigators for eligibility. Upon referral, they will undergo 
assessment to determine if they are a surgical candidate by their primary physician. Potential surgical 
candidates will be approached for study participation and informed consent about participating on this trial. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
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Date:  
March 10, 2020 
 
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6.2.1 Subjects who qualify for preoperative laparoscopic assessment 
Laparoscopic surgery is part of standard of care practices. At our center, most patients presenting with 
presumed advanced-stage high-grade serous ovarian, fallopian tube, or primary peritoneal cancer are 
considered for laparoscopic tumor evaluation and sample collection prior to a primary tumor reductive 
surgery. A validated scoring system is utilized to determine ability to resect to no gross residual disease 
(R0) (Fagotti et al, 2006). Patients that are scored as < 10 proceed to a primary tumor reductive surgery at 
a later date. Patients that are scored as ≥ 10 will receive neoadjuvant chemotherapy with subsequent interval 
tumor reductive surgery. As part of our standard practice, tissue is obtained at the time of laparoscopy from 
4 sites for diagnosis (described below) and tumor banking for research. Potential subjects that are to undergo 
neoadjuvant chemotherapy based on Fagotti score ≥ 10 will then be informed further about this study, and 
informed consent documents will be reviewed and signed. Patients may elect to leave the study at any time. 
Upon confirmed eligibility, subjects will proceed to treatment as described below. Patients that are to 
undergo upfront tumor reductive surgery based on Fagotti score will not proceed on this trial. 
6.2.2 Subjects who do not undergo preoperative laparoscopic assessment 
In addition to patients described in the section above, others will not qualify for the preoperative 
laparoscopy but can still participate on this trial. Patients with suspected but un-diagnosed disease with 
evidence of not being resectable via scans (e.g. visible lung or abdominal metastases) or who elect not to 
receive a laparoscopy can be enrolled. Fresh tissue from their standard-of-care diagnostic biopsy will be 
used for protocol-specific analyses. Additionally, patients who have a tissue histologic diagnosis may still 
be eligible; however, these subjects may require a biopsy to provide adequate tissue for the primary 
endpoint of this protocol. 
6.2.3 Subjects who have had previous NACT treatment 
Neoadjuvant chemotherapy treatment with carboplatin and paclitaxel is part of standard of care practices. 
At our center, most patients presenting with presumed advanced-stage high-grade serous ovarian, fallopian 
tube, or primary peritoneal cancer are considered for carboplatin and paclitaxel in the neoadjuvant setting. 
Patients that have had no more than four previous induction cycles of carboplatin and paclitaxel as standard 
of care treatment and have fresh frozen tissue will be considered for this trial. Patients must sign consent 
and enroll on study at or prior to the tumor reduction surgery pre-operative visit. Patients who have had 
previous NACT treatment, must have available fresh tissue from their standard-of-care diagnostic biopsy 
to be used for protocol-specific analysis  
6.2.4 Subjects who have had interval debulking surgery. 
Patients who have undergone interval debulking surgery will be considered for this trial. Patients must sign 
consent and enroll on study at or prior to treatment with adjuvant therapy to include carboplatin and 
paclitaxel plus investigational agent, pembrolizumab. Patients may participate provided fresh tissue is 
available from the interval debulking surgery and have not received post-surgical chemotherapy. 
6.3 
Dose Selection/Modification 
6.3.1 Dose Selection 
Pembrolizumab infusion solution will be administered at a fixed dose of 200 mg IV on Day 1 q 21 days. 
Details on the dose preparation and administration are provided in the Study Drug Preparation and 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 29 of 77 
 
Administration document located in Appendix I. Paclitaxel will be administered based on the subject’s BSA 
in m2 according to the manufacturer’s guidelines. Carboplatin will be administered based on the subject’s 
creatinine clearance and target AUC of 6. Details of dose preparation and administration will be as per 
manufacturer’s guidelines. Carboplatin and paclitaxel will be administered according to department 
guidelines. 
6.3.2 Dose Modification  
6.3.2.1 Dose Modification of Pembrolizumab 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may represent an 
immunologic etiology. The adverse events may occur shortly after the first dose or several months after the 
last dose of treatment. Pembrolizumab must be withheld for drug-related toxicities and severe or life-
threatening AEs as per Table 2 below. See Section 9.1.3.2 and Events of Clinical Interest Guidance 
Document for supportive care guidelines, including the use of corticosteroids. 
TABLE 2: DOSE MODIFICATION GUIDELINES FOR DRUG-RELATED 
ADVERSE EVENTS. 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
 
Toxicity resolves to Grade 0-1. 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose. 
3-4 
Permanently discontinue 
(see exception below)1 
Permanently discontinue 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T1DM or  
3-4 
Hold pembrolizumab for new 
onset Type 1 diabetes mellitus 
or Grade 3-4 hyperglycemia 
associated with evidence of 
beta cell failure. 
Resume pembrolizumab when 
patients are clinically and 
metabolically stable. 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab 
can be continued while 
endocrine replacement therapy 
is instituted 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
Hyperthyroidism  
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 30 of 77 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Treatment Discontinuation 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
 
Therapy with pembrolizumab 
can be continued while thyroid 
replacement therapy is 
instituted 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted. 
Infusion 
Reaction 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicity2 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks. 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-
threatening event. 
1 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT 
increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week then patients 
should be discontinued. 
2 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician 
discretion. Permanently discontinue study drug for persistent Grade 2 adverse reactions for which 
treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last 
dose. 
 
Dosing interruptions of pembrolizumab are permitted in the case of medical/surgical events or logistical 
reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be 
documented in the patient’s study record. 
In case toxicity does not resolve to Grade 0-1 within 3 weeks after last infusion, Study treatment should be 
discontinued after consultation with the MDACC. With investigator and MDACC agreement, subjects with 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 31 of 77 
 
a laboratory adverse event still at Grade 2 after 3 weeks may continue treatment in the Study only if 
asymptomatic and controlled. For information on the management of adverse events, see Section 6.6.1.  
Subjects who experience a recurrence of the same severe or life-threatening event at the same grade or 
greater with re-challenge of Pembrolizumab should be discontinued from study treatment. 
Under certain conditions, a dose interruption of carboplatin or paclitaxel may be required. Should the dose 
interruption last for >21 days, the patient should be discontinued from study treatment. Further, if a patient 
does not tolerate the lowest possible dose, treatment with Pembrolizumab must be discontinued. Treatment 
modifications regarding chemotherapy will be employed in a sequential manner using cycle delay and dose 
reduction. Patients who experience grade 4 thrombocytopenia (<25,000 platelets/mcl) or bleeding 
associated with grade 3 thrombocytopenia (25,000 to <50,000/mcl), will have a dose reduction of 
carboplatin one level, without change in paclitaxel dosage. Study treatment modification that results in 
interruption of study treatment for more than 21 days will require premature study treatment 
discontinuation.  
 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 32 of 77 
 
TABLE 
3: 
CRITERIA 
FOR 
TREATMENT 
MODIFICATIONS 
AND 
MANAGEMENT OF TOXICITIES 
Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & Management 
of Toxicities 
NONE 
No toxicity 
Maintain dose level 
HEMATOLOGICAL 
Neutropenia (ANC) 
Grade 1 (ANC < LLN - 1.5 x 109/L)  
Grade 2 (ANC < 1.5 - 1.0 x 109/L) 
Maintain dose level 
Grade 3 (ANC < 1.0 - 0.5 x 109/L)  
Grade 4 (ANC < 0.5 x 109/L) 
On Day 1 of each cycle: 
Hold all treatment if ANC < 1.0 x 109/L 
On Days 8 & 15 of each cycle: 
Hold treatment (paclitaxel only) if ANC < 0.5 x 109/L 
 
First occurrence: 
Hold all treatment (chemotherapy and Pembrolizumab) 
until ANC ≥ 1.0 x 109/L then (may give G-CSF): 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then  1 dose level (all 
treatment) 
Second occurrence: 
Hold all treatment (may give G-CSF) until ANC,≥ 1.0 x 
109/L ,then  1 dose level (all treatment) 
Febrile neutropenia  
(ANC < 1.0 x 109/L, fever ≥ 38.5°C) 
or Grade 3/4 neutropenia with 
documented infection 
First occurrence: 
Hold all treatment until resolved to ≤ Grade 2 (may 
give G-CSF):, then: 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then  1 dose level (all 
treatment) 
Second occurrence: 
Hold all treatment until resolved to ≤ Grade 2 (may 
give G-CSF), then  1 dose level (all treatment) or 
discontinue patient from study treatment at the 
investigator’s discretion 
Thrombocytopenia 
Grade 1 (PLT < LLN - 75 x 109/L) 
Grade 2 (PLT < 75 - 50 x 109/L) 
Maintain dose level unless Day 1 of each cycle: 
Hold all treatment if PLT < 100 x 109/L 
 
On all other study days; maintain dose level. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
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Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & Management 
of Toxicities 
Grade 3 (PLT < 50-25 x 109/L) 
On days 8 & 15 of each cycle: 
Hold treatment (paclitaxel only) if PLT < 50 x 109/L 
 
First occurrence: 
Hold all treatment until resolved to ≤ Grade 1, then: 
• If resolved in ≤ 7 days, then maintain dose level 
• If resolved in > 7 days, then  1 dose level (all 
treatment) 
Second occurrence: 
Hold all treatment until resolved to ≤ Grade 1, then  1 
dose level (all treatment) 
Grade 4 (PLT < 25 x 109/L) 
First occurrence: 
Hold all treatment until resolved to ≤ Grade 1, then  1 
dose level (all treatment) 
Second occurrence: 
Hold all treatment until resolved to ≤ Grade 1, then  1 
dose level (all treatment) or discontinue patient from 
study treatment at the investigator’s discretion 
HEPATIC 
Bilirubin** 
(for patients with Gilbert Syndrome these dose modifications apply to changes in direct bilirubin 
only) 
Grade 1 (> ULN - 1.5 x ULN) 
Maintain dose level 
Grade 2 (> 1.5 - 3.0 x ULN), with 
ALT or AST ≤ 3.0 x ULN 
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days, then maintain dose level 
• 
If resolved in > 7 days, then  1 dose level (all 
treatment) 
Grade 3 (> 3.0 - 10.0 x ULN), with 
ALT or AST ≤ 3.0 x ULN 
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days,  1 dose level (all 
treatment) 
• 
If resolved in > 7 days discontinue patient from 
study treatment** 
Continue to monitor LFTs* every other week or more 
frequently if clinically indicated until the end of 
treatment with study medication. 
Grade 4 (> 10.0 x ULN) 
Hold all treatment and discontinue patient from 
Pembrolizumab therapy** 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 34 of 77 
 
Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & Management 
of Toxicities 
 
AST or ALT** 
Grade 1 (> ULN - 3.0 x ULN) 
Grade 2 (> 3.0 - 5.0 x ULN) if not 
increased from baseline and without 
bilirubin elevation to > 2.0 x ULN 
Maintain dose level 
Grade 2 (> 3.0 - 5.0 x ULN) if 
increased from baseline and without 
bilirubin elevation to > 2.0 x ULN  
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ grade 1, then 
• 
If resolved in ≤ 7 days, then maintain dose level 
• 
If resolved in > 7 days, then ↓ 1 dose level (all 
treatment) 
Grade 3 (> 5.0 - 20.0 x ULN) without 
bilirubin elevation to > 2.0 x ULN 
Hold all treatment and monitor LFTs* weekly until 
resolved to ≤ Grade 1 (or ≤ Grade 2 in case of liver 
metastasis), then 
• 
If resolved in ≤ 7 days, then maintain dose level 
• 
If resolved in > 7 days, then  1 dose level (all 
treatment) 
Continue to monitor LFTs* every other week or more 
frequently if clinically indicated until the end of 
treatment with study medication. 
Grade 4 (> 20.0 x ULN) without 
bilirubin elevation to > 2.0 x ULN 
Hold all treatment until resolved to ≤ grade 1, then ↓ 1 
dose level (all treatment) 
 
Worst toxicity (CTCAE Grade)** 
Recommended Dose Modifications & 
Management of Toxicities 
Drug induced liver injury (Hy’s Law) 
Patients with AST/ALT > 3 x ULN and total bilirubin > 2 x ULN with no evidence of 
obstruction (such as elevated ALP, malignancy, impaired glucuronidation (Gilbert syndrome) or 
pharmacologic factors), with no other explanation (e.g. viral, alcoholic or autoimmune hepatitis, 
hepatobiliary disorders, cardiovascular causes, concomitant medications) may have drug-
induced liver injury.  
In such cases,  
• 
discontinue** the patient from Pembrolizumab (remove from study but may continue 
chemotherapy at discretion of study chair) and report as SAE. 
In any case,  
• 
monitor patient, including LFTs*, weekly or more frequently if clinically indicated until 
resolved to ≤ grade 1 or stabilization.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 35 of 77 
 
* LFTs include: albumin, ALT, AST, total bilirubin (fractionated if total bilirubin > 2.0 x ULN), 
AP (fractionated if AP is grade 2 or higher) and GGT). For patients with Gilbert Syndrome: total 
and direct bilirubin must be monitored, intensified monitoring applies to changes in direct 
bilirubin only. 
** Patients who discontinue study treatment should be monitored weekly, including LFTs or 
more frequently if clinically indicated until resolved to ≤ grade 1 or stabilization (no CTCAE 
grade change over 4 weeks). 
Fatigue (asthenia) 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Hold all treatment until resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days, maintain dose level 
• 
If resolved in > 7 days,  1 dose level (all 
treatment) 
Grade 4 
Hold all treatment and discontinue patient from 
Pembrolizumab (may continue chemotherapy at 
discretion of study chair). 
Peripheral neuropathy 
Grade 1 or 2 
Maintain dose level 
Grade 3 
Hold all treatment until resolved to ≤ Grade 1, then: 
• 
If resolved in ≤ 7 days, maintain dose level 
• 
If resolved in > 7 days,  1 dose level (paclitaxel 
only) 
Grade 4 
Hold all treatment and discontinue patient from 
Pembrolizumab (may continue chemotherapy at 
discretion of study chair). 
** Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. 
 
 
6.3.2.2 
Dose Modification of Paclitaxel 
6.3.2.2.1 Docetaxel (Taxotere) Substitution 
Chemotherapy induced neuropathy is a known hematologic toxicity associated with paclitaxel. Studies that 
compared docetaxel-carboplatin versus paclitaxel-carboplatin as first line chemotherapy for ovarian cancer 
indicated docetaxel-carboplatin appears to be similar in treatment response and progression-free survival 
to paclitaxel-carboplatin. For the purposes of this trial, docetaxel may be substituted according to standard 
of care practices for patients with a contraindication to IV paclitaxel. 
 All patients should be pre-medicated with oral corticosteroids for 3 days starting 1 day prior to 
docetaxel administration in order to reduce the incidence and severity of fluid retention as well as the 
severity of hypersensitivity reactions. Please refer to Table 3 in section 6.3.2.1 for guidelines on 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 36 of 77 
 
treatment modifications and management of toxicities. Refer to paclitaxel language for guidance with 
docetaxel substitution. 
If treatment is delayed more than 21 days for reasons of toxicity, then protocol-directed therapy is ended. 
6.4 
Timing of Dose Administration 
Study treatment should be administered on Day 1 of each cycle after all procedures/assessments have been 
completed as detailed on the Schedule of Assessments (Section 7.1). Study treatment may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons. 
All Study treatments will be administered on an outpatient basis. 
Post-operative adjuvant therapy will commence once the patient’s treating physician deems the patient’s 
medical condition appropriate for adjuvant therapy. Therapy will start no sooner than 3 weeks 
postoperatively and no longer than 6 weeks postoperatively. 
6.4.1 Dosing of Pembrolizumab 
Pembrolizumab will be administered first and as a 30 minute IV infusion (treatment cycle intervals may be 
increased due to toxicity as described in Section 6.3.2.1). 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). 
Appendix I contains specific instructions for Pembrolizumab dose reconstitution, preparation of the 
infusion fluid, and administration. 
6.4.2 Dosing of Paclitaxel 
Paclitaxel will be dosed at 80 mg/m2 infused according to institutional standards on day 1, 8 and 15 every 
21 days followed by carboplatin for 3 cycles. 
Paclitaxel dose will be capped at a body surface are (BSA) of 2.0. 
Preparative regimen for paclitaxel: for all courses where paclitaxel is to be administered, it is recommended 
that a preparative regimen be employed to reduce the risk associated with hypersensitivity reactions. This 
regimen should include dexamethasone (either IV or p.o.), anti-histamine H1 (such as diphenhydramine) 
or anti-histamine H2 (such as cimetidine, rantidine, or famotidine). 
Recommendations for premedication are for dexamethasome 20 mg IV, diphenhydramine 50 mg IV and 
famotidine 20 mg IV 30 minutes prior to administration of paclitaxel.  
Suggested method of chemotherapy administration: paclitaxel (infusion according to institutional 
standards) plus carboplatin (1 hour infusion): Premedications dexamethasone 20 mg IV, diphenhydramine 
50 mg IV and famotidine 20 mg IV 30 minutes prior to administration. Paclitaxel administered (if 
ondansetron 8 mg IV needs to be given during paclitaxel infusion, it should be 30 minutes prior to 
carboplatin infusion) followed by carboplatin 1 hour infusion. The regimen can be administered in an 
outpatient setting.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 37 of 77 
 
The cycle length is three weeks (21 days). Treatment with protocol therapy will continue until one or more 
of the criteria listed in the discontinuation section are met.  
6.4.3 Dosing of Carboplatin 
Carboplatin will be dosed on AUC of 6 on Day 1 every 21 days following administration of paclitaxel. 
The dose will be calculated to reach a target area under the curve (AUC) of concentration x time according 
to the Calvert formula using an estimated calculated creatinine clearance to present the glomerular filtration 
rate (GFR).  
Preparative regimen for carboplatin: An antiemetic regimen is recommended. The antiemetic regimen used 
should be based on peer-reviewed consensus guidelines. Suggested regimen is ondansetron 8 mg IV given 
30 minutes prior to administration of carboplatin.  
Carboplatin solutions will be infused IV over 60 minutes on Day 1 of each cycle. Dosing of carboplatin 
will be based on the Calvert formula: carboplatin dose (mg) = (Target AUC) x (GFR + 25). For the purposes 
of this protocol, the GFR is considered to be equivalent to the estimated creatinine clearance (calculated by 
the method of Cockcroft and Gault, 1976). Maximum GFR is not to exceed 125 ml/minute.  
Creatinine clearance (CrCl) from IDMS reported serum creatinine (using current [actual] weight): 
 
 
 
 
CrCl= (140-age) x (ABW*) x (0.85) [female] 
 
 
 
(72 x serum creatinine) 
Where: CrCl = estimated creatinine clearance in ml/min 
 Age = patient’s age in years 
 
 SCr = IDMS serum creatinine in mg/dL 
In patients with an abnormally low serum creatinine (< 0.6 mg/dL), due to reduced protein intake and/or 
low muscle mass, the creatinine clearance should be estimated using a minimum value of 0.7 mg/dL.  
6.5 
 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing Study. If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the Study, discontinuation from Study therapy or vaccination may be 
required. The investigator should discuss any questions regarding this with the MDACC. The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the subject's primary physician. 
However, the decision to continue the subject on Study therapy or vaccination schedule requires the mutual 
agreement of the Investigator, the MDACC, and the subject.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
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6.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be administered at the 
discretion of the investigator in keeping with the community standards of medical care. All concomitant 
medication will be recorded on the case report form (CRF) including all prescription, over-the-counter 
(OTC), herbal supplements, and IV medications and fluids. If changes occur during the Study 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 Study treatment and 30 days 
after the last dose of Study treatment should be recorded. Concomitant medications administered after 30 
days after the last dose of Study treatment should be recorded for SAEs and ECIs as defined in Section 
9.1.3. 
Permitted concomitant therapy: In general, the use of any concomitant medication/therapies deemed 
necessary for the care of the patient is permitted, except as specifically prohibited.  
6.5.1.1 
Antiemetics: Use of anti-emetics is allowed. Prophylactic anti-emetics may be used.  
6.5.1.2 
Permitted concomitant therapy requiring caution and/or action 
6.5.1.2.1 
Hematopoietic growth factors: Hematopoietic growth factors (e.g. erythropoietins, G-CSF, 
and GM-CSF) are not to be administered prophylactically. Routine prophylactic use of G-CSF 
(Neupogen or Neulasta) is not permitted. Use of these drugs should be reserved to patients 
with severe neutropenia and anemia as per the labeling of these agents or as dictated by local 
practice (see also the guidelines by the American Society of Clinical Oncology (ASCO) 
available under http://jco.ascopubs.org/cgi/content/full/24/19/3187). However, therapeutic use 
in patients with serious neutropenic complications such as grade 3 toxicity or higher, cases of 
febrile neutropenia or sepsis may be considered at the investigator’s discretion.  
6.5.1.2.2 
Corticosteriods: Prolonged systemic corticosteroid treatment should not be given during the 
study except for topical applications (e.g. rash), inhaled sprays (e.g. obstructive airway 
diseases), eye drops or local infections (e.g. intra-articular). Systemic corticosteroid use for 
chemotherapy pre-medication or for de-sensitization is allowed. A short duration (< 2 weeks) 
of systemic corticosteroids is allowed (e.g. for chronic obstructive pulmonary disease, or as an 
anti-emetic).  
6.5.1.2.3 
Anticoagulation: Anticoagulants other than warfarin/Coumadin derivatives or anti-aggregation 
agents may be administered under the discretion of the investigator provided they are 
discontinued in an appropriate time frame prior to surgical intervention 
6.5.1.2.4 
Contraceptives: For contraception, adequate barrier methods of contraception include 
diaphragm, condom, intrauterine device (copper), sponge or spermicide. Reliable 
contraception should be maintained throughout the study and for 120 days after study drug 
discontinuation. 
6.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and Treatment Phase 
(including retreatment for post-complete response relapse) of this Study: 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
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• 
Anti-cancer systemic chemotherapy or biological therapy  
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than Pembrolizumab 
• 
Radiation therapy  
o Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
after consultation with MDACC.  
• 
Live vaccines within 30 days prior to the first dose of Study treatment and while participating in 
the Study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; however intranasal 
influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed.  
• 
Glucocorticoids for any purpose other than as premedication for chemotherapy or 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 MDACC.  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned treatments 
for clinical management should be removed from the Study. Subjects may receive other medications that 
the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this Study. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
6.6 
Rescue Medications & Supportive Care 
6.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the treating 
investigator. Suggested supportive care measures for the management of adverse events with potential 
immunologic etiology are outlined below and in greater detail in the ECI guidance document. 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 6.3.2 for dose modification.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 40 of 77 
 
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:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids. Administer additional 
anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of prolonged steroid 
administration. 
 
• 
Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, blood or mucus in stool, with or without fever) and of bowel perforation (such as 
peritoneal signs and ileus).  
 
o All subjects who experience diarrhea/colitis should be advised to drink liberal quantities of 
clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should be 
substituted via IV infusion. For Grade 2 or higher diarrhea, consider GI consultation and 
endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous steroids 
followed by high dose oral steroids.  
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks. 
 
 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria.  
 
Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide.  
 
• 
Hypophysitis: 
 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 41 of 77 
 
 
• 
Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid 
function (at the start of treatment, periodically during treatment, and as indicated based on clinical 
evaluation) and for clinical signs and symptoms of thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 3-4 hypothyroidism): 
 
In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are suggested 
as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine or 
liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 
Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
 
• 
Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned to baseline 
values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started and continued 
over no less than 4 weeks. 
 
• 
Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and continued 
over no less than 4 weeks.  
 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Table 4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
 
 
 
 
 
 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 42 of 77 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 43 of 77 
 
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 subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be held 
until symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further trial treatment 
administration. 
Subject may be 
premedicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab (MK-
3475) with: 
Diphenhydramine 50 
mg p.o. (or equivalent 
dose of antihistamine). 
Acetaminophen 500-
1000 mg p.o. (or 
equivalent dose of 
antipyretic). 
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., 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
No subsequent dosing 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 44 of 77 
 
 
6.6.2 Supportive Care Guidelines for Events of Clinical Interest and Immune-related 
Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology (irECIs) may be defined as an adverse event 
of unknown etiology, associated with drug exposure and is consistent with an immune phenomenon. IrAEs 
may be predicted based on the nature of the Pembrolizumab compound, its mechanism of action, and 
reported experience with immunotherapies that have a similar mechanism of action. Special attention 
should be paid to AEs that may be suggestive of potential irAEs. An irAE can occur shortly after the first 
dose or several months after the last dose of treatment.  
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin or other 
etiologic causes prior to labeling an adverse event as an irAE. Information on how to identify, evaluate, and 
report irAEs has been developed and is included in the Event of Clinical Interest and Immune-Related 
Adverse Event Guidance Document located in the Administrative Binder. Subjects who develop a Grade 2 
or higher irAE should be discussed immediately with the MDACC.  
Recommendations to managing irAEs not detailed elsewhere in the protocol are detailed in Table 5. 
TABLE 5 GENERAL APPROACH TO HANDLING IRAES 
irAE 
Withhold/Discontinue 
Pembrolizumab? 
Supportive Care 
Grade 1 
No action 
Provide symptomatic treatment 
Grade 2 
May 
withhold 
Pembrolizumab 
Consider 
systemic 
corticosteroids 
in 
addition 
to 
appropriate 
symptomatic 
treatment 
Grade 3 and Grade 4 
Withhold 
Pembrolizumab 
Discontinue if unable to 
reduce 
corticosteroid 
dose to < 10 mg per day 
prednisone 
equivalent 
Systemic corticosteroids are indicated in 
addition 
to 
appropriate 
symptomatic 
treatment. May utilize 1 to 2 mg/kg 
prednisone or equivalent per day. 
renal impairment, pulmonary 
infiltrates) 
Life-threatening; pressor or 
ventilatory support indicated 
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 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration. 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
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Date:  
March 10, 2020 
 
Page 45 of 77 
 
within 
12 
weeks 
of 
toxicity 
Steroid taper should be considered once 
symptoms improve to Grade 1 or less and 
tapered over at least 4 weeks. 
 
6.7 
Diet/Activity/Other Considerations 
6.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, 
nausea or vomiting. 
6.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if Pembrolizumab 
has transient adverse effects on the composition of sperm. Non-pregnant, non-breast-feeding women may 
be enrolled if they are willing to use 2 methods of birth control or are considered highly unlikely to conceive. 
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a woman who is 
≥45 years of age and has not had menses for greater than 1 year will be considered postmenopausal), or 3) 
not heterosexually active for the duration of the study. The two birth control methods can be either two 
barrier methods or a barrier method plus a hormonal method to prevent pregnancy. Subjects should start 
using birth control from study Visit 1 throughout the study period up to 120 days after the last dose of study 
therapy.  
The following are considered adequate barrier methods of contraception: diaphragm, condom (by the 
partner), copper intrauterine device, sponge, or spermicide. Appropriate hormonal contraceptives will 
include any registered and marketed contraceptive agent that contains an estrogen and/or a progestational 
agent (including oral, subcutaneous, intrauterine, or intramuscular agents). 
Subjects should be informed that taking the study medication may involve unknown risks to the fetus 
(unborn baby) if pregnancy were to occur during the study. In order to participate in the study they must 
adhere to the contraception requirement (described above) for the duration of the study and during the 
follow-up period defined in section 9.1.2 -Reporting of Pregnancy and Lactation to the MDACC and to 
Merck. If there is any question that a subject will not reliably comply with the requirements for 
contraception, that subject should not be entered into the study. 
6.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with Pembrolizumab, the subject will 
immediately be removed from the study. The site will contact the subject at least monthly and document 
the subject’s status until the pregnancy has been completed or terminated. The outcome of the pregnancy 
will be reported to the MDACC and to Merck without delay and within 24 hours if the outcome is a serious 
adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to obtain permission 
to follow the outcome of the pregnancy and report the condition of the fetus or newborn to the MDACC. If 
a male subject impregnates his female partner the study personnel at the site must be informed immediately 
and the pregnancy reported to the MDACC and to Merck and followed as described above and in Section 
9.1.2. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
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Date:  
March 10, 2020 
 
Page 46 of 77 
 
6.7.4 Use in Nursing Women 
It is unknown whether Pembrolizumab is excreted in human milk. Since many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are 
breast-feeding are not eligible for enrollment. 
7.0 STUDY PROCEDURES 
The Schedule of Assessments found in section 7.1 summarizes the study procedures to be performed at 
each visit. Due to scheduling, these visits may occur +/- 3 days from the required time point. Additionally, 
it may be necessary to perform these procedures at unscheduled time points if deemed clinically necessary 
by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the MDACC and/or Merck for 
reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive in 
nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed consent 
be obtained from the subject. In these cases, such evaluations/testing will be performed in accordance with 
those regulations. 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 47 of 77 
 
7.1 
Schedule of Assessments and Segments 
7.1.1 Schedule of Assessments 
Study Assessments 
Screening Phase 
Neoadjuvant Treatment 
Pre-op visit 
(-14 days) 
Tumor Reduction 
Post-op visits 
Adjuvant Treatment 
Maintenance 
Post-Tx 
 
Pre-
screening 
Main 
Study 
Screening 
Cycle 1 
Cycle 2 
Cycle 3+z 
Cycle 4 
Cycle 5 
Cycle 6t 
(up to 20 
cycles) 
Discont.y 
Survival 
Follow 
Up 
 
 
 
 
 
 
 
 
 
 
 
Day -28 to 
-1 
Day -21 
to -1 
Day (+ 3 days) 
Day (+ 3 days) 
 
At time of 
Discont. 
 
1a 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
1 
8 
15 
 
 
 
Administrative Procedures 
Informed Consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteriab 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical Historyc 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Prior and 
Concomitantd 
Medication Review 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
X 
 
Post-study 
Anticancer therapy 
statuse 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Survival Status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse 
Events 
X 
 
as clinically indicated 
 
 
 
 
as clinically indicated 
 
Full Physical 
Examinationf 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
Directed Physicalg 
Examination 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Vital Signs and 
Weighth 
X 
 
as clinically indicated 
 
 
 
 
as clinically indicated 
 
ECOG Performance 
Statusi 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – 
Urine or Serum Beta-
HCGm 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
PT/INR and aPTT 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xaa 
 
CBC with 
Differentialj 
Xl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Comprehensive 
Serum Chemistry 
Panelk 
Xl 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
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Date:  
March 10, 2020 
 
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a No study activity may be performed until signed informed consent is on file. 
b Subject must meet all inclusion and exclusion criteria in order to go on study. Any exceptions to eligibility criteria must be reviewed by the Principal Investigator and IRB 
approved prior to beginning any study procedures. 
c A medical history will be obtained by the investigator or qualified designee. Medical history will include active conditions, and any condition diagnosed within the prior 10 years 
that are considered to be clinically significant by the investigator. Details regarding the disease for which the subject has enrolled in this study will be recorded separately and 
not listed as medical history. 
d The investigator or qualified designee will review prior medication use, including any protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the Study. The investigator or qualified designee will record medication, if any, taken by the subject during the Study. All medications related to 
reportable SAEs and ECIs should be recorded as defined in Section 9.1.3. 
e The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last dose of Study treatment. If a subject initiates a new anti-cancer therapy 
within 30 days after the last dose of Study treatment, the 30 day Safety Follow-up visit must occur before the first dose of the new therapy. Once new anti-cancer therapy has 
been initiated the subject will move into survival follow-up.  
fTo include review of: general appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph nodes, thyroid, 
musculo-skeletal (including spine and extremities), genital/rectal, and neurological systems. Height will be measured at screening only.  
g To include review of: upper and lower extremities, eye exam, and blood pressure 
h Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure.  
i The investigator or qualified designee will assess ECOG status at screening, prior to the administration of each new cycle of Study treatment and discontinuation of Study 
treatment as specified in the Schedule of Assessments. After Cycle 8 assessment of ECOG status will be performed every other cycle in conjunction with the directed or full 
physical exam. 
j To include: Hematocrit; Hemoglobin; Platelet count; WBC (total and differential); Red Blood Cell Count; Absolute Neutrophil Count. Maintenance phase blood work is to occur 
on Day 1 of each subsequent treatment cycle. Enrolled patients are required to have platelets > 75,000/mcL on Day 1 of each cycle and platelets > 50,000/mcL on day 8 and 15 
of each cycle.  
Urinalysism 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Amylase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xw 
 
 
Lipase 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xw 
 
 
T3, T4, TSH 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xx 
 
 
Efficacy Assessments 
Tumor Imagingn  
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Xw 
Xn 
 
CA-125v 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
X 
Xw 
 
RECIST 
Measurements 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Xw 
 
Correlatives 
Tissue Collection 
X 
Xo 
 
 
 
 
 
 
 
 
 
 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Collectionq 
 
 
X 
 
 
 
 
 
 
 
 
Xr 
 
 
Xq 
 
 
Xq 
 
 
Xq 
 
 
 
X 
 
Study Drugs 
Pembrolizumabs 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Paclitaxelt 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Carboplatinu 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
Page 49 of 77 
 
k To include: Albumin; Alkaline phosphatase; ALT (SGPT); AST (SGOT); LDH; Uric Acid; Amylase, Lipase, Calcium; Chloride; Glucose; Phosphorus; Potassium; Sodium; 
Magnesium; Total Bilirubin; Direct Bilirubin (If total bilirubin is elevated above the upper limit of normal); Total protein; BUN;CO2 (if considered standard of care in your 
region). 
lLaboratory tests for screening or entry into the Second Course Phase should be performed within 10 days prior to the first dose of treatment. After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing. Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of 
Study treatment.  
m To include: Blood; Glucose; Protein; Specific gravity; microscopic exam (if abnormal); Urine Pregnancy test (perform on women of childbearing potential only. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. 
nTumor assessment may be performed on non-measurable but evaluable disease. CT or MRI to be performed at baseline post cycle 3, post cycle 6, every 12 weeks (+/- 7 days) 
during the maintenance phase, and at the end of the maintenance phase. For maintenance scans only: A chest CT is indicated as part of the radiographical assessment if used at 
baseline to assess target or non-target, evaluable disease. Imaging will also take place if patient discontinues at any time other than the scheduled imaging in maintenance 
phase. If a patient discontinues treatment for any reason other than progression, imaging will take place every 12 weeks (+/- 7 days) until time of progression or start of a new 
anti-cancer therapy. 
o To be obtained prior to neoadjuvant therapy initiation.  
p To be obtained during second-look laparoscopy if undertaken. 
q This blood work is to occur on Day 1 of the treatment cycle.  
r This blood test must occur prior to debulking surgery as part of the standard of care procedures. Patients who are prescribed a fourth cycle of neoadjuvant treatment at the pre-op 
visit must repeat pre-op bloodwork at the re-scheduled pre-op visit. 
s Pembrolizumab (MK-3475) administration will begin on Day 1 of each treatment cycle beginning in Cycle 4.  
t Paclitaxel will be administered on Days 1, 8 & 15 of treatment cycles 1-6. 
u Carboplatin will be administered on Day 1 of treatment cycles 1-6. 
v CA125 test will take place on a monthly basis per standard of care. If Cycle 1 Day 1 is within 28 days of the Screening blood draw, it is unnecessary to repeat the blood draw. 
w Urinalysis and tumor imaging should take place every 12 weeks (+/- 7 days) in the Maintenance Phase. 
x TSH will be measured at every cycle during maintenance therapy; free T3 and T4 will be measured if TSH is abnormal 
y Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 3 months to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first.  
z If clinically indicated, subjects may receive more than three cycles of neoadjuvant chemotherapy per physician’s discretion. 
aa Not to be performed if patient is removed from study due to disease progression. 
 
 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 50 of 77 
 
 
7.1.2 Screening Phase 
Screening procedures will be performed up to 28 days before Day 1, unless otherwise specified. All 
subjects must first read, understand, and sign the IRB/REB/IEC-approved ICF before any study-
specific screening procedures are performed. After signing the ICF, completing all screening 
procedures, and being deemed eligible for entry, subjects will be enrolled in the study. Procedures that 
are performed prior to the signing of the ICF and are considered standard of care may be used as 
screening assessments if they fall within the 28-day screening window.  
Pre-treatment evaluation and testing: 
The tests and procedures that are standard of care will only be reviewed for the purposes of this protocol. 
Pre-treatment testing may be completed on the day of the patient’s initial visit to their primary physician 
or they may be scheduled for a return appointment within 14 days prior to initiation of drug therapy. 
All testing will be completed prior to initiation of drug therapy. Please see the study calendars for 
detailed explanations of the procedures and assessments. 
7.1.3 Treatment Phase 
Procedures to be conducted during the treatment phase of the study are presented in the Schedule of 
Assessments.  
Toxicity will be monitored at the pre-operative and post-operative visits for the tumor reductive surgery 
and graded using CTCAE v4.03. Treatment will be discontinued if patients are unable to tolerate it due 
to adverse events. 
Interval Tumor Reductive Surgery Evaluation and Testing 
Standard of care tests for the planned surgery may be completed on the day of the patient’s pre-operative 
visits for their tumor reductive surgery. Attention to toxicities during the tumor reductive surgery is 
critical, due to the unknown risk profile of the PD-L1 inhibitor prior to surgery. At this time, the impact 
of PD-L1 inhibitors on surgical parameters and post-operative complications is unknown. Thus, the 
anesthesia team will be notified prior to surgery that the patient was on a PD-L1 inhibitor treatment 
pre-surgery. 
Blood will be collected at the pre-operative and post-operative visits for the tumor reductive surgery. 
This study allows patients to receive either 3 or 4 cycles of neoadjuvant therapy consisting of 
carboplatin, paclitaxel, and pembrolizumab at the investigator’s discretion. The decision to include a 
fourth cycle of treatment is usually made at the pre-operative visit after blood collection. In the event a 
patient’s treatment plan is revised to have an additional cycle of therapy, the pre-operative blood work 
must be repeated. Consequently, it is possible patients will potentially have two pre-operative blood 
work collections. Tumor tissue will also be collected during the interval tumor reductive surgery. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
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Details for blood collection and processing are located in Section 7.3. All blood and tissue samples will 
be processed and stored at MDACC by the Gynecologic Oncology Tumor Bank. 
7.1.4 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose 
of Study treatment or before the initiation of a new anti-cancer treatment, whichever comes first. All 
AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an AE of Grade 
> 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-
neoplastic therapy, whichever occurs first. SAEs that occur within 90 days of the end of treatment or 
before initiation of a new anti-cancer treatment should also be followed and recorded.  
7.1.5 Follow-up Visits 
Subjects who discontinue Study treatment for a reason other than disease progression will move into 
the Follow-Up Phase and should be assessed every 12 weeks (± 7 days) by radiologic imaging to 
monitor disease status. Every effort should be made to collect information regarding disease status until 
the start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject 
begins retreatment with Pembrolizumab as detailed in Section 6.3.2.1. Information regarding post-study 
anti-neoplastic treatment will be collected if new treatment is initiated. 
Subjects who are eligible to receive retreatment with Pembrolizumab according to the criteria in Section 
6.0 will move from the follow-up phase to the Second Course Phase when they experience disease 
progression. Details are provided in Section 6.3.2.1.  
7.1.6 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 3 months 
to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs 
first.  
7.1.7  
Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to Study completion, all applicable activities scheduled 
for the final Study visit should be performed at the time of discontinuation. Any adverse events which 
are present at the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 9.1 - Assessing and Recording Adverse Events. Subjects who a) attain 
a CR or b) complete 24 months of treatment with pembrolizumab may discontinue treatment with the 
option of restarting treatment if they meet the criteria specified in Section 6.3.2.1. After discontinuing 
treatment following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.4) and then proceed to the Follow-Up Period of the study (described in 
Section 7.1.5). 


 
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7.2 
Description of study procedures 
7.2.1 Medical history and physical exam 
Findings from medical history (obtained at screening) and physical examination shall be given a 
baseline grade according to the procedure for AEs. Increases in severity of pre-existing conditions 
during the study will be considered AEs, with resolution occurring when the grade returns to the pre-
study grade or below. 
Physical examinations will be performed on study days noted in the Schedule of Assessments. 
A complete physical examination will be performed and will include an assessment of the following 
(as clinically indicated): general appearance, respiratory, cardiovascular, abdomen, skin, head and neck 
(including ears, eyes, nose and throat), lymph nodes, thyroid, musculo-skeletal (including spine and 
extremities), genital/rectal, and neurological systems and at screening only, height.  
Vital signs (temperature, blood pressure, pulse rate, weight, and respiratory rate) will be measured on 
study days noted in the Schedule of Assessments. On pembrolizumab treatment days, vital signs will 
be measured within an hour prior to start of pembrolizumab administration, at 30 minutes during the 
infusion (± 5 minutes), at the end of infusion (+ 5 minutes), and at 30 minutes (± 5 minutes) and 60 
minutes (± 5 minutes) post-infusion. If the infusion takes longer than 60 minutes, then blood pressure 
and pulse measurements should follow the principles described here, or more frequently if clinically 
indicated. For subsequent doses (at dose levels of 750mg or less), the 1-hour observation period will 
not be required unless a subject experiences an infusion-related reaction. 
7.2.2 Laboratory Procedures/Assessments 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in the Schedule of 
Assessments. The total amount of blood/tissue to be drawn/collected over the course of the Study 
(from pre-Study to post-Study visits), including approximate blood/tissue volumes drawn/collected 
by visit and by sample type per subject can be found in the Blood and Tissue Collection Manual.  
 
7.3 
Pharmacodynamics Sampling 
 
7.3.1 Collection, Storage, and Handling of Specimen (s) 
Adequate tissue will be acquired at the time points noted in the schedule of assessments in Section 7.1.1 
(prior to first dose of study drug and at tumor reduction surgery). The pre-treatment tissue may be 
obtained from one of three possible options. 
• 
Option 1 (for subjects who have undergone a standard-of-care diagnostic laparoscopy): 
Tissue acquisition will occur under LAB02-188. 


 
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• 
Option 2 (for subjects who do not yet have a tissue histological diagnosis of ovarian, 
primary peritoneal, or fallopian tube cancer): Tissue acquisition will occur at the time of 
a standard-of-care diagnostic biopsy. 
• 
Option 3 (for subjects who did not have a standard-of-care laparoscopy and have 
previously undergone a tissue histologic confirmation procedure but adequate tissue is 
not available for analysis): Tissue acquisition will occur at the time of a research-only 
biopsy. 
Up to 40 ml of blood will be collected (7- 10 mL in four lavender top [EDTA] collection tubes) at each 
time point specified in the schedule of assessments in Section 7.1.1. Blood samples will be processed 
to separate blood fractions (e.g., plasma, white blood cells or PBMCs). Plasma will be frozen into 
cryotubes and PMBCs will be cryopreserved. Each sample will be labelled as per the "Blood and Tissue 
Collection Manual." The blood fractions will then be stored in the freezer at -80℃ in the Gynecologic 
Oncology Tumor Bank at the University of Texas MD Anderson. 
 
7.3.2 Pharmacodynamics Procedures (PD) 
The tissue samples and blood fractions will be utilized for the characterization of biological molecules, 
DNA, RNA, protein including circulating nucleic acids and exosome as well as activation status of 
hematopoietic and immune cells. Where sufficient material of appropriate quality is available, we will 
assess DNA mutations and copy number with targeted or whole exome sequencing (WES), RNA levels 
by RNA-sequencing, and protein levels by reverse phase protein array (RPPA) or 
immunohistochemistry. Assays will be selected based on the amount of tissue, the tumor content, blood 
(plasma, white blood cells or PBMC), and whether frozen or paraffin samples are available from each 
patient. The approaches to perform these research assays are rapidly evolving both in the Gynecologic 
Oncology Tumor Bank at the MD Anderson Cancer Center and across the world. We will thus perform 
these assays with the current state of the art assays such as NanoString technology that are available at 
the time of analysis. 
Additionally, immune analyses, including but not limited to evaluation of CD4 and CD8 T cells, will 
be performed in peripheral blood and tumor samples, as previously published (Liakou CI, et al 2008; 
Carthon BC, et al 2010; Tang DN, et al 2013; Chen H, et al; 2014). 
7.3.3 Analyses and Processes for Ovarian Cancer Moon Shot Program 
In addition to IHC assays, DNA/RNA next generation sequencing may be performed for genotype-
protein expression. Internal/External Sequencing may be done here at MD Anderson, in one of the Core 
labs such as the Cancer Genomics Lab, but in some cases samples may be sent to outside collaborators 
for sequencing and/or analysis such as the Broad Institute. Any sharing or sequencing of samples 
performed by Broad or any other external collaborator will be conducted under specific contract or 
Material Transfer Agreement (MTA). We will protect participant’s privacy by coding samples and 


 
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keeping the master list of identifiers accessible to only key project staff. Data will be kept on secure 
computers and samples will be kept in freezers in locked laboratories and buildings. Additionally in 
some other cases, samples may be provided from outside collaborators or institutions for discovery and 
research purposes. In such cases, the samples should be obtained under IRB-approved protocols at these 
outside collaborators and institutions to allow them for participation in this protocol and under a specific 
grant/ contract or Material Transfer Agreement (MTA) with MD Anderson Cancer Center. 
7.3.4 Analyses and Process for QualTek Molecular Laboratories 
In addition to IHC assays performed under the Ovarian Cancer Moon Shot at MD Anderson Cancer 
Center, non-STAT PD-L1 IHC testing will be performed with QualTek Molecular Laboratories in a 
non-CLIA laboratory. QualTek will provide PD-L1 IHC staining and pathology scoring for up to 
approximately 60 samples from those patients that have enrolled onto study. Samples will be shipped 
to QualTek as sectioned slides to be used to perform the PD-L1 IHC assay using Merck mouse 
monoclonal antibody clone 22C3. Samples will be scored only by board-certified pathologists(s) with 
documented training/pathologist concordance for scoring PD-L1 IHC for the tumor indications for this 
study. 
An H&E stain will be reviewed for confirmation of tumor presence. If a sample does not contain 
sufficient tumor for evaluation, QualTek will document and inform MD Anderson Cancer Center who 
will request a new sample for the GYN Tumor Bank if available. If QualTek is unable to evaluate due 
to unusual histology or staining patterns, the sample will be scored as not-interpretable. 
Data will be reported to MD Anderson Cancer Center in a spreadsheet format deemed acceptable and 
appropriate by both MD Anderson and QualTek. The final dataset encompassing all samples will be 
provided at the end of the study. Investigator should notify QualTek of any Interim Analysis (IA) 
required prior to end of study. 
A final Clinical Sample Analysis Summary Report will be provided within 2 weeks after the final 
sample is analyzed. Necessary information includes (a) Report Summary (b) Assay Objective and 
Overview (c) Sample Reconciliation, i.e. received, assayed, failed, lost, lab locations, contact person), 
(d) table of all results generated during the course of the study, (e) reviewed and approved by 
appropriate QualTek personnel (i.e. Medical Director, Lab Director, Study Director and Quality 
Director). 
7.4 
Withdrawal of informed consent for donated biological samples 
 
If a subject withdraws consent to the use of donated samples, the samples will be disposed of/destroyed, 
and the action documented. As collection of the biological samples is an integral part of the study, then 
the subject is withdrawn from further study participation.  
The Principal Investigator: 


 
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• 
Ensures that biological samples from that subject, if stored at the study site, are immediately 
identified, disposed of /destroyed, and the action documented 
• 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed, the action documented and the signed document 
returned to the study site 
• 
Ensures that the subject is informed about the sample disposal. 
8.0 DISEASE EVALUATION AND METHODS 
8.1 
Tumor Imaging and Assessment of Disease (RECIST v1.1) 
 
8.1.1 Physical examination 
• Lesions detected by physical examination will only be considered measurable if superficial, e.g., 
skin nodules and palpable lymph nodes. Documentation by color photography including ruler is 
recommended for estimating the size of skin lesions. 
8.1.2 Radiological Imaging Guidelines/Procedures 
• Study assessments will be performed based on calendar start dates and not by course of therapy to 
reduce ascertainment bias. 
8.1.2.1 
CT scan with contrast of the chest, abdomen, and pelvis 
• CT scans should be performed with contiguous cuts in slice thickness of 5 mm or less. Spiral CT 
should be performed using a 5-mm contiguous reconstruction algorithm. 
8.1.2.2 
MRI scans 
• MRI of the abdomen and pelvis is acceptable for measurement of lesions provided that the same 
anatomical plane is used for serial assessments. If possible, the same imaging device should be used 
for serial evaluations. In case of MRI, measurements will be preferably performed in the axial 
(transverse) plane on contrast-enhanced T1-weighted images. However, there are no specific 
sequence recommendations. 
8.2 
Measurability of Tumor Lesions 
Tumor lesions will be categorized as follows: 
• Measurable Lesions - Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of:  


 
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• 10 mm by CT scan (irrespective of scanner type) and MRI (no less than double the slice thickness 
and a minimum of 10 mm).  
• 10 mm caliper measurement by clinical exam (when superficial).  
• Malignant lymph nodes are 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).  
• Nonmeasurable Lesions - Nonmeasurable lesions are defined as 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). Lesions considered truly nonmeasurable include the 
following: leptomeningeal disease, ascites, pleural/pericardial effusion, and inflammatory 
breast disease, lymphangitic involvement of skin or lung, abdominal masses /abdominal 
organomegaly identified by physical exam that is not measurable by reproducible imaging 
techniques. 
• Target Lesions - All lesions up to a maximum of 5 lesions total (and a maximum of 2 lesions per 
organ) representative of all involved organs should be identified as target lesions. 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.  
• Non-target Lesions - It is possible to record multiple nontarget lesions involving the same organ as 
a single item on the case record form (e.g., “multiple enlarged pelvic lymph nodes” or 
“multiple liver metastases”).     
8.3 
Response Criteria 
8.3.1 Evaluation of Target Lesions 
• 
Complete Response - Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm (the sum may not 
be “0” if there are target nodes).  
• 
Partial Response - At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters.  


 
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• 
Progressive Disease - At least a 20% increase in the sum of 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 progression.)  
• 
Stable Disease - Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum of diameters while on study.    
8.3.2 Evaluation of Non-target Lesions 
• 
Complete Response - 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).  
• 
Non-complete response/Non-progressive disease - Persistence of 1 or more non-target 
lesion(s) and/or maintenance of tumor marker level above the normal limits.  
• 
Progressive Disease - Unequivocal progression of existing non-target lesions will be defined 
as the overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. In the absence of measurable disease, change in non-measurable 
disease comparable in magnitude to the increase that would be required to declare PD for 
measurable disease. Examples include an increase in a pleural effusion from ‘trace’ to ‘large,’ 
an increase in lymphangitic disease from localized to widespread. 
8.3.3 Appearance of New Lesions 
The appearance of new lesions is considered PD according to RECIST v 1.1 guidelines. Considering 
the unique response kinetics that have been observed with immunotherapy, new lesions may not 
represent true disease progression. In the absence of rapid clinical deterioration, subjects may 
continue to receive pembrolizumab if investigators consider that subjects continue to benefit from 
treatment. 
8.3.4 Evaluation of Overall Response with Modifications 
Confirmation of CR, PR, as well as PD is required by a repeat, consecutive assessment no less than 4 
weeks from the date of first documentation. Treatment with pembrolizumab will continue between 
the initial assessment of PD and confirmation for PD. 
Tables 6 and 7 provide overall responses for all possible combinations of tumor responses in target 
and non-target lesions with or without the appearance of new lesions. 


 
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TABLE 6. EVALUATION OF OVERALL RESPONSE 
Target 
Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Complete 
response 
Complete response (or no 
non- target lesion) 
No 
Complete response 
No target 
lesion at 
baseline 
Complete response 
No 
Complete response 
Complete 
response 
Not evaluable  
No 
Partial response 
Complete 
response 
Non-complete response / 
non-progressive disease 
No 
Partial response 
Partial 
response 
Non-progressive disease 
and not evaluable (or no 
non-target lesion)  
No 
Partial response 
Stable 
disease 
Non-progressive disease 
and not evaluable (or no 
non-target lesion)  
No 
Stable disease 
 
 
 
 
TABLE 7. EVALUATION OF OVERALL RESPONSE 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
Not all evaluated 
Non-progressive 
disease 
No 
Not evaluable 
No target lesion  
Not all evaluated 
No 
Not evaluable 


 
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No target lesion  
Non-complete 
response / non-
progressive disease 
No 
Non-complete response / 
non-progressive disease 
Progressive disease 
Any 
Yes/No 
Progressive disease 
Any 
Progressive disease 
Yes/No 
Progressive disease 
Any 
Any 
Yes 
Progressive disease 
No target lesion  
Unequivocal 
progressive disease 
Yes/No 
Progressive disease 
No target lesion  
Any 
Yes 
Progressive disease 
 
8.4 
MRI Scans 
Specific lesions must be evaluated serially, and comparative analysis of changes in the area of 
contrast enhancement, as well as the non-enhancing component, should be performed. The product of 
the maximal cross-sectional enhancing diameters will be used to determine the size of the contrast-
enhancing lesions. 
Minimum sequences required: 
• Pre-contrast T1, T2/ fluid attenuated inversion recovery (FLAIR)  
• Post-contrast T1, with two orthogonal planes (or a volume acquisition) recommended  
• Recommended slice thickness ≤ 5 mm with no gap    
8.4.1 Measurability of Tumor Lesions    
8.4.2 Tumor lesions are categorized as follows:  
• Measurable disease is defined as bi-dimensionally contrast enhancing lesions with clearly defined 
margins by CT or MRI scan, with two perpendicular diameters of at least 10 mm, visible on 
two or more axial slices that are preferably, at most, 5 mm apart with 0-mm skip.  
• Nonmeasurable disease is defined as either unidimensionally measurable lesions, masses with 


 
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margins not clearly defined, or lesions with maximal perpendicular diameters less than 10 
mm. Subjects without measurable disease, such as those who undergo a gross total resection, 
cannot respond and can only achieve SD as their best radiographic outcome.  
◦ 
There are two types of non-target lesions  
 
 
 
▪ Enhancing (T1 with contrast)  
 
 
 
▪ Non-enhancing (T2/FLAIR)  
◦ 
These are assessed subjectively. Some rules are recommended for objective assessment of 
progression e.g., if a nonmeasurable enhancing lesion becomes measurable, AND 
either has absolute increase of > 5 mm OR > 25% in sum of products of diameter    
8.4.3 Response Criteria 
8.4.3.1 
 Evaluation of Target Lesions  
• Complete response - Requires all of the following: complete disappearance of all enhancing 
measurable and nonmeasurable disease sustained for at least 4 weeks; no new lesions; stable 
or improved non-enhancing (T2/FLAIR) lesions; patients must be off corticosteroids (or on 
physiologic replacement doses only); and stable or improved clinically. Note: Subjects with 
nonmeasurable disease only, cannot have a CR; the best response possible is SD.  
• Partial response - Requires all of the following: 50% decrease compared with baseline in the sum 
of products of perpendicular diameters of all measurable enhancing lesions sustained for at 
least 4 weeks; no progression of nonmeasurable disease; no new lesions; stable or improved 
non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with 
baseline scan; the corticosteroid dose at the time of the scan evaluation should be no greater 
than the dose at time of baseline scan; and stable or improved clinically. Note: Subjects with 
nonmeasurable disease only, cannot have a PR; the best response possible is SD.  
• Stable disease - Requires all of the following: does not qualify for CR, PR, or progression; stable 
non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids compared with 
baseline scan. In the event that the corticosteroid dose was increased for new symptoms and 
signs without confirmation of disease progression on neuroimaging, and subsequent follow-
up imaging shows that this increase in corticosteroids was required because of disease 
progression, the last scan considered to show SD will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.  


 
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• Progression - Defined by any of the following: 25% increase in sum of the products of 
perpendicular diameters of enhancing lesions compared with the smallest tumor measurement 
obtained either at baseline (if no decrease) or best response, on stable or increasing doses of 
corticosteroids; significant increase in T2/FLAIR non-enhancing lesion on stable or 
increasing doses of corticosteroids compared with baseline scan or best response after 
initiation of therapy not caused by comorbid events (e.g., radiation therapy, demyelination, 
ischemic injury, infection, seizures, postoperative changes, or other treatment effects); any 
new lesion; clear clinical deterioration not attributable to other causes apart from the tumor 
(e.g., seizures, medication adverse events, complications of therapy, cerebrovascular events, 
infection) or changes in corticosteroid dose; failure to return for evaluation as a result of 
death or deteriorating condition; or clear progression of nonmeasurable disease. 
8.4.3.2 
Evaluation of Enhancing Non-target Lesions 
• Complete response - All enhancing non-target lesions have disappeared completely  
• Incomplete response/SD - Enhancing lesions present; stable or decreased in size  
• Progressive disease - Unequivocal progression  
• Unable to assess - Unable to evaluate enhancing lesions because of technical factors    
8.4.3.3 
Evaluation of T2/FLAIR Lesion Response  
• Improved - Signal abnormality decreased  
• Unchanged - Unchanged compared to prior imaging  
• Worse - Unequivocal worsening/progression of signal abnormality  
• Unable to assess - Unable to evaluate non-enhancing lesions because of technical factors  
9.0 SAFETY ASSESSMENTS 
9.1 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a causal 


 
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relationship with this treatment. An adverse event can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of a medicinal product or protocol-specified procedure, whether or not 
considered related to the medicinal product or protocol-specified procedure. Any worsening (i.e., any 
clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is 
temporally associated with the study agents, is also an adverse event. 
Adverse events may occur during the course of the study or within the follow-up period specified by 
the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline period as a result 
of a protocol-specified intervention, including washout or discontinuation of usual therapy, diet, or a 
procedure. 
All adverse events will be recorded from the time the consent form is signed through 30 days following 
cessation of treatment and at each examination on the Adverse Event case report forms/worksheets. 
The reporting timeframe for adverse events meeting any serious criteria is described in section 9.1.3. 
Adverse events will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified procedure or 
intervention. If the subject requires a blood draw, fresh tumor biopsy etc., the subject is first required 
to provide consent to the main study and AEs will be captured according to guidelines for standard AE 
reporting. 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Assessments and more frequently if clinically indicated. 
Adverse experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 4.0 (see Section 9.1). Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to Study treatment. All 
toxicity information will be collected in the institutional Data Management Initiative (DMI) database. 
All AEs of unknown etiology associated with Pembrolizumab exposure should be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic etiology 
(irAE). See Section 9.1.3.2 and the separate guidance document in the administrative binder regarding 
the identification, evaluation and management of AEs of a potential immunological etiology.  
Please refer to section 9.1 for detailed information regarding the assessment and recording of AEs.  
 


 
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9.1.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the MDACC 
and to Merck 
For purposes of this Study, an overdose will be defined as any dose exceeding the prescribed dose for 
Pembrolizumab by 20% over the prescribed dose. No specific information is available on the treatment 
of overdose of Pembrolizumab. In the event of overdose, Pembrolizumab does not need to be 
discontinued, however, the subject should be observed closely for signs of toxicity. Appropriate 
supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose, the adverse event(s) is reported 
as a serious adverse event, even if no other seriousness criteria are met. 
If a dose meeting the protocol definition of overdose is taken without any associated clinical symptoms 
or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest 
(ECI), using the terminology “accidental or intentional overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to the 
Principal Investigator and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220 or 215-661-6229 or 267-305-0809 or aer_mailbox@merck.com) 
9.1.2 Reporting of Pregnancy and Lactation to the MDACC and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported 
to them), including the pregnancy of a male subject's female partner that occurs during the Study or 
within 120 days of completing the Study completing the Study, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier. All subjects and female 
partners of male subjects who become pregnant must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious 
events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported. 
Such events must be reported within 24 hours to the Principal Investigator and within 2 working days 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220 or 215-661-6229 or 
267-305-0809 or aer_mailbox@merck.com) 
9.1.3 Immediate Reporting of Adverse Events to the MDACC and to Merck 
9.1.3.1 
Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either the 
investigator or the sponsor, it results in any of the following outcomes: 
• 
Death 


 
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• 
A life-threatening adverse drug experience – any adverse experience that places the patient, in 
the view of the initial reporter, at immediate risk of death from the adverse experience as it 
occurred. It does not include an adverse experience that, had it occurred in a more severe form, 
might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions. 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, be life threatening, or require hospitalization 
may be considered a serious adverse drug experience when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug dependency or 
drug abuse (21 CFR 312.32). 
• 
Important medical events as defined above, may also be considered serious adverse 
events. Any important medical event can and should be reported as an SAE if deemed 
appropriate by the Principal Investigator or the IND Sponsor, IND Office. 
• 
All events occurring during the conduct of a protocol and meeting the definition of a SAE must 
be reported to the IRB in accordance with the timeframes and procedures outlined in “The 
University of Texas M. D. Anderson Cancer Center Institutional Review Board Policy for 
Investigators on Reporting Unanticipated Adverse Events for Drugs and Devices”. Unless 
stated otherwise in the protocol, all SAEs, expected or unexpected, must be reported to the IND 
Office, regardless of attribution (within 5 working days of knowledge of the event). 
All life-threatening or fatal events, that are unexpected, and related to the study drug, must have a 
written report submitted within 24 hours (next working day) of knowledge of the event to the 
Safety Project Manager in the IND Office. 
• 
Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB.  
• 
Serious adverse events will be captured from the time of the first protocol-specific intervention, 
until 30 days after the last study treatment/intervention, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete and 
laboratory tests have returned to baseline, progression of the event has stabilized, or there has 
been acceptable resolution of the event. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
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• 
Additionally, any serious adverse events that occur after the 30 day time period that are related 
to the study treatment must be reported to the IND Office. This may include the development 
of a secondary malignancy. 
Reporting to FDA: 
• 
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety Project Manager 
IND Office) according to 21 CFR 312.32. 
It is the responsibility of the PI and the research team to ensure that serious adverse events are reported 
according to the Code of Federal Regulations, Good Clinical Practices, the protocol guidelines, the 
sponsor’s guidelines, and Institutional Review Board policy. 
Investigator Communication with Merck Pharmaceutical: 
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to any cause 
other than progression of the cancer under study that occurs to any subject from the time the consent is 
signed through 90 days following cessation of treatment, or the initiation of new anti-cancer therapy, 
whichever is earlier, whether or not related to Merck product, must be reported within 24 hours to the 
MDACC and within 2 working days to Merck Global Safety.  
Non-serious Events of Clinical Interest will be forwarded to Merck Global Safety and will be handled in 
the same manner as SAEs.  
Additionally, any serious adverse event, considered by an investigator who is a qualified physician to 
be related to Merck product that is brought to the attention of the investigator at any time outside of the 
time period specified in the previous paragraph also must be reported immediately to the MDACC and 
to Merck. 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number: +1-215-993-1220 or +1-215-661-6229 or +1-267-305-0809 or the Merck 
AER mailbox: aer_mailbox@merck.com 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, European 
Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local regulators. 
Investigators will cross reference this submission according to local regulations to the Merck 
Investigational Compound Number (IND, CSA, etc.) at the time of submission. Additionally 
investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: Worldwide Product Safety; 
FAX 215 993-1220 or 215-661-6229 or 267-305-0809 or at the Merck AER mailbox: 
aer_mailbox@merck.com) at the time of submission to FDA. 
All subjects with serious adverse events must be followed up for outcome. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
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9.1.3.2 
Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) 
and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 
24 hours to the MDACC and within 2 working days to Merck Global Safety. (Attn: Worldwide Product 
Safety; FAX 215 993-1220 or 215-661-6229 or 267-305-0809 or at the Merck AER mailbox: 
aer_mailbox@merck.com) 
Events of clinical interest for this Study include: 
1. an overdose, as defined in Section 9.1.1 - Definition of an Overdose for This Protocol and Reporting 
of Overdose to the MDACC, that is not associated with clinical symptoms or abnormal laboratory 
results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and 
an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at 
the same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as 
determined by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the 
criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation 
for an underlying etiology. The Study site guidance for assessment and follow up of these criteria 
can be found in the Investigator Study File Binder (or equivalent). 
3. In the event a subject develops any of the following AEs, a detailed narrative of the event should be 
reported as an ECI to the MDACC within 24 hours and to Merck Global Safety within 2 working days 
of the event: 
a. Grade ≥ 3 diarrhea 
b. Grade ≥ 3 colitis 
c. Grade ≥ 2 pneumonitis 
d. Grade ≥ 3 hypo- or hyperthyroidism 
 
A separate guidance document has been provided entitled “event of Clinical Interest and Immune-
Related Adverse Event Guidance Document.” This document provides guidance regarding 
identification, evaluation and management of ECIs and irAEs. Additional ECIs are identified in this 
guidance document and also need to be reported to the Principal Investigator within 24 hours and to 
Merck Global Safety within 2 working days of the event.  
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and 
subjects should be asked for signs and symptoms suggestive of an immune-related event. Subjects who 
develop an ECI thought to be immune-related should have additional testing to rule out other etiologic 
causes. If lab results or symptoms indicate a possible immune-related ECI, then additional testing 
should be performed to rule out other etiologic causes. If no other cause is found, then it is assumed to 
be immune-related.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 67 of 77 
 
ECIs that occur in any subject from the date of first dose through 90 days following cessation of 
treatment, or the initiation of a new anticancer therapy, whichever is earlier, whether or not related to 
the Merck’s product, must be reported within 24 hours to the MDACC and to Merck Global Safety 
within 2 working days. 
9.1.4 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event which changes 
CTCAE grade over the course of a given episode will have each change of grade recorded on the 
adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 
Adverse events can be “expected” or “unexpected.” 
9.1.5 Attribution of Adverse Events 
Attribution is the relationship between an adverse event or serious adverse event and the study 
treatment. Attribution will be assigned as follows: 
1. Definite – The AE is clearly related to the study treatment 
2. Probable – The AE is likely related to the study treatment 
3. Possibly – The AE may be related to the study treatment 
4. Unlikely – The AE is doubtfully related to the study treatment 
5. Unrelated – The AE is clearly NOT related to the study treatment 
 
9.1.6 MDACC Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations. Adverse event information will be captured in the DMI 
database.  
All adverse events experienced by participants will be collected from the time of consent until the final 
study visit. Participants continuing to experience toxicity at the off-study visit may be contacted for 
additional assessments until the toxicity has resolved or is deemed irreversible. 
For patients that have received no more than 4 previous induction cycles prior to starting study, 
retrospective adverse event collection should occur as reasonably possible based on first reported data 
received from outside scanned medical notes in the patient’s electronic medical record. The capturing 
of AE’s must follow protocol requirements from the time of consent and going forward. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 68 of 77 
 
10.0 STATISTICAL ANALYSIS PLAN 
10.1 Statistical Analysis Plan Summary 
 
Futility Monitoring 
 
We will enroll at least 10 patients and at most 30 patients at a rate of 1 patient per month. We will 
follow all patients for at least 12 months, and we will monitor futility and feasibility as described below. 
We will use the methods described by Thall et al.41 to monitor progression-free survival (PFS), and we 
will stop enrolling patients early if, based on the available data, we have reason to believe that the 
median PFS is less than that observed with conventional therapy (i.e., 12 months). Formally, we will 
stop enrolling patients early if 
 
Pr (median PFSexperimental ≥ median PFSconventional | data from the trial) < 0.05 
 
That is, if there is less than a 5% chance that the median PFS is more than that observed with 
conventional therapy (i.e., 12 months), then we will stop enrolling patients. Details of how this 
monitoring rule was constructed are explained in the “Technical Details” section below. The operating 
characteristics of this monitoring rule are shown in the table below and are based on 10,000 simulations 
of the monitoring rule performed with the “OneArmTTE Version 4.11” program developed in the MD 
Anderson Cancer Center Department of Biostatistics.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Operating Characteristics for Futility Monitoring Rule 
Median PFS 
(months) 
12-month 
PFS 
Pr(Stop Early) 
Sample Size 
Average Trial 
Duration (months) 
P25 
Mean 
P75 
6 
0.250 
0.9815 
10 
15.7 
19 
16.4 
9 
0.397 
0.5337 
17 
24.2 
30 
30.8 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
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12 
0.500 
0.1514 
30 
28.1 
30 
38.4 
15 
0.574 
0.0443 
30 
29.3 
30 
40.8 
18 
0.630 
0.0170 
30 
29.7 
30 
41.5 
21 
0.673 
0.0072 
30 
29.9 
30 
41.8 
24 
0.707 
0.0037 
30 
29.3 
30 
41.9 
 
We will use the Clinical Trial Conduct (CTC) website, which is housed on a secure server at MD 
Anderson and maintained by the Department of Biostatistics, to implement the futility monitoring rule. 
The CTC website is found at https://biostatistics.mdanderson.org/ClinicalTrialConduct. Access to the 
CTC website will be gained through usernames and passwords provided by the MD Anderson 
Department of Biostatistics to study personnel responsible for enrolling patients and updating, 
reviewing, and analyzing patient data. Training on the use of the CTC website will be provided by the 
study statistician, which particular attention to the importance of timely updating of follow-up dates 
and recording of events. 
Technical Details 
At any point in the trial the PFS can be calculated for each patient, with the time interval regarded as 
censored at the date of last follow-up if the patient is still alive without progressive disease. At each 
interim analysis, we will apply a Bayesian method for updating prior information with PFS observed 
to that time. We assume that the PFS for each patient is exponentially distributed with a median of λC 
months for the conventional treatment and a median of λE for the experimental treatment. Given the 
historical data (Greer et al. 2005) and a median PFS of 16 months, we assume λC follows an inverse 
gamma distribution with mean 12 months and standard deviation of 1 month. The middle 95% of this 
distribution is between 10.20 and 14.11 months. We assume λE follows an inverse gamma distribution 
with a mean of 12 months and a standard deviation of 12 months. The middle 95% of this distribution 
is between 3.32 and 38.79 months. 
The goal of the futility monitoring rule is to guard against a median PFS rate less than that observed 
with conventional therapy (i.e., 12 months). Patient enrollment will be stopped early if, based on the 
available data, Pr (λE ≥ λC | data from the trial) < 0.05. This futility rule was chosen to achieve a 
relatively high early stopping probability if the true median PFS is less than 12 months for the 
experimental treatment, while maintaining a relatively low early stopping probability if the median PFS 
is greater than 12 months for the experimental treatment.  
 
 
 
 
 
Feasibility Monitoring 
 
We will monitor feasibility, defined as the ability to complete all planned cycles of adjuvant therapy, 
using the methods of Thall et al.42. Adjusted doses where the patient completes the treatment cycle will 
count as a completed cycle. Study drug may be discontinued at any time at the discretion of the treating 
physician. We will stop enrolling patients early if P (% of patients unable to complete all planned cycles 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 70 of 77 
 
of therapy > 10% | data from the trial) > 0.95. That is, given the outcomes from the patients who have 
been evaluated, if we determine that there is more than a 95% chance that more than 10% of patients 
are unable to complete all planned cycles of therapy we will stop enrolling patients. This decision rule 
gives the following monitoring rule. We assume a uniform prior distribution for the percent of patients 
unable to complete all planned cycles of therapy. Stop enrolling patients if  
 
[# patients unable to complete all planned cycles of therapy / # patients evaluated] 
 
≥ 3/10, 4/15, 5/20, 5/25, 6/30 
 
The operating characteristics of this monitoring rule are shown in the table below and are based on 
10,000 simulations of the monitoring rule. The feasibility monitoring rule and operating characteristics 
were calculated using the Stata command developed by Fellman43. 
 
Operating Characteristics of Feasibility Monitoring Rule 
 
 
Sample Size 
Mean # Unable 
to Complete 
Therapy 
% of Pts. Unable to 
Complete Therapy 
Pr(Stop Early) 
P25 
Mean 
P75 
5% 
0.0173 
30 
30 
30 
1.5 
10% 
0.1390 
30 
30 
30 
2.8 
15% 
0.3686 
20 
30 
30 
3.7 
20% 
0.6196 
10 
25 
30 
4.1 
25% 
0.8161 
10 
15 
25 
4.3 
30% 
0.9216 
10 
10 
20 
4.4 
 
Analysis 
 
We will use descriptive statistics to summarize the demographic and clinical characteristics of patients. 
We will tabulate tumor response and estimate the rates of residual disease (complete resection, <1 cm 
residual disease, and >1cm residual disease), interval response (pCR) and overall response (CR) with 
90% confidence intervals, and we will compare response rates with a contemporary control group using 
Fisher’s exact test. 
 
We will estimate the median PFS with a 90% credible interval, and we will report the posterior 
probability that the median PFS is greater than 12 months. We will also report the posterior probability 
that the median PFS is greater than 16 months.  
 
We will also estimate PFS with the product-limit estimator of Kaplan and Meier44, and we will model 
PFS as a function of potential prognostic factors (e.g., biomarkers) using Cox45 proportional hazards 
regression.  
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 71 of 77 
 
We will estimate the percent of patients unable to complete all planned cycles of therapy with a 90% 
credible interval. If we enroll 30 patients and find 0 patients unable to complete all planned cycles of 
therapy, then our 90% credible interval will be 0.2% to 9.2%. We will also report the posterior 
probability that the percent of patients unable to complete all planned cycles of therapy is more than 
10%. If we enroll 30 patients and find 0 patients unable to complete all planned cycles of therapy, then 
the posterior probability that the percent of patients unable to complete all planned cycles of therapy is 
more than 10% is 0.038. We will tabulate adverse events by grade and relationship to study drug. 
 
Biomarkers 
 
We assume that a particular biomarker will increase (or decrease) with probability 0.50 if there is no 
effect of chemotherapy. With 30 patients we will have 80% power with a 1-sided significance level of 
0.05 to detect a probability of a particular biomarker’s expression increasing (or decreasing) of 0.72 
using an exact binomial test. In other words, if chemotherapy has the effect of increasing (or decreasing) 
expression of a particular biomarker in 72% of patients, we will have 80% power to detect that effect. 
This same sample size will also give us 80% power with a 1-sided significance level of 0.05 using 
Fisher’s exact test to detect a difference in increasing (or decreasing) expression rates of 0.83 and 0.50 
between patients treated with chemotherapy and a corresponding control group of 30 untreated patients, 
respectively. A sample of 30 patients will also give us 80% power with a 2-sided significance level of 
0.05 and a paired t-test to detect an effect size of 0.53 standard deviations for the change in biomarker 
expression from pre-treatment to post-treatment with chemotherapy. Thirty patients treated with pre- 
and post-chemotherapy will yield 80% power with a 2-sided significance level of 0.05 using a 2-sample 
t-test to detect a difference of 0.74 standard deviations between treated and untreated patients with 
respect to the change in biomarker expression. No adjustment for multiple testing is made, as these 
analyses are considered exploratory in nature. These sample size calculations were performed using 
nQuery Advisor ® 8.0 (Copyright © 1995-2007, Statistical Solutions, Saugus, MA). We will also use 
Cox proportional hazards regression to model PFS and OS as a function of biomarker expression. 
 
11.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
11.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 8. 
 
 
 
Table 8 Product Descriptions 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 72 of 77 
 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Solution for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
12.0 ADMINISTRATIVE AND REGULATORY DETAILS 
12.1 Confidentiality 
The data will be kept in a database on a password protected computer in a secure office. This 
information will only be accessible to the study investigators. Once the clinical information is 
obtained, all patient identifying information will be deleted from the database. No patient identifiers 
will be used when analyzing the data, or reporting the results.  
 
12.2 Compliance with Financial Disclosure Requirements 
12.3 Compliance with Law, Audit and Debarment 
This study is to be conducted according to the following considerations, which represent good and 
sound research practice: 
1. E6 Good Clinical Practice: Consolidated Guidance 
www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM129515.pdf  
2. US Code of Federal Regulations (CFR) governing clinical study conduct and ethical 
principles that have their origin in the Declaration of Helsinki 
o Title 21 Part 11 – Electronic Records; Electronic Signatures 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr11_02.html 
o Title 21 Part 50 – Protection of Human Subjects 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr50_02.html  
o Title 21 Part 54 – Financial Disclosure by Clinical Investigators 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr54_02.html  
o Title 21 Part 56 – Institutional Review Boards 
www.access.gpo.gov/nara/cfr/waisidx_02/21cfr56_02.html 
3. State laws: It is understood that deviations from the protocol should be avoided, 
except when necessary to eliminate an immediate hazard to a research participant. In 
such case, the deviation must be reported to the IRB according to the local reporting 
policy. 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 73 of 77 
 
12.4 Compliance with Study Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and 
Drug Administration Amendments Act (FDAAA), the MDACC of the Study is solely responsible for 
determining whether the Study and its results are subject to the requirements for submission to the 
Clinical Studies Data Bank, http://www.clinicaltrials.gov. Information posted will allow subjects to 
identify potentially appropriate Studies for their disease conditions and pursue participation by calling 
a central contact number for further information on appropriate Study locations and Study site contact 
information.  
12.5 Quality Management System 
The study team, including the PIs, research nurse, and data coordinator, will perform monthly reviews 
of case histories and regulatory documents. Audits will be performed as per institutional standard. 
 
12.6 Data Management 
All study-related documents must be retained for the maximum period required by applicable 
federal regulations and guidelines or institutional policies. 
 
Study data will be collected and managed using Data Management Initiative (DMI) electronic data 
capture tools hosted at MD Anderson. DMI is a secure, web-based application with controlled access 
designed to support data capture for research studies, providing: 1) an intuitive interface for validated 
data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated export 
procedures for seamless downloads to common statistical packages; and 4) procedures for importing 
data from external sources. In the case of multi-center studies DMI uses Data Access Groups (DAGs) 
to ensure that personnel at each institution are blinded to the data from other institutions. DMI is 
hosted on a secure server by MD Anderson Cancer Center's Department of Research Information 
Systems & Technology Services. DMI has undergone a Governance Risk & Compliance Assessment 
(May 2014) by MD Anderson's Information Security Office and found to be compliant with HIPAA, 
Texas Administrative Codes 202-203, University of Texas Policy 165, federal regulations outlined in 
21CFR Part 11, and UTMDACC Institutional Policy #ADM0335. Those having access to the data file 
include the study PI and research team personnel. Users are authenticated against MDACC's Active 
Directory system. External collaborators are given access to the database once approved by the PI, 
with their access expiring in 6 months but renewable in 6 months increments at the request of the PI. 
The application is accessed through Secure Socket Layer (SSL). All protected health information 
(PHI) will be removed from the data when it is exported from DMI for analysis. All dates for a given 
patient will be shifted by a randomly generated number between 0 and 364, thus preserving the 
distance between dates. Dates for each patient will be shifted by a different randomly generated 
number. Following publication study data will be archived in DMI. 
 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 74 of 77 
 
13.0 REFERENCES 
1. 
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Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 
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3. 
Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
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Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz O, Wood CR, et al. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. 
J Immunol 2003;170:1257-66.  
5. 
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunol 
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6. 
Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 expressed 
by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell 
carcinoma. Clin Caner Res 2007;13(6):1757-61.  
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Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or Hyde. 
Cancer Metastasis Rev 2007;26:373-400. 
8. 
Usubütün A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.  
9. 
Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic effect of 
epithelial and stromal symphocyte infiltration in non-small cell lung cancer. Clin Cancer Res 
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10. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. Tumor 
infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer patients. BMC 
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11. Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et al. Histopathologic 
prognostic score in colorectal adenocarcinomas. Anticancer Res 1998;18:689-94.  
12. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pagès C, et al. Type, 
density, and location of immune cells within human colorectal tumors predict clinical outcome. 
Science 2006;313:1960-4.  
13. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular biology. Int 
J Clin Oncol 2010;15:544-51.  


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
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14. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival of a 
patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell 
infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-30.  
15. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan Pathol 
2010;37(Suppl 1):48-53.  
16. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 2009;10(840):841.  
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19. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et al. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of 
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21. Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T cells 
in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal 
cell carcinoma. BJU Intern 2010;107:1500-6.  
22. Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. Prognostic value of tumour-
infiltrating lynmphocytes (TILs) in colorectal cancer. J Pathol 1997;182:318-24.  
23. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. Adoptive cell 
transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the 
treatment of patients with refractory metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.  
24. Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of metastatic 
melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 2008;358(25):2698-
703.  
25. Ölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. Foxp3+ cell 
infiltration and granzyme B+/Foxp3+ cell ratio are associated with outcome in neoadjuvant 
chemotherapy-treated ovarian carcinoma. Cancer Immunol Immunother 2010;59:909-19.  
26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. PNAS 2001;98(24):13866-71. 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 76 of 77 
 
27. Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisted. Annu Rev Immunol 
2005;23:515-48.  
28. Homsi J, Kashani-Sabet M, Messina JL, Daud A. Cutaneous melanoma: prognostic factors. 
Cancer Control 2005;12(4):223-9.  
29. Iannone R, Gergich K, Cong C, Kang P, Daud A, Dronca R, et al. Efficacy and safety of 
Pembrolizumab in patients with advanced melanoma. Pigment Cell Melanoma Res 2012;25:836-
903. 
30. 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:doi: 
10.1056/NEJMoa1200690.  
31. Lyford-Pike S, Peng S, Young GD, et al. Evidence for a role of the PD-1:PD-L1 pathway in 
immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res 
2013;73(2): Published online January 3. 
32. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent R, Ford R, et al. New response 
evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J Cancer 
2009;45(2):228-47. 
33. Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the evaluation 
of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res 
2009;15(23):7412-20. 
34. Blum JL, Jones SE, Buzdar AU, LoRusso PM, et al. Multicenter Phase II Study of Capecitabine 
in Paclitaxel-Refractory Metastatic Breast Cancer. J Clin Oncol 17: 485-493, 1999 
35. Martin M, Ruiz A, Munoz M, Balil A, Garcia-Mata J, Calvo L, et al. Gemcitabine plus vinorelbine 
monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and 
taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) Study. 
Lancet Oncol. 2007;8(3):219. 
36. Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, et al. Phase III Study of Doxorubicin, 
Paclitaxel, and the Combination of Doxorubicin and Paclitaxel as Front-Line Chemotherapy for 
Metastatic Breast Cancer: An Intergroup Study (E1193). J Clin Oncol. 2003;21(4):588. 
37. Stewart JSW, Ezra E.W. Cohen EEW, Licitra L, Van Herpen CML, et al. Phase III Study of 
Gefitinib Compared With Intravenous Methotrexate for Recurrent Squamous Cell Carcinoma of 
the Head and Neck. J Clin Oncol. 2009;27(11):1864. 
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Multicenter Phase II Study to Evaluate the Efficacy and Toxicity of Cetuximab As a Single Agent 


 
Investigational Drug  
Substance(s): 
Pembrolizumab, Paclitaxel,  
Carboplatin 
Study Number: 
2014-0662 
 
Version Number: 
15 
Date:  
March 10, 2020 
 
  
 
 
 
 
 
Page 77 of 77 
 
in Patients With Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck 
Who Failed to Respond to Platinum-Based Therapy. J Clin Oncol. 2007;25(16):2171. 
39. Bellmunt J, Théodore C, Demkov T, Komyakov B, Sengelov L, et al. Phase III Study of 
Vinflunine Plus Best Supportive Care Compared With Best Supportive Care Alone After a 
Platinum-Containing Regimen in Patients With Advanced Transitional Cell Carcinoma of the 
Urothelial Tract. J Clin Oncol. 2009;27(27):4454 
40. Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, et al. Phase II Study of Pemetrexed 
for Second-Line Treatment of Transitional Cell Cancer of the Urothelium. J Clin Oncol. 
2006;24(21):3451 
41. Thall PF, Wooten LH, Tannir NM. Monitoring Event Times in Early Phase Clinical Trials: Some 
Practical Issues. Clinical Trials 2005;2:467-478. 
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1994;50(2):337-49. 
43. Fellman, B. M. Stata command for calculating adverse event and efficacy stopping boundaries for 
phase II single-arm trials. Stata Journal 2014;14(2):407-417. 
44. Kaplan EL and Meier P. Nonparametric estimation from incomplete observations. Journal of the 
American Statistical Association 1958;53:457-481. 
45. Cox DR. Regression models and life tables (with discussion). Journal of the Royal Statistical 
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46. Vasey PA1, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, Parkin D, Paul J, Hay 
A, Kaye SB; Scottish Gynaecological Cancer Trials Group. Phase III randomized trial of 
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carcinoma. Journal National Cancer Institution. 2004; 96 (22): 1682-91. 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
Protocol 2014-0662 
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Page 1 of 16 
Informed Consent 
INFORMED CONSENT/AUTHORIZATION FOR PARTICIPATION 
IN RESEARCH 
Matched Paired Pharmacodynamics and Feasibility Study of Pembrolizumab 
in Combination with Chemotherapy in Frontline Ovarian Cancer 
2014-0662 
Subtitle: Neoadjuvant Pembrolizumab in Frontline Ovarian Cancer
Study Chair: 
Amir Jazaeri 
_________________________ 
_____________________________ 
Participant’s Name  
Medical Record Number  
This is an informed consent and authorization form for a research study. It includes a 
summary about the study. A more detailed description of procedures and risks is 
provided after the summary. 
STUDY SUMMARY 
The goal of this clinical research study is to learn about the safety of giving the combination 
of pembrolizumab, carboplatin, and paclitaxel to patients with high-grade epithelial non-
mucinous ovarian, primary peritoneal, or Fallopian tube cancer. Researchers want to find out 
how the disease responds to therapy with pembrolizumab. 
This is an investigational study. Pembrolizumab is FDA-approved and commercially 
available for the treatment of certain types of melanoma.  Its use in patients with 
ovarian cancer is investigational.  Carboplatin and paclitaxel are both FDA-approved 
and commercially available for the treatment of advanced ovarian cancer. The study 
doctor can explain how the study drug combination is designed to work. 
The study drug(s) may help to control the disease. Future patients may benefit from 
what is learned.  There may be no benefits for you in this study. 
Your participation is completely voluntary. Before choosing to take part in this study, 
you should discuss with the study team any concerns you may have, including side 
effects, potential expenses, and time commitment. 
You can read a full list of potential side effects below in the Possible Risks section of 
this consent. 
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You will the receive study drug(s) for up to 23 cycles, or possibly more if the doctor 
thinks it is appropriate for you to have more than 3 Neoadjuvant Treatment cycles. 
 
Pembrolizumab will be provided at no cost to you while you are on study. You and/or 
your insurance provider will be responsible for the cost of carboplatin, paclitaxel, and 
surgery. 
 
You may choose not to take part in this study. You may choose to receive the 
standard treatment for the disease.  You may choose to receive other investigational 
therapy, if available.  You may choose not to have treatment for cancer at all.  In all 
cases, you will receive appropriate medical care, including treatment for pain and other 
symptoms of cancer. 
 
 
1.  STUDY DETAILS 
 
Screening Tests 
Signing this consent form does not mean that you will be able to take part in this study. 
You will have the following screening tests to help the doctor decide if you are eligible 
to take part in this study: 
• You will have a physical exam, including an exam of your pelvis.   
• Blood (about 3 tablespoons) and urine will be collected for routine tests and to 
check the level of fat in your blood, your blood sugar level, and to check your 
thyroid function.  If you can become pregnant, part of this urine and/or blood 
sample will be used for a pregnancy test.  To take part in this study, you must not 
be pregnant. 
• You will have a computed tomography (CT) scan or magnetic resonance imaging 
(MRI) to check the status of the disease.  
• You will have leftover tissue from a previous biopsy collected to confirm the 
diagnosis. 
 
Tumor tissue will be used for research testing after being collected with one of 
the following methods: 
• Tumor tissue will be collected from the laparoscopy surgery if you are scheduled 
to have or have already had this type of surgery. 
• Tumor tissue will be collected from a diagnostic biopsy if the ovarian, primary 
peritoneal, or fallopian tube cancer has yet to be confirmed; OR 
• You will have a tumor biopsy to collect tumor tissue if the ovarian, primary 
peritoneal, or fallopian tube cancer diagnosis has been confirmed but you are not 
planning to have a laparoscopy surgery before beginning treatment. The type of 
biopsy you will have will be explained to you. 
 
The study doctor will discuss the screening test results with you.  If the screening tests 
show that you are not eligible to take part in the study, you will not be enrolled.  Other 
treatment options will be discussed with you.  
 
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Up to 30 participants will be enrolled in this study. All will take part at MD Anderson.  
 
 
Treatment 
If you are found to be eligible to take part in this study and agree, you will have 
standard chemotherapy, your scheduled surgery, and then chemotherapy in 
combination with pembrolizumab.  
 
Neoadjuvant Treatment 
You will receive standard chemotherapy treatment for three 21-day cycles, or possibly 
more cycles if the doctor thinks it is in your best interest: 
On Day 1 of each cycle, you will receive carboplatin by vein over 1 hour. 
On Days 1, 8, and 15 of each cycle, you will receive paclitaxel by vein over 1 hour.  
 
Surgery 
You will then have your scheduled surgery. Some of the tissue removed during the 
surgery will be used for immune system testing and to compare to tissue collected 
before chemotherapy. 
 
Adjuvant Treatment and Maintenance 
After you have recovered from surgery (about 3-6 weeks later), you will begin 
receiving chemotherapy again along with the drug pembrolizumab.  You will receive 
the standard chemotherapy in the same way you received it during Cycles 1-3. 
On Day 1 of each cycle, you will receive pembrolizumab by vein over 30 minutes 
during Cycles 4-26. Cycles 7-26 are called the Maintenance Phase. 
You will receive carboplatin and paclitaxel during Cycles 4-6 only. 
 
Study Visits 
On Day 1 of each cycle during Neoadjuvant Treatment: 
• You will have a physical exam.  If the study doctor thinks it is needed, you will 
also have a pelvic exam.  
• Blood (about 3 tablespoons) will be collected for routine tests. If you can become 
pregnant, urine will be collected and/or part of this blood sample will be used for a 
pregnancy test. 
• In Cycle 1 only, blood (about 1 tablespoon) will be drawn for biomarker testing. 
The biomarker tests in this study may include genetic biomarkers. Biomarkers are 
found in the blood and tissue and may be related to your reaction to the study 
drug. 
 
Study Visits during Neoadjuvant Therapy 
On Days 1, 8 and 15 of each cycle during Neoadjuvant Treatment, blood (about 1-
2 tablespoons) will be drawn for routine tests. 
 
At your visit before the surgery: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine and biomarker testing. 
• You will have a CT scan or MRI to check the status of the disease. 
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You will sign a separate consent form for the surgery that explains the 
procedure and its risks. During the surgery, tumor tissue will be collected for 
biomarker and genetic testing. All samples will be stored at MD Anderson for an 
unlimited amount of time for testing related to this study. 
 
On the day of surgery, blood (about 3 tablespoons) will be drawn for routine testing. 
 
At your postoperative visit (visit after surgery): 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine testing. 
 
Study Visits during Adjuvant Therapy 
On Day 1 of each cycle during Adjuvant Treatment: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be drawn for routine and biomarker testing. 
• Urine will be collected for routine testing.  If you can become pregnant, part of 
this urine and/or blood sample will be used for a pregnancy test. 
 
On Days 8 and 15 of each cycle during Adjuvant Treatment, blood (about 1-2 
tablespoons) will be drawn for routine tests. 
 
Study Visits during Maintenance Therapy: 
• You will have a physical exam. 
• Blood (about 3 tablespoons) will be collected for routine tests and to check your 
thyroid function. 
• Urine will be collected for routine testing. 
 
Every 12 weeks, you will have a CT scan or MRI to check the status of the disease.  
 
Length of Study 
You will the receive study drug(s) for up to 23 cycles, or possibly more if the doctor 
thinks it is appropriate for you to have more than 3 Neoadjuvant Treatment cycles. You 
will no longer be able to take the study drugs if the disease gets worse, if intolerable 
side effects occur, or if you are unable to follow study directions.  
 
After you are no longer taking any study drugs, the study staff will continue to call you 
every 3 months to check the status of your health. 
 
Post-Treatment Visits 
After the last dose of study drug(s), the following tests and procedures will be 
performed: 
• You will have a physical exam. 
• You will have a CT or MRI to check the status of the disease.  
• Blood (about 1-2 tablespoons) will be drawn for routine tests. 
 
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About 30 days after the last dose of study drugs, you will have a physical exam.  
 
 
 
 
2.  POSSIBLE RISKS 
 
While on this study, you are at risk for side effects.  These side effects will vary from 
person to person.  The more commonly occurring side effects are listed in this form, as 
are rare but serious side effects.  You should discuss these with the study doctor.  You 
may also want to ask about uncommon side effects that have been observed in small 
numbers of patients but are not listed in this form.  Many side effects go away shortly 
after the drugs are stopped, but in some cases side effects may be serious, long-
lasting or permanent, and may even result in hospitalization and/or death. 
 
Tell the study staff about any side effects you may have, even if you do not think they 
are related to the study drugs and procedures.  You should talk to your doctor before 
taking all drugs, supplements, and vaccinations while on study. 
 
Carboplatin, pembrolizumab, and paclitaxel may each cause low blood cell counts (red 
blood cells, platelets, and/or white blood cells):  
• A low red blood cell count (anemia) may cause difficulty breathing and/or fatigue. 
You may need a blood transfusion.  
• A low platelet count increases your risk of bleeding (such as nosebleeds, 
bruising, stroke, and/or digestive system bleeding). You may need a platelet 
transfusion.  
• A low white blood cell count increases your risk of infection (such as pneumonia 
and/or severe blood infection). Infections may occur anywhere and become life-
threatening. Symptoms of infection may include fever, pain, redness, and 
difficulty breathing.  
 
Pembrolizumab Side Effects 
 
Common (occurring in more than 20% of patients)  
 
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• fatigue 
• fever 
• skin rash and/or itching 
• abnormal salts, minerals, 
and/or acids in the blood 
(possible weakness, 
swelling, fatigue, low blood 
pressure, organ failure, 
heart problems, changes in 
mental status, and/or 
seizure) 
• high blood sugar 
(possible diabetes) 
• high blood levels of fat 
(possible heart disease 
and/or stroke) 
• loss of appetite 
• nausea 
• constipation 
• diarrhea 
• abdominal pain 
• low blood cell count 
(white/red/platelets)  
• abnormal liver test 
(possible liver damage) 
• pain 
• abnormal kidney test 
(possible kidney 
damage) 
• cough 
• difficulty breathing 
 
Occasional (occurring in 3-20% of patients)   
 
• swelling (face/arm/leg) 
• inflammation of the 
tissue around the heart 
(possible chest pain) 
• irregular heartbeat 
• headache 
• confusion 
• patches of skin color 
• underactive thyroid 
gland (possible weight 
gain, heart failure, 
and/or constipation) 
• overactive thyroid gland 
(possible weight loss, 
diarrhea, mood swings, 
difficulty sleeping, heart 
rate changes, and/or 
sweating) 
• low blood sugar 
• weight loss 
• fluid in the abdomen 
• blood in the urine 
• vomiting 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• weakness 
• nerve damage 
(possible numbness, 
pain, and/or loss of 
motor function) 
• difficulty breathing 
(possibly due to lung 
inflammation) 
• flu-like symptoms 
• infusion reaction 
(possible dizziness, low 
blood pressure, 
nausea, pain, and/or 
difficulty breathing) 
 
Frequency Unknown 
• heart failure 
• heart attack 
• build-up of fluid 
around the heart 
(possible heart 
failure) 
• abnormal 
connections or 
passageways 
between organs or 
vessels 
• bleeding in the 
rectum and/or 
uterus 
• blockage in the lung 
(possible pain 
and/or shortness of 
breath) 
• nosebleed 
• coughing up blood 
 
 
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Rare but serious (occurring in fewer than 3% of patients)  
 
• low blood pressure 
(possible 
dizziness/fainting) 
• heart inflammation 
• build-up of fluid in the 
tissue around the heart  
• blood vessel inflammation 
(possible bleeding and/or 
bruising) 
• seizure 
• immune system damage 
to the nervous system 
(causing muscle 
weakness, numbness,  
and/or paralysis) 
• spinal cord inflammation 
(possible pain, weakness, 
loss of feeling or 
movement, and/or 
paralysis) 
• brain inflammation 
(possible paralysis and/or 
coma)  
• shedding, scaling and/or 
inflammation of the skin 
(possible fatal loss of 
bodily fluids) 
• large skin blisters 
• very severe blistering skin 
disease (loss of large 
portion of skin and/or 
ulcers of the skin and 
digestive tract) 
• hormonal deficiency 
that affects the body's 
ability to control blood 
pressure and react to 
stress 
• pituitary gland 
inflammation (possible 
headaches) 
• inflammation of the 
thyroid gland (possible 
tenderness in the 
neck) 
• diabetes requiring 
insulin 
• severe high blood 
sugar due to 
uncontrolled diabetes 
• decreased production 
of adrenal hormones 
(possible weakness 
and/or low blood 
pressure)  
• inflammation of the 
pancreas (possible 
abdominal pain) 
• anemia due to 
destruction of red 
blood cells  
• liver damage 
(hepatitis) 
• inflammation inside 
the eye (possible 
vision problems)  
• kidney inflammation 
(possible kidney 
damage/failure) 
 
• kidney failure 
• build-up of fluid 
around the lungs  
• immune response that 
causes the body to 
attack itself (possible 
organ damage) 
• multi-organ disease 
causing lesions, most 
often in the lungs 
(sarcoidosis)  
• immune response 
(causing muscle 
weakness) 
• immune system 
reaction (possible 
fever, jaundice, 
liver/spleen 
enlargement, 
irritability, and/or 
seizures) 
• severe life-threatening 
infection (possible low 
blood pressure, kidney 
failure, and/or heart 
failure) 
• Vogt Koyanagi Harada 
syndrome -- 
pigmented tissue 
(possible eye 
pain/swelling and 
changes in vision, 
hearing loss, and/or 
white patches on the 
skin) 
If you have a solid tumor type and you have an organ transplant, pembrolizumab may 
increase your risk for the transplant to be rejected by your body. 
 
Pembrolizumab works by boosting the immune system. This may cause unknown side 
effects resulting from your immune system attacking your organs. This may cause 
inflammation and inflammation-related side effects in any organ or tissue. These side 
effects can affect more than one of your normal organs and tissues at the same time. 
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Carboplatin Side Effects 
 
Common (occurring in more than 20% of patients) 
 
• abnormal salts, 
minerals, and/or acids 
in the blood (possible 
weakness, swelling, 
fatigue, low blood 
pressure, organ failure, 
heart problems, 
changes in mental 
status, and/or seizure) 
• vomiting 
• low blood counts 
(red/white/platelets) 
• pain 
• abnormal liver tests 
(possible liver damage) 
• abnormal kidney test 
(possible kidney 
damage) 
 
Occasional (occurring in 3-20% of patients) 
 
• nerve damage (possible 
numbness, pain, and/or 
loss of motor function) 
• hair loss (partial or total) 
• abdominal pain 
• nausea 
• constipation 
• diarrhea 
• weakness 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• allergic reaction 
• infection  
 
 
Rare but serious (occurring in fewer than 3% of patients)  
 
• high blood pressure 
• low blood pressure 
(possible 
dizziness/fainting) 
• heart failure 
• stroke 
• dehydration 
• blood vessel blockage  
• destruction of red blood 
cells (possible anemia, 
kidney damage, and/or 
failure) 
• reduced blood supply to 
the arms and legs 
• blindness 
• hearing loss 
• difficulty breathing due 
to narrowing of the 
airways 
• tissue death at the 
injection site caused by 
drug leakage 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 
 
Carboplatin may rarely cause the cancer to spread. 
 
It is not known how often the following side effects may occur: 
 
• decreased bone marrow function 
 
Paclitaxel Side Effects 
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Common (occurring in more than 20% of patients) 
 
• abnormal EKG 
• swelling 
• flushing 
• hair loss (partial or 
total) 
• mouth blisters/sores 
(possible difficulty 
swallowing) 
• nausea/vomiting 
• diarrhea  
• low blood cell counts 
(red/platelets/white ) 
• abnormal liver tests 
(possible liver damage) 
• pain (muscle/joint) 
• nerve damage 
(possible numbness, 
pain, and/or loss of 
motor function) 
• abnormal kidney test 
(possible kidney 
damage) 
• allergic reaction   
• infection 
 
Occasional (occurring in 3-20% of patients) 
 
• low blood pressure 
(possible dizziness/ 
fainting) 
• slow heartbeat  
• skin rash 
• abdominal pain 
• abnormal liver tests 
(possible yellowing of 
the skin and/or eyes) 
• weakness 
• injection site reaction 
(possible redness, 
swelling, skin 
discoloration) 
 
Rare but serious (occurring in fewer than 3% of patients) 
 
• fast/irregular heartbeat  
• blood clots in a vein 
(possible pain, swelling, 
and/or redness) 
• heart failure 
• heart attack 
• decreased blood supply 
to the heart 
• high blood pressure 
• fainting 
• decreased brain 
function (possible 
paralysis and/or coma) 
• decreased brain 
function due to liver 
damage 
• seizure 
• severe sunburn-like 
rash at site of previous 
radiation (called 
radiation recall)  
• death of skin 
• inflammation at the site 
of previous tissue death 
• very severe blistering 
skin disease (with 
ulcers of the skin and 
digestive tract)  
• very severe blistering 
skin disease (loss of 
large portion of skin) 
• inflammation of the 
pancreas (possible 
abdominal pain) 
• inflammation of the 
intestines 
• dehydration 
• paralysis of the 
intestines 
• intestinal blockage 
• hole in the intestines 
(possible leaking 
contents into the 
abdomen) 
• difficulty walking 
• liver damage and/or 
failure 
• blind spot 
• hearing loss 
• decreased kidney 
function 
• blockage in the lung 
(possible pain and/or 
shortness of breath) 
• lung inflammation 
and/or damage 
(possible difficulty 
breathing) 
• blood clots in the lung 
(possible failure to 
breathe) 
• difficulty breathing 
• life-threatening allergic 
reaction (such as 
difficulty breathing, low 
blood pressure, and/or 
organ failure) 
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Other Risks 
 
Blood draws may cause pain, bleeding, and/or bruising.  You may faint and/or 
develop an infection with redness and irritation of the vein at the site where blood is 
drawn.  Frequent blood collection may cause anemia (low red blood cell count), which 
may create a need for blood transfusions. 
 
Having biopsies performed may cause pain, bruising, bleeding, redness, low blood 
pressure, swelling, and/or infection at the site of the biopsies.  An allergic reaction to 
the anesthetic may occur.  A scar may form at the biopsy site. 
 
The type of genetic testing being performed in this study will not provide you or 
your doctor information about diseases that are passed down in families.  It will not 
tell the study researchers anything that will prevent you from getting health 
insurance, and it will not tell the study researchers anything about any diseases or 
conditions you may get in the future. 
 
This study may involve unpredictable risks to the participants. 
 
Pregnancy Related Risks 
Taking part in this study can result in risks to an unborn or breastfeeding baby, so you 
should not become pregnant or breastfeed a baby while on this study. You must use birth 
control during the study if you are sexually active. 
 
Birth Control Specifications:  You must use 2 of the following forms of birth control during 
this study and for 120 days after your last dose of study drugs: 
• Birth control pills, injections, or implants  
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) (such as the 
coil) 
• Barrier methods of birth control: condom or occlusive cap (such as a diaphragm or 
cervical/vault cap) with spermicide  
• Male partner with sterilization/vasectomy 
 
Females:  If you are pregnant, you will not be enrolled on this study. If you become 
pregnant or suspect that you are pregnant, you must tell your doctor right away. 
 
Getting pregnant may result in your removal from this study. 
 
3. COSTS AND COMPENSATION  
 
• worsening of existing 
scleroderma (severe 
hardened skin, which 
can cause difficult 
movement) 
• decreased blood flow to 
part of the bowel 
(possibly causing death 
of tissue) 
• tissue death at the 
injection site caused by 
drug leakage 
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If you suffer injury as a direct result of taking part in this study, MD Anderson health 
providers will provide medical care.  However, this medical care will be billed to your 
insurance provider or you in the ordinary manner. You will not be reimbursed for 
expenses or compensated financially by MD Anderson or Merck Pharmaceuticals for 
this injury.  You may also contact the Chair of MD Anderson’s IRB at 713-792-6477 
with questions about study-related injuries. By signing this consent form, you are not 
giving up any of your legal rights. 
 
Certain tests, procedures, and/or drugs that you may receive as part of this study may 
be without cost to you because they are for research purposes only.  However, your 
insurance provider and/or you may be financially responsible for the cost of care and 
treatment of any complications resulting from the research tests, procedures, and/or 
drugs.  Standard medical care that you receive under this research study will be billed 
to your insurance provider and/or you in the ordinary manner.  Before taking part in this 
study, you may ask about which parts of the research-related care may be provided 
without charge, which costs your insurance provider may pay for, and which costs may 
be your responsibility.  You may ask that a financial counselor be made available to you 
to talk about the costs of this study.  
 
Samples that are collected from you in this study may be used for the development of 
treatments, devices, new drugs, or patentable procedures that may result in 
commercial profit. 
 
There are no plans to compensate you for any patents or discoveries that may result 
from your participation in this research. 
 
You will receive no compensation for taking part in this study.  
 
Additional Information  
 
4. 
You may ask the study chair (Dr. Amir Jazaeri, at 713-745-1613) any questions 
you have about this study. You may also contact the Chair of MD Anderson's 
Institutional Review Board (IRB - a committee that reviews research studies) at 
713-792-6477 with any questions that have to do with this study or your rights as a 
study participant. 
 
5. 
You may choose not to take part in this study without any penalty or loss of 
benefits to which you are otherwise entitled. You may also withdraw from 
participation in this study at any time without any penalty or loss of benefits. If you 
decide you want to stop taking part in the study, it is recommended for your safety 
that you first talk to your doctor. If you withdraw from this study, you can still 
choose to be treated at MD Anderson. 
 
6. 
This study or your participation in it may be changed or stopped without your 
consent at any time by the study chair, Merck Pharmaceuticals, the U.S. Food and 
Drug Administration (FDA), the Office for Human Research Protections (OHRP), or 
the IRB of MD Anderson. 
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7. 
You will be informed of any new findings or information that might affect your 
willingness to continue taking part in the study and you may be asked to sign 
another informed consent and authorization form stating your continued willingness 
to participate in this study. 
 
8. 
MD Anderson may benefit from your participation and/or what is learned in this 
study. 
 
9.  This study is sponsored and/or supported by: Merck Pharmaceuticals. 
 
10.  In a medical emergency, you may be cared for by someone who has a financial 
interest with the study sponsor(s)/supporter. If you have any questions about this, you 
may call the IRB at 713-792-6477. 
 
Future Research 
 
Your personal information and/or samples are being collected as part of this study. 
These data and/or samples may be used by researchers at MD Anderson or shared 
with other researchers and/or institutions for use in future research.  
 
Before being shared for future research, every effort will be made to remove your 
identifying information from any data and/or samples. If all identifying information is 
removed, you will not be asked for additional permission before future research is 
performed.  
 
In some cases, all of your identifying information may not be removed before your 
data or samples are used for future research. If this research is performed at MD 
Anderson, the researchers must get approval from the Institutional Review Board 
(IRB) of MD Anderson before your data and/or samples can be used. At that time, 
the IRB will decide whether or not further permission from you is required. The IRB is 
a committee of doctors, researchers, and community members that is responsible for 
protecting study participants and making sure all research is safe and ethical.  
 
If this research is not performed at MD Anderson, MD Anderson will not have 
oversight of any data and/or samples. 
 
Genetic Research 
 
Samples collected from you as part of this study will be used for genetic research, 
which may include whole genome sequencing. Whole genome sequencing is a type 
of testing in which researchers study your entire genetic makeup (DNA). This may 
help researchers learn how changes in the ordering of genes may affect a disease or 
response to treatment. 
 
Conflict of Interest 
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Dr. Anil Sood (Collaborator) has received compensation from Merck as a Consultant.  
The financial interests are within the limits of the conflict of interest policy. 
 
Authorization for Use and Disclosure of Protected Health Information (PHI): 
 
A.  During the course of this study, MD Anderson will be collecting and using your 
PHI, including identifying information, information from your medical record, and 
study results. For legal, ethical, research, and safety-related reasons, your doctor 
and the research team may share your PHI with: 
• 
Federal agencies that require reporting of clinical study data (such as the 
FDA, National Cancer Institute [NCI], and OHRP) 
• 
The IRB and officials of MD Anderson 
• 
Merck Pharmaceuticals, who is a sponsor or supporter of this study, and/or 
any future sponsors/supporters of the study 
• 
QualTek Molecular Laboratories 
• 
Study monitors and auditors who verify the accuracy of the information 
• 
Individuals who put all the study information together in report form 
 
Study sponsors and/or supporters receive limited amounts of PHI. They may also 
view additional PHI in study records during the monitoring process. MD Anderson’s 
contracts require sponsors/supporters to protect this information and limit how they 
may use it.  
 
QualTek Molecular Laboratories will also receive slides of tissue for research 
testing. 
 
B. 
Signing this consent and authorization form is optional but you cannot take part in 
this study or receive study-related treatment if you do not agree and sign. 
 
C. 
MD Anderson will keep your PHI confidential when possible (according to state 
and federal law). However, in some situations, the FDA could be required to reveal 
the names of participants. 
 
Once disclosed outside of MD Anderson, federal privacy laws may no longer 
protect your PHI. 
 
D.  The permission to use your PHI will continue indefinitely unless you withdraw your 
authorization in writing. Instructions on how to do this can be found in the MD 
Anderson Notice of Privacy Practices (NPP) or you may contact the Chief Privacy 
Officer at 713-745-6636. If you withdraw your authorization, you will be removed 
from the study and the data collected about you up to that point can be used and 
included in data analysis. However, no further information about you will be 
collected. 
 
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 E. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, 
as required by U.S. Law. This Web site will not include information that can identify 
you. At most, the Web site will include a summary of the results. You can search 
this Web site at any time. 
 
 
 
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CONSENT/AUTHORIZATION 
I understand the information in this consent form.  I have had a chance to read the 
consent form for this study, or have had it read to me. I have had a chance to think 
about it, ask questions, and talk about it with others as needed. I give the study chair 
permission to enroll me on this study.  By signing this consent form, I am not giving up 
any of my legal rights. I will be given a signed copy of this consent document. 
 
________________________________________ 
_______ 
SIGNATURE OF PARTICIPANT 
DATE 
 
_________________________________         
PRINTED NAME OF PARTICIPANT                 
 
LEGALLY AUTHORIZED REPRESENTATIVE (LAR) 
The following signature line should only be filled out when the participant does not have 
the capacity to legally consent to take part in the study and/or sign this document on his 
or her own behalf. 
_____________________________________________________ 
_________ 
SIGNATURE OF LAR 
DATE 
 
 
 
PRINTED NAME and RELATIONSHIP TO PARTICIPANT 
 
WITNESS TO CONSENT 
I was present during the explanation of the research to be performed under Protocol  
2014-0662. 
_____________________________________________________  
_________ 
SIGNATURE OF WITNESS TO THE VERBAL CONSENT  
  
DATE  
PRESENTATION (OTHER THAN PHYSICIAN OR STUDY CHAIR) 
A witness signature is only required for vulnerable adult participants. If witnessing the assent of a 
pediatric participant, leave this line blank and sign on the witness to assent page instead. 
 
 
PRINTED NAME OF WITNESS TO THE VERBAL CONSENT 
 
PERSON OBTAINING CONSENT 
I have discussed this research study with the participant and/or his or her authorized 
representative, using language that is understandable and appropriate.  I believe that I 
have fully informed this participant of the nature of this study and its possible benefits 
and risks and that the participant understood this explanation. 
 
______________________________________________ 
  
_________ 
PERSON OBTAINING CONSENT  
 
 
 
 
 
DATE 
 
______________________________________________ 
PRINTED NAME OF PERSON OBTAINING CONSENT 
 
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TRANSLATOR 
I have translated the above informed consent as written (without additions or 
subtractions) into 
and assisted the people 
(Name of Language) 
obtaining and providing consent by translating all questions and responses during the 
consent process for this participant. 
 
 
_____________________       _______________________________    
___________ 
NAME OF TRANSLATOR       SIGNATURE OF TRANSLATOR 
 DATE 
 
   Please check here if the translator was a member of the research team.  (If checked, 
a witness, other than the translator, must sign the witness line below.) 
 
____________________________________________________   
___________ 
SIGNATURE OF WITNESS TO THE VERBAL TRANSLATION  
  
DATE  
(OTHER THAN TRANSLATOR, PARENT/GUARDIAN,  
OR STUDY CHAIR) 
 
_____________________________________________________ 
PRINTED NAME OF WITNESS TO THE VERBAL TRANSLATION 
 
 
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