A Phase II Study to Evaluate the Efficacy and Safety of Pembrolizumab in Combination With Mitotane in Patients With Advanced Adrenocortical Carcinoma
Phase: PHASE2
Conditions: Adrenocortical Carcinoma
Sponsor: M.D. Anderson Cancer Center

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SPONSOR:  
 
TITLE: A Phase II Study to evaluate the efficacy and safety of pembrolizumab in combination with 
mitotane in patients with advanced adrenocortical carcinoma 
 
 
IND NUMBER: EXEMPT 
 
 
 
 

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Documentation History Page 

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TABLE OF CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 9 
2.0 
TRIAL DESIGN.......................................................................................................... 9 
2.1 
Trial Schema ........................................................................................................... 9 
2.2 
Schedule of Activities ............................................................................................ 11 
3.0 
OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) ............................... 15 
3.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) .................................... 15 
3.2 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) ................................ 15 
3.3 
Exploratory Objective(s) ...................................................................................... 15 
4.0 
BACKGROUND & RATIONALE .......................................................................... 16 
4.1 
Background ........................................................................................................... 16 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 17 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 17 
4.2 
Rationale ................................................................................................................ 17 
4.2.1 Rationale for the Trial and Selected Population ................................................. 17 
4.2.2 Justification for Dose .......................................................................................... 18 
4.2.3 Rationale for Endpoints ...................................................................................... 18 
4.2.3.1 Efficacy Endpoints ....................................................................................... 19 
4.2.3.2 Planned Exploratory Biomarker Research ................................................... 19 
5.0 
METHODOLOGY ................................................................................................... 21 
5.1 
Study Population ................................................................................................... 21 
5.1.1 Participant Inclusion Criteria .............................................................................. 21 
5.1.2 Participant Exclusion Criteria ............................................................................. 23 

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5.1.3 Lifestyle Considerations ..................................................................................... 25 
5.1.3.1 Meals and Dietary Restrictions .................................................................... 25 
5.1.3.2 Contraception ............................................................................................... 25 
5.1.4 Pregnancy ............................................................................................................ 25 
5.2 
Trial Intervention(s) ............................................................................................. 25 
5.2.1 Treatment ............................................................................................................... 26 
5.2.2 Second Course ....................................................................................................... 26 
5.2.3 Timing of Dose Administration ............................................................................. 26 
5.2.4 Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab and IO combination partners ..................................................... 27 
5.3 
Randomization or Treatment Allocation ............................................................ 36 
5.4 
Stratification .......................................................................................................... 36 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) ..................... 36 
5.5.1 Acceptable Concomitant Medications ................................................................ 36 
5.5.2 Prohibited Concomitant Medications.................................................................. 37 
5.5.3 Rescue Medications & Supportive Care ............................................................. 38 
5.6 
Participant Discontinuation Criteria .................................................................. 38 
5.7 
Participant withdrawal From Study ................................................................... 39 
5.8 
Participant Replacement Strategy ...................................................................... 39 
5.9 
Clinical Criteria for Early Trial Termination ................................................... 39 
6.0 
TRIAL ASSESSMENTS AND PROCEDURES .................................................... 41 
6.1 
Trial Procedures ................................................................................................... 41 
6.1.1 Administrative and General Procedures ............................................................. 41 
6.1.1.1 Informed Consent......................................................................................... 41 
6.1.1.3 Inclusion/Exclusion Criteria ........................................................................ 43 

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6.1.1.4 Medical History ........................................................................................... 43 
6.1.1.5 Prior and Concomitant Medications Review ............................................... 43 
6.1.1.5.1 Prior Medications .................................................................................. 43 
6.1.1.5.2 Concomitant Medications ..................................................................... 43 
6.1.1.6 Disease Details and Treatments ................................................................... 43 
6.1.1.6.1 Disease Details ...................................................................................... 43 
6.1.1.6.2 Prior Treatment Details ......................................................................... 43 
6.1.1.6.3 Subsequent Anti-Cancer Therapy Status .............................................. 44 
6.1.1.7 Assignment of Screening Number ............................................................... 44 
6.1.1.8 Assignment of Randomization Number....................................................... 44 
6.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) ................................... 44 
6.1.2 Clinical Procedures/Assessments ........................................................................ 44 
6.1.2.1 Adverse Event (AE) Monitoring .................................................................. 44 
6.1.2.2 Physical Exam .............................................................................................. 44 
6.1.2.3 Full Physical Exam ...................................................................................... 44 
6.1.2.4 Directed Physical Exam ............................................................................... 45 
6.1.2.5 Vital Signs .................................................................................................... 45 
6.1.2.6 Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 45 
6.1.2.7 Electrocardiograms ...................................................................................... 45 
6.1.2.8 Elevated Transaminases With Treated HBV or HCV ................................. 45 
6.1.3 Clinical Safety Laboratory Assessments............................................................. 46 
6.1.3.2 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 46 
6.1.3.3 Pregnancy Testing ........................................................................................ 46 
6.1.4 Tumor Imaging and Assessment of Disease ....................................................... 47 

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6.1.4.1   Initial Tumor Imaging ................................................................................... 47 
6.1.4.2   Tumor Imaging During the Study ............................................................. 47 
6.1.4.3   End of Treatment and Follow-up Tumor Imaging .................................... 48 
6.1.4.4   Second Course (Retreatment) Tumor Imaging ......................................... 48 
6.1.4.5   RECIST 1.1 Assessment of Disease ......................................................... 48 
6.1.4.6    iRECIST Assessment of Disease ............................................................. 49 
6.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling ................... 53 
6.1.6 Other Procedures ................................................................................................. 53 
6.1.6.1 Discontinuation and withdrawal .................................................................. 53 
6.1.6.2 Blinding/Unblinding .................................................................................... 53 
6.1.7 Visit Requirements .............................................................................................. 53 
6.1.7.1 Screening...................................................................................................... 54 
6.1.7.1.1 Screening Period ................................................................................... 54 
6.1.7.2 Treatment Period .......................................................................................... 54 
6.1.7.3 Post-Treatment Visits................................................................................... 54 
6.1.7.3.1 Safety Follow-Up Visit ......................................................................... 54 
6.1.7.3.2 Efficacy Follow-up Visits ..................................................................... 54 
6.1.7.3.3 Survival Follow-up Contacts ................................................................ 54 
6.1.7.3.4 Post Study ............................................................................................. 55 
6.2 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety 
Events ..................................................................................................................... 55 
6.2.1 Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety 
Event Information ............................................................................................... 55 
6.2.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events ............. 58 
6.2.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information .......... 58 

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6.2.4 Sponsor Responsibility for Reporting Adverse Events ...................................... 58 
6.2.5 Pregnancy and Exposure During Breastfeeding ................................................. 58 
6.2.6 Events of Clinical Interest (ECIs) ....................................................................... 58 
7.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 59 
7.1 
Statistical Analysis Plan Summary .......................... Error! Bookmark not defined. 
7.2 
Statistical Analysis Plan ............................................ Error! Bookmark not defined. 
8.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES
..................................................................................................................................... 61 
8.1 
Investigational Product ........................................................................................ 61 
8.2 
Packaging and Labeling Information ................................................................. 61 
8.3 
Clinical Supplies Disclosure ................................................................................. 61 
8.4 
Storage and Handling Requirements .................................................................. 61 
8.5 
Returns and Reconciliation .................................................................................. 62 
9.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 62 
10.0 
References .................................................................................................................. 62 
11.0 
APPENDICES ........................................................................................................... 63 
Appendix 1: ECOG Performance Status ........................................................................ 63 
Appendix 2: Clinical Laboratory Tests .......................................................................... 64 
Appendix 3: Contraceptive Guidance and Pregnancy Testing .................................... 66 
Contraception Requirements ........................................................................................... 66 
Pregnancy Testing ........................................................................................................... 71 
Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression
 ................................................................................................................................ 72 
Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .................................................................................... 76 
11.1.1 Definition of AE ................................................................................................. 76 

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11.1.2 Definition of SAE ............................................................................................... 77 
11.1.3 Additional Events Reported in the Same Manner as SAE .................................. 78 
11.1.4 Recording AE and SAE ...................................................................................... 78 
11.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck .... 82 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab plus mitotane for adrenocortical carcinoma 
Trial Phase 
II 
Clinical Indication 
Recurrent/Metastatic Disease 
Trial Type 
Single arm, open label 
Type of control 
Historical control 
Route of administration 
Mitotane: PO.   Pembrolizumab: IV 
Treatment Groups  
1 
Number of trial participants 
Up to 50 
Estimated enrollment period 
48 months 
Estimated duration of trial 
60 months 
Duration of Participation 
Up to 24 months 
Estimated average length of 
treatment per patient 
12 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 Trial Schema 
 

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2.2 Schedule of Activities 
Table 1 Study Schedule of Activities 
 
 
Screen
ing 
 
 
Lead-in 
phase   
Treatment Period (cycles are 42 days) 
+/-5 -day window 
All CXD1 assessments may be 
performed up to 7 days before infusion 
 
 
Progression 
Study 
Completion
/Early 
Terminatio
n Visit 
Follow-
Up 12 
Day 
-28 
through 
day -1 
(Days 1-28 
days± 5) 
C1 
D1 
C2
D1 
C3
D1 
 
  C4 
  D1  
 
C5D1
-last 
course 
h 
 
 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
x 
X * 
 
 
 
 
 
 
 
 
Demographic data 
x 
 
 
 
 
 
 
 
 
 
Pregnancy test 1 
x 
x 
x 
x 
x 
x 
x 
 
 
 
Physical Examination & 
ECOG PS 2 
x 
 
x 
x 
x 
x 
x 
 
x 
 
Routine labs 3 
x 
 
x 
x 
x 
x 
x 
 
x 
 
Fasting Lipid Panel 4 
x 
 
 
x 
 
x 
x4 
 
 
 
Adrenal Hormones Panel 5 
x 
 
x 
 
x 
 
 x 5 
 
 
 
Mitotane level 6 
x 6 
 
x 
x 
x 
x 
x 
 
x 
 
12-lead ECG 7 
x 
 
 
 
 
 
 
 
 
 
Mitotane therapy 8 
 
x 
x 
x 
x 
x 
x 
 
 
 

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Pembrolizumab infusion 9 
 
 
x 
x 
x 
x 
x 
 
 
 
Response assessment 10  
x 
x 11 
Scans will be done every 12 weeks (+/-7 days) starting on 
C2D1 
 
 
 
Concomitant medications  
x 
 
x 
x 
x 
x 
x 
 
x 
 
Adverse events 
x 
 
x 
x 
x 
x 
x 
 
x 
x 
Optional Biopsy 
x 
 
 
 
 
x 
 
x 
 
 
1 Pregnancy test, serum or urine at baseline, urine or blood within 72 hours prior to every cycle for women of child-bearing potential; All WOCBP must have a negative serum or 
urine pregnancy test within 72 hours prior to start of study drug. 
2 Physical examination at screening and day 1 of each cycle (+/- 7 days). ECOG performance status must be documented within 10 days prior to each cycle and can be obtained 
remotely or in person.  
3 Hemoglobin, hematocrit, platelet count, RBC count, WBC count, percent and absolute differential count, sodium, potassium, chloride, bicarbonate, glucose, BUN, creatinine, 
calcium, total and direct bilirubin, total protein, albumin, ALT, AST, alkaline phosphatase, TSH, free T4.  
4 Fasting Lipid panel at screening, Cycle 2, Cycle 4, and Cycle 6. May be repeated with every other cycle per treating physician discretion.  
5 Adrenal Hormones Panel: ACTH, Cortisol, plasma renin activity, plasma aldosterone concentration, DHEA-Sulfate, testosterone (in women), estradiol (in men and postmenopausal 
women), and 11-deoxycortisol. All patients must have full hormonal evaluation at screening. Adrenal Hormonal labs may be repeated (complete or partial panel) every other cycle 
starting Cycle 1 per treating physician discretion. 
6 Serum mitotane level: Only patients who are already on mitotane at time of screening will have mitotane level checked during screening. Otherwise, mitotane level will be checked 
cycles 1-5 with the option of having mitotane levels checked every other cycle starting Cycle 5 per treating physician discretion. 
7 All patients will undergo 12-lead EKG at screening. Further, evaluation of EKG can be repeated with other cycles per treating physician discretion. 
8 Patients who were on mitotane prior to consent and meet eligibility criteria do not need to have lead-in phase (including leading phase assessments) and can start on combination 
therapy if completed 28 days of mitotane therapy  

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9 Patients will be treated for a maximum of 18 cycles with pembrolizumab but may continue mitotane beyond the 18 cycles per treating physician discretion outside the clinical trial 
 
10 Response assessment by cross-sectional imaging such as CT, MRI, or PET-CT as per standard of care for each patient.  Screening assessment must occur within 28 days prior to 
lead-in phase and imaging to be repeated within 7 days of Cycle 1 Day 1 of combination therapy.  PET/CTs may be substituted for CT or MRI at baseline and re-staging, if in the 
opinion of the treating physician.  
11 Response assessment by cross-sectional imaging will consider baseline scan as the study done within 7 days of Cycle 1 Day 1 of combination therapy.  
12 All patients who discontinue treatment without objective disease progression will be followed up with tumor assessment every 12 weeks (±14 days) or as determined by the 
principal investigator or designee) until disease progression or the start of a different anti-cancer therapy. Survival follow-up via phone call, medical record review, or visit with 
physician will occur every 3 months for 2 years once they are off study treatment or until patient death, withdrawal of consent, patient is lost to follow-up, or study termination, 
whichever occurs first. 
*  Please refer to Table.5. The lead-in phase is primarily designed to ensure patients safety and to have initial evaluation of potential AEs attributed to MT use with particular attention 
to liver enzymes. If MT use caused elevated ALT or AST during the lead-in phase not meeting eligibility criteria for LFTs or if participants developed ≥ G3 non-hematological 
toxicity, then these patients will not go through the combination therapy and may come off protocol at the discretion of the PI and will be replaced if excluded by other patients and 
considered as screen failure. Patients who were on prior MT therapy must complete 28 days of MT use prior to moving to combination therapy and must meet eligibility criteria 
stated at screening phase and will not need to have the lead-in phase assessment. 
 
Table 2 Study Schedule of Activities: Survival Status 
 
 
1 1 
Study Period 
Screening 
Phase 
Lead-
in 
 phase 
Treatment Cycles 
(6-Week Cycles) 1 
EOT 
Post Treatment 
Visits 2 
Treatment Cycle  Screening 
(Visit 1) 
 
1 
2 
3 
4 
5 
6 
to 
18 
DC 
Safety 
Follow-
up 
Survival 
Follow-
up  
Notes:   
Scheduling 
Window (Days): 
-28 to -1 
Days 1-
28 days 
(± 5) 
±5 
±5 
±5 
±5 
±5 
±5 
Time 
of 
DC  
30 Days 
from the 
last dose 
(±7days) 
Every 
12 
Weeks 
(±14 
days) 
Subsequent 
Anti-neoplastic 
Therapy Status 
 
 
 
 
 
 
 
 
X 
X 
 

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Patients will be treated for a maximum of 18 cycles with pembrolizumab but may continue on mitotane beyond the 18 cycles per treating physician discretion outside the clinical 
trial. 
2All patients who discontinue treatment without objective disease progression will be followed up with tumor assessment every 12 weeks (±14 days) or as determined by the principal 
investigator or designee) until disease progression or the start of a different anti-cancer therapy. Survival follow-up via phone call, medical record review, or visit with physician will 
occur every 3 months for 2 years once they are off-study treatment or until patient death, withdrawal of consent, patient is lost to follow-up, or study termination, whichever occurs 
first. 
Table 3 Study Schedule of Activities: Tumor Imaging 
Study Period:  
Screening 
Phase   
Lead-in 
phase 
Combination Treatment Cycles (6-Week Cycles)  
End of Treatment  
Treatment Cycle/Title 1: 
Screening 
(Visit 1) 
28 days 
1  
2  
3  
4  
To be repeated 
beyond 6 
cycles  
Discon  
Survival Follow-Up 
 
5  
6  
1 Scheduling Window 
(Days):  
-28 to -1 
X 3 
  
±7  
±7  
±7  
At time of 
discontinuation ±7  
2 Every 12 weeks post 
discontinuation ±14   
 
1 Baseline assessment must occur within 28 days prior to day 1 of lead-in phase. After baseline assessment during screening, scans will be done during the lead-in phase 
within 7 days of combination therapy and then every 12 weeks (+/-7 days) starting on C2D1. Response assessment by cross-sectional imaging such as CT, MRI, or PET-CT as per 
standard of care for each patient. PET/CTs may be substituted for CT or MRI at baseline and re-staging, if in the opinion of the treating physician.  
2 All patients who discontinue treatment without objective disease progression will be followed up with tumor assessment every 12 weeks (±14 days) or as determined by the principal 
investigator or designee) until disease progression or the start of a different anti-cancer therapy. Survival follow-up via phone call, medical record review, or visit with physician will 
occur every 3 months for 2 years once they are off-study treatment or until patient death, withdrawal of consent, patient is lost to follow-up, or study termination, whichever occurs 
first. 
3 Patients who start with lead-in phase need to have imaging within 7 days of C1D1 of combination therapy as a baseline to assess response to therapy. Patients who were on mitotane 
prior to consenting will not need lead-in phase and will go directly to combination therapy and the screening phase imaging will be considered the baseline for future tumor 
measurement.  
 
 

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3.0 OBJECTIVE(S), HYPOTHESIS(ES), AND ENDPOINT(S) 
3.1 
Primary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective: Assess the clinical efficacy of the combined use of MT with PEM in patients with 
advanced ACC. 
Hypothesis: We hypothesize that adding PEM will enhance the clinical efficacy of MT. This 
additive/synergistic effect could be related to the intrinsic adrenolytic activity of MT that could 
lead to antigens exposures to immune cells.  Furthermore, the cortisol lowering effect of mitotane 
is expected to alter the tumor microenvironment leading to a change the milieu of the tumor 
infiltrating immune cells to make ACC more susceptible to PEM.  Also, cortisol lowering can 
reduce lymphocytes inhibition and enhances the efficacy of PEM. 
Primary Endpoint: Overall response rate (ORR) assessed objectively using RECIST 1.1 criteria 
defined as the percentage of patients who have a partial or complete response to the combined 
treatment of MT plus PEM   
3.2 
Secondary Objective(s), Hypothesis(es), and Endpoint(s) 
(1) Objective:  Evaluate the safety and efficacy of the combined use of MT plus PEM in patients 
with advanced ACC.   
Hypothesis: The optimal MT plasma levels have not been established prospectively in metastatic 
ACC. We hypothesize that mitotane level of 14-20 mg/L is associated with oncological 
responses, but we also anticipate that the combined use of PEM MT could be associated with 
responses at lower levels of MT which might be associated with more favorable AE profile of 
MT. 
Secondary Endpoints:  
1. Overall survival (OS), defined as the time from combination therapy to death from any cause.  
2. Progression Free Survival (PFS), defined as the time from the start of combination therapy 
phase to disease progression or death from any cause. 
3. Explore the association between MT level and response to therapy 
4. Safety assessment by the Common Terminology Criteria for Adverse Events (CTCAE) V5.0 
 
3.3 
Exploratory Objective(s) 
(1) Objective: Correlate safety and efficacy data with steroid profile, immune markers and MT 
levels.    

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1. Obtain optional tumor biopsy prior to, during, and after treatment with MT/PEM 
combination to study immune markers such as infiltrating tumor lymphocytes, and 
other immune markers during therapy.  
2. Study the changes in circulating markers (MT level, immune cytokines, steroid profile) 
in blood samples obtained prior to, during, and after treatment with MT/PEM 
combination  
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
 Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with high recurrence rates and   
mortality. ACC has an annual incidence of about 1-2 cases per million (Else T et al. Endocr Rev. 
2014). ACC patients often cluster in few centers across the world with known experience in managing 
this disease. Currently, ACC patients receive systemic therapy that has suboptimal and short-lived 
benefit.  
Mitotane 
(MT) 
(Lysodren®) 
(o,p′-DDD 
or 
1,1-dichloro-2[o-chlorophenyl]-2-[p-
chlorophenyl]ethane) is a pesticide isomer that is directly toxic to adrenocortical cells. MT is a unique 
drug with dual benefit in ACC. MT has an adrenolytic activity in addition to its ability to block 
steroidogenesis enzymes and thus it reduces circulating cortisol levels. Furthermore, MT changes the 
peripheral metabolism of cortisol and reduces circulating cortisol levels. MT is administered orally in 
tablets of 500 mg.  MT is the only FDA-approved drug to treat advanced ACC and considered the 
standard of care in these patients. MT has been in use for almost 5 decades and is associated with 
objective response rate of 11-20.5% and median progression free survival of 4.1 months (Reidy-Lagunes 
et al. 2017; Megerle et al. 2018). MT is often combined with cytotoxic chemotherapy. The most 
commonly used regimen is (etoposide, doxorubicin, and cisplatin) [MT-EDP]. This regimen is 
associated with response rate of 23% with median time to progression of about 5 months while 58% of 
patients had serious AEs (Fassnacht et al. 2012). Considering the limited efficacy and the high toxicity 
of the commonly used therapy (MT-EDP), the lack of highly effective second line therapy, and the 
paucity of available clinical trials for ACC patients, there is a critical unmet need to provide an effective 
and less toxic systemic therapy to ACC patients as an alternative to MT-EDP.   
 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) with 
high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 
interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in clinical 
development as an intravenous (IV) immunotherapy for advanced malignancies. Keytruda® 
(pembrolizumab) is indicated for the treatment of patients across a number of indications because of its 
mechanism of action to bind the PD-1 receptor on the T cell.  For more details on specific indications 
refer to the Investigator brochure (IB). 
 

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4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (Disis 2010).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term survival 
in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; 
malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can be expanded ex 
vivo and reinfused, inducing durable objective tumor responses in cancers such as melanoma (Dudley 
et al. 2005; Hunder et al. 2008). 
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 immunoglobulin (Ig) superfamily member related 
to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
that has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands 
(PD-L1 and/or PD-L2) (Greenwald, Freeman, and Sharpe 2005; Okazaki et al. 2001). 
The structure of murine PD-1 has been resolved (Zhang et al. 2004). PD-1 and its family members are 
type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail 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, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of effector 
molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-associated protein 
kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade(Okazaki et al. 2001; 
Chemnitz et al. 2004; Sheppard et al. 2004; Riley 2009).  The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both molecules 
regulate an overlapping set of signaling proteins(Parry et al. 2005; Francisco, Sage, and Sharpe 2010).  
Therefore, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in ACC. 
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Population 
Recently, two phase II studies showed that PEM monotherapy in ACC resulted in objective response 
rates of 14-23% and disease control/clinical benefit rates of 52-57% while the risk of serious AEs was 
low and seen in only 13% of patients in both studies (Habra et al. 2019; Raj et al. 2019).  
 

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The combined use of MT with PEM has not been studied prospectively. A retrospective case series of 
6 patients with metastatic ACC, for whom MT alone or with chemotherapy failed, and who were 
subsequently treated with a combination of PEM and MT.  Two patients had a partial response and the 
remaining 4 patients had prolonged stable disease (8 to 19 months). All 6 patients lived for at least 16 
months after adding PEM to MT therapy. The combination was reported to be appeared to be effective 
in both microsatellite instability-high and microsatellite stable tumors, suggesting some synergistic 
effect with mitotane (Head et al. 2019).  
 
We anticipate that MT will have synergistic effect when combined with PEM through at least two 
different mechanisms. 1- In the first few weeks of MT use, mitotane is expected to exert a 
steroidogenesis blocker effect leading to reduced cortisol levels in the tumor microenvironment and 
blood this could enhance efficacy of PEM by reducing the immunosuppressive effects of cortisol on 
lymphocytes. 2- With prolonged MT use, the adrenolytic activity of mitotane is usually seen when 
serum MT level approaches 14 mg/L and this could release adrenal specific antigens that can further 
enhance the efficacy of PEM. 
4.2.2 Justification for Dose  
The planned dose of PEM for this study is 400 mg IV every 6 weeks (Q6W).  Based on the totality of 
data generated in the Keytruda development program, both PEM 200 mg Q3W and PEM 400 mg Q6W 
are approved for clinical use. The FDA granted accelerated approval of the 400 mg Q6W for PEM 
(KEYTRUDA, Merck) across all currently approved adult indications, in addition to the 200 mg Q3W 
dosing regimen. The approval was based on pharmacokinetic modeling and exposure-response analyses 
that compared the predicted exposure of pembrolizumab 400 mg Q6W to observed exposures of 
pembrolizumab in patients who received pembrolizumab at 2 mg/kg every three weeks, 200 mg Q3W, 
and 10 mg/kg administered every 2 weeks. The pharmacokinetic modeling was supported by additional 
exposure-response analyses across the PEM development program and an interim analysis of 
pharmacokinetics and overall response rate (ORR) in a cohort of patients (Cohort B) enrolled in Study 
KEYNOTE-555 (NCT03665597). Cohort B of Study KEYNOTE-555 was an international, single-arm, 
multi-center study that enrolled 101 patients with advanced or metastatic melanoma who had not 
received prior PD-1, PD-L1, or CTLA-4 inhibitors (other than CTLA-4 inhibitors in the adjuvant 
setting). The ORR was 39% (95% CI: 24, 55) in the first 44 patients enrolled in KEYNOTE-555. 
MT will be administered orally to reach a plasma level of 14–20 mg/L (or the maximum tolerated dose 
if unable to reach therapeutic levels).  Analysis of serum mitotane levels will be performed by a CLIA 
certified laboratory to reflect standards of care of mitotane management.   In general, mitotane starting 
dose will be 1-2 grams per day to be escalated up to 6 grams per day according to the treating 
physician’s judgment if the levels remain below 14 mg/L. Reduction of mitotane dosage should be 
considered for asymptomatic plasma levels over 30 mg/L or for significant mitotane-related adverse 
effect. Asymptomatic mitotane levels of 20-30 mg/L may not require dose reduction at the discretion 
of the site principal investigator. 
 
4.2.3 Rationale for Endpoints 
ACC has low response to currently available treatments. MT has adrenolytic activity in addition to 
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single agent MT in advanced ACC has been seen in 11-20.5% range with median progression free 
survival of 4.1 months (Reidy-Lagunes et al. 2017; Megerle et al. 2018; Fassnacht et al. 2012). The 
combined use of MT with EDP chemotherapy is associated with low response rate (23%) and serious 
AEs seen in 56% of patients (Fassnacht et al. 2012).  
PEM monotherapy in ACC is associated with response rate of 14-23% with favorable AE profile (severe 
AEs in 13%) of subjects. The combined use of MT as standard of care with PEM has not been studied 
prospectively.  We hypothesize that MET use with PEM will have synergistic effect. We would like to 
assess the overall response rate of MT combined with PEM in ACC patients. In addition, we would like 
to assess other endpoints related to efficacy and safety as well as study exploratory markers to assess 
immune changes during the combination therapy.  
4.2.3.1 Efficacy Endpoints 
In addition to the intrinsic adrenolytic activity of MT, we hypothesize that adding PEM will enhance the 
clinical efficacy of MT. The cortisol lowering effect of mitotane is expected to alter the tumor 
microenvironment leading to a change the milieu of the tumor infiltrating immune cells to make ACC 
more susceptible to PEM.   
Primary Endpoint:  Overall response rate (ORR) assessed objectively using RECIST 1.1 
criteria defined as the percentage of patients who have a partial or complete response to the 
combined treatment of MT plus PEM. 
Efficacy Secondary Endpoints:  
Overall survival (OS), defined as the time from the start of combination therapy to death from 
any cause.  
Progression Free Survival (PFS), defined as the time from the start of combination therapy phase 
to disease progression or death from any cause. 
4.2.3.2 Planned Exploratory Biomarker Research 
As an exploratory objective, we also aim to generate crucial data about the changes in immune 
markers in association with MT-PEM therapy. The adrenal gland can be recognized by the immune 
system and develop autoimmune adrenalitis and adrenal insufficiency (Addison’s disease). 
Mononuclear cells infiltrating (mainly CD3+) the adrenal glands on autopsies are more common in 
people 60 years and older (63%) compared to subjects <49 years old (7%). CD4+ cells are more common 
than CD8+ cells and are thought to have been activated by interleukin 2 receptor (Feldmeyer et al. 2016) 
. It remains unknown if MT has any direct or indirect effects on immune cells in ACC.  We presume 
that MT cortisol reduction will affect have immunomodulatory effect that enhances the sensitivity of 
tumor cells to T cell-mediated lysis. Thus, data generated from patients in this study can further our 
understanding of the complex effect of MT on tumor immune infiltrate and could lead to new treatment 
combinations in the future.  
Analyses of tumor and blood samples: These studies will be performed at MDACC in collaboration with 
Translational Molecular Pathology - Immunoprofiling Laboratory (TMP-IL). Patient samples will be 
collected to perform immunologic analyses. The study will allow for the collection of blood samples to 

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be drawn at the time of routine blood-draw to assess circulating immune markers. Whole blood, plasma, 
serum, peripheral blood mononuclear cells (PBMCs) and other secreted markers (such as cytokines) 
may be collected at 3 time points (before and during treatment and at time of disease progression) and 
processed at the TMP-IL for further downstream analyses.  
Optional biopsies will be used for immune-profiling analysis (core needle biopsies (CNBs). Fresh tissue 
samples will be sent immediately after collection to TMP-IL. Core biopsy is typically performed using 
21-18-gauge needle and with condition permitting, up to 5 cores should be collected, including 2 for 
clinical processing and 3 additional passes will be attempted to obtain the research core samples.   
Cores 1 and 2: Immediate and overnight fixation in 10% buffered formalin for paraffin 
embedding, usually within 20-24 hour after fixation. For biopsies performed on Friday, fixation 
time may extend to 48 hours (FFPE samples) 
Cores 3-4: Flash freezing in liquid nitrogen.  
Core 5: Flow cytometry analysis of TIL and TME on fresh tissue. 
All tissue specimens collected will be reviewed by reference pathologists. At least, three types of QC 
activities for specimens collected will be performed: a) histology/cytology examination of the tissues 
and cells to confirm the presence of tumor cells, as well as their abundance (tumor cellularity); b) 
tissue quality assessment of fresh specimens for extraction of DNA, RNA and proteins, and to prepare 
histology specimens such as whole sections for immunohistochemistry and immunofluorescence; and, 
c) quality assessment of DNA, RNA and protein extracted. All histology stained samples will be 
scanned, and digital images will be available for review. 
Using immunohistochemistry (IHC) and multiplex immunofluorescence (IF) approach that is 
available in the TMP-IL, we will quantitatively assess multiple immune markers. Fresh frozen tissues 
will be also used for analysis of immune markers. IHC and IF will be performed using autostainers. All 
antibodies used will be optimized for IHC/IF by examination of positive and negative controls and 
testing of the antibodies standard methods, including Western blotting. All pathology slides will be 
scanned into a digital image scanner and analyzed using image analysis software; IHC analysis will be 
performed using the Aperio Image Toolbox™ (Leica Biosystems) and IF analysis using the Vectra 
Inform™ (Perkin-Elmer) software. Nucleic acids (DNA and RNA) and protein extraction: Blood 
(plasma and PMBCs) and tumor (CNB) samples will be subjected to extraction using standard methods. 
DNA and RNA quantity and integrity will be assessed using NanoDrop 1000 spectrophotometer 
(Nanodrop technologies) and Pico-green analyses.  Also, protein lysate will be extracted using standard 
methods. 
High order flow cytometry panels will focus on 1) delineation of major immune cell types (T cells, B 
cells, NK cells, DC), 2) determination of T cell differentiation status and limited functionality (IFNγ, 

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TNFα, GB) and 3) defining the expression level of costimulatory and coinhibitory molecules on T cells 
and their respective receptors such as PD-L1 on infiltrating myeloid cells or tumor. Briefly, 50 cc of 
heparinized peripheral blood from cancer patients prior to the initiation of treatment, during treatment, 
and at time of progression will be processed fresh (within 24h of being drawn) for PBMC isolation by 
ITB. PBMCs will be cryopreserved and stored in Liquid Nitrogen until use. Flow cytometric analysis 
will be conducted retrospectively on cryopreserved PBMCs. When appropriate, cells will be thawed and 
stained immediately. All time points belonging to a patient will be stained and acquired at the same time 
to avoid any technical variation (sample at time of progression will be omitted for responders if analysis 
needs to be completed when patient is still responding). We expect that half of the study participants 
will agree to have the optional biopsies and we anticipate collecting blood samples from all participants. 
Steroid profiling will be done on the stored plasma samples at the end of the study. In addition to the 
standard of care check of select steroid hormones as standard of care while managing ACC.  
 
5.0 METHODOLOGY 
5.1 Study Population 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
 
1. Male/female participants who are at least 18 years of age on the day of signing informed consent 
with histologically confirmed diagnosis of ACC will be enrolled in this study. 
 
2. Male participants: 
A male participant must agree to use a contraception as detailed in Appendix 3 of this protocol 
during the treatment period and an additional 180 days after the last dose of study treatment and 
refrain from donating sperm during this period. 
 
 
3. Female participants: A female participant is eligible to participate if she is not pregnant (see 
Appendix 3), not breastfeeding, and at least one of the following conditions applies:  
a. a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3  
OR  
b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the 
treatment period plus 180 days after the last dose of study treatment. 
 
4. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial.   
 
5. Have measurable disease based on RECIST 1.1.  Lesions situated in a previously irradiated area 
are considered measurable if progression has been demonstrated in such lesions. 
 

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6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.  Evaluation 
of ECOG is to be performed within 10 days prior to the first dose of MT therapy.   
 
7. Have adequate organ function as defined in the following table (Table 4).  Specimens must be 
collected within 10 days prior to the start of study intervention. 
8. The study will accept therapy naïve patients with metastatic ACC, patients who failed one prior 
line of therapy not including immunotherapy, patients who started MT within 4 weeks for 
metastatic disease, and patients who developed metastases while on adjuvant mitotane therapy.  
Patients who failed platinum-based chemotherapy combined with MT may be eligible to join 
the study at the discretion of the PI if their treatment ended > 6 months before consenting for 
this study or if did not achieve therapeutic MT levels during prior treatment (MT level ≥ 14 
mg/L).  
 
9. For patients receiving therapeutic anticoagulation: stable anticoagulant regimen in the 28 days 
immediately preceding initiation of study treatment 
 
10. Criteria for known Hepatitis B and C positive subjects 
 
Hepatitis B and C screening tests are not required unless: 
 
 
•Known history of HBV or HCV infection  
•As mandated by local health authority 
 
10.1 Hepatitis B positive subjects 
• Participants who are HBsAg positive are eligible if they have received HBV antiviral 
therapy for at least 4 weeks and have undetectable HBV viral load prior to 
randomization. 
• Participants should remain on anti-viral therapy throughout study intervention and 
follow local guidelines for HBV anti-viral therapy post completion of study 
intervention. 
 
10.2 Participants with history of HCV infection are eligible if HCV viral load is undetectable at 
screening. 
Participants must have completed curative anti-viral therapy at least 4 weeks prior 
to randomization.  
Table 4 Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1500/µL 

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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to pembrolizumab 
treatment (see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required. 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).  
 
3. Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks  
4. Has received prior radiotherapy within 2 weeks of start of study intervention.  Participants must 
have recovered from all radiation-related toxicities, not require corticosteroids, and not have had 
radiation pneumonitis.  A 1-week washout is permitted for palliative radiation (≤2 weeks of 
radiotherapy) to non-CNS disease. 
Platelets 
≥100 000/µL 
Hemoglobin 
≥9.0 g/dL or ≥5.6 mmol/La 
Renal 
 
Creatinine OR 
Measured or calculated b creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants 
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal. 
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.  
b Creatinine clearance (CrCl) should be calculated per institutional standard. 
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies. 

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5. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of 
study intervention.  Administration of killed vaccines is allowed. 
6. Is currently participating in or has participated in a study of an investigational agent or has used 
an investigational device within 4 weeks prior to the first dose of study intervention. 
7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing 
exceeding 10 mg daily of prednisone equivalent at the time of screening) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug. 
Higher dose 
of steroid may be permitted as replacement doses while on mitotane therapy to follow acceptable 
standards of care while on mitotane Known additional malignancy that is progressing or has 
required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin or carcinoma in situ, excluding carcinoma in situ 
of the bladder, that have undergone potentially curative therapy are not excluded. 
8. Has known active CNS metastases and/or carcinomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically stable, i.e. 
without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat 
imaging should be performed during study screening), clinically stable and without requirement 
of steroid treatment for at least 14 days prior to first dose of study intervention. 
9. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
10. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with 
use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement 
therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.  
11. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease. 
12. Has an active infection requiring systemic therapy. 
13. Has a known history of Human Immunodeficiency Virus (HIV) infection   
14. Concurrent active Hepatitis B (defined as HBsAg positive and/or detectable HBV DNA) and 
Hepatitis C virus (defined as anti-HCV Ab positive and detectable HCV RNA) infection. 
Note: Hepatitis B and C screening tests are not required unless: 
• Known history of HBV and HCV infection 
• As mandated by local health authority 
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality or other 
circumstance that might confound the results of the study, interfere with the participant’s 

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participation for the full duration of the study, such that it is not in the best interest of the 
participant to participate, in the opinion of the treating investigator.   
16. Has known psychiatric or substance abuse disorders that would interfere with cooperation with 
the requirements of the trial. 
17. Is pregnant or breastfeeding or expecting to conceive or father children within the projected 
duration of the study, starting with the screening visit through 120 days after the last dose of trial 
treatment. 
18. Has had an allogenic tissue/solid organ transplant. 
 
5.1.3 Lifestyle Considerations  
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical condition).   
5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention(s).  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 working 
days 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 Merck.  If a male participant impregnates his female partner, the study 
personnel at the site must be informed immediately and the pregnancy must be reported to Merck and 
followed as described in Section 6.2. 
 
5.2 Trial Intervention(s) 
The intervention(s) to be used in this trial is outlined below in Table 5 

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Table 5 Trial 
Intervention(s) 
Drug 
 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Mitotane 
 
1000-6000 
mg 
Daily 
PO 
4 weeks lead-in 
phase* (+/-5 days) 
followed by 
maintenance 
therapy per 
acceptable clinical 
standards 
Standard of 
Care 
Pembrolizumab 
 
400 mg 
Q6W 
IV infusion 
Day 1 of each 6-week 
cycle (after MT lead-
in phase) 
Experimental 
 * The lead-in phase is primarily designed to ensure patients safety and to have initial evaluation of potential AEs attributed to MT use 
with particular attention to liver enzymes. If MT use caused elevated ALT or AST during the lead-in phase not meeting eligibility criteria 
for LFTs or if participants developed ≥ G3 non-hematological toxicity, then these patients will not go through the combination therapy 
and may come off protocol at the discretion of the PI and will be replaced if excluded by other patients and considered as screen failure. 
Patients who were on prior MT therapy must complete 28 days of MT use prior to moving to combination therapy and must meet eligibility 
criteria stated at screening phase and will not need to have the lead-in phase assessment. 
 
Trial intervention(s) should begin as close as possible to the date on which intervention is 
allocated/assigned. 
 
 
5.2.1 Treatment 
• Pembrolizumab will be given for a maximum of 2 years i.e. a total of 18 cycles of 
pembrolizumab with the Q6 week dosing. 
• Mitotane will be given following standards of clinical practice and could extend beyond the 
study period  
 
5.2.2 Second Course 
N/A 
5.2.3 Timing of Dose Administration 
Trial interventions should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Schedule of Activities, Section 2.2.  Trial interventions may 
be administered up to 5 days before or after the scheduled Day 1 of each cycle due to administrative 
reasons. 
All trial interventions will be administered on an outpatient basis. 
Pembrolizumab 400 mg will be administered as a 30-minute IV infusion every 6 weeks.  Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  However, given 

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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). 
MT use will follow acceptable clinical practice pattern with starting dose of 500 mg PO BID or TID to 
be titrated every to achieve therapeutic serum level of 14-20 mg/L (maximum dose 6,000 milligrams 
per day). For MT naïve patients, the first 4 weeks (+/- 5 days) will be a lead-in phase then they will 
continue MT therapy in combination with PEM in 6-week cycles.  
5.2.4 Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab and IO combination partners  
AEs associated with pembrolizumab or IO/IO combination exposure, may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab/combination treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical study data, most irAEs were reversible and could be 
managed with interruptions of pembrolizumab/combination treatment, administration of 
corticosteroids and/or other supportive care. For suspected irAEs, ensure adequate evaluation to 
confirm etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Dose modification and toxicity 
management guidelines for irAEs associated with pembrolizumab/combination treatment are provided 
in Table 6. 
Attribution of Immune-Related Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to a single 
component is likely to be difficult.  Therefore, while the investigator may attribute a toxicity event to 
the combination, to pembrolizumab, or to MT, all IO drugs must be held according to the criteria in 
[Table 6 Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse 
Events Associated with Pembrolizumab]. 
Holding Study IO Interventions: 
When study interventions are administered in combination, if the AE is considered immune-related, all 
IO interventions should be held according to recommended dose modification criteria 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the participant must 
discontinue all IO therapy. 
Restarting Study Interventions: 
Participants may restart pembrolizumab and MT as described below. 

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• If the toxicities do resolve and conditions are aligned with what is defined in [Table 6], the 
study interventions may be restarted at the discretion of the investigator.

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Table 6 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab and IO 
combination partners  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. All IO treatments must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of the 
last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If IO treatments have been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
+ all IO Drugs 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever)  

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
+ all IO Drugs 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
 
and of bowel perforation (ie, peritoneal signs and 
ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
•  Participants with 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 
AST or ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
+ all IO Drugs 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
associated with 
evidence 
of 
β-cell failure 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
+ all IO Drugs 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Asymptomatic 
cardiac enzyme 
elevation 
with 
clinical 
suspicion 
of 
myocarditis 
(previously 
CTCAE 
v4.0 
Grade 1) 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold 
or 
discontinue based 
on the event e  
Recurrent 
Grade 3 
or 
Grade 4  
Permanently 
discontinue 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
+ all IO Drugs 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab or its IO combination partner is at the discretion of the investigator or treating physician. If control 
achieved or ≤ Grade 2, pembrolizumab or its IO combination partner may be resumed. 
e Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 

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CT 
Table 7 Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further 
study drug intervention 
Participant may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
study intervention with: 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (e.g., 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
No subsequent dosing 

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renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
intervention. 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at http://ctep.cancer.gov 

 
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Other allowed dose interruption for pembrolizumab  
Pembrolizumab monotherapy or in combination may be interrupted for situations other than treatment-
related AEs such as medical / surgical events and/or unforeseen circumstances not related to study 
intervention. However, intervention is to be restarted within 3 weeks of the originally scheduled dose and 
within 42 days of the previously administered dose, unless otherwise discussed with the Sponsor. The 
reason for study intervention interruption is to be documented in the patient's study record. 
 
5.3 Randomization or Treatment Allocation 
N/A 
5.4 Stratification 
N/A 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing trial.  If there is a clinical indication for one of these or other medications or vaccinations 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may be required.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or the 
participant's primary physician. However, the decision to continue the participant on study intervention 
requires the mutual agreement of the investigator, the Sponsor, and the participant. 
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be administered 
at the discretion of the investigator in keeping with the community standards of medical care.  All 
concomitant medication will be recorded on the case report form (CRF) including all prescription, over-
the-counter (OTC), herbal supplements, and IV medications and fluids.  If changes occur during the trial 
period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. 
All concomitant medications received within 28 days prior to the first dose of trial intervention and up 
to 30 days after the last dose of trial intervention should be recorded.  If participants experience an SAE 
or ECI, concomitant medications administered30 days after the last dose of trial intervention are to be 
recorded as defined in Section 6.2. 

 
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5.5.2 Prohibited Concomitant Medications 
Participants are prohibited from receiving the following therapies during the Screening and Treatment 
Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy is discouraged but radiation therapy to a symptomatic solitary lesion or to 
the brain may be allowed at the investigator’s discretion,  
• Live or attenuated vaccines within 30 days before the first dose of study intervention and while 
participating in the study.   
 
 
• Systemic glucocorticoids except when used for the following purposes: 
• To modulate symptoms of an AE that is suspected to have an immunologic etiology 
• For the prevention of emesis 
• To premedicate for IV contrast allergies 
• To treat COPD exacerbations (only short-term oral or IV use in doses >10 mg/day 
prednisone equivalent) 
• For chronic systemic replacement while on MT therapy 
 
• Other glucocorticoid use except when used for the following purposes: 
• For topical use or ocular use 
• Intraarticular joint use 
• For inhalation in the management of asthma or chronic obstructive pulmonary disease 
 
Participants who, in the assessment by the investigator, require the use of any of the aforementioned 
treatments for clinical management should be removed from the study.  All treatments that the 
Investigator considers necessary for a participant’s welfare may be administered at the discretion of the 
Investigator in keeping with the community standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study.  If there is a clinical indication for any medication or vaccination specifically prohibited 

 
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during the study, discontinuation from study therapy or vaccination may be required.  The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the participant's primary 
physician.  However, the decision to continue the participant on study treatment requires the mutual 
agreement of the investigator, the Sponsor and the participant. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator, the Sponsor, and the 
participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the treating 
investigator.  Suggested supportive care measures for the management of AEs with potential 
immunologic etiology are outlined along with the dose modification guidelines in Section 5.2.4, [Table 
6].   
5.6 Participant Discontinuation Criteria 
Discontinuation of study intervention does not represent withdrawal from the study. 
As certain data on clinical events beyond study intervention discontinuation may be important to the 
study, they must be collected through the participant’s last scheduled follow-up, even if the participant 
has discontinued study intervention.  Therefore, all participants who discontinue study intervention prior 
to completion of the protocol-specified treatment period will still continue to be monitored in this study 
and participate in the study visits and procedures as specified in Section 2.2 unless the participant has 
withdrawn from the study (Section 5.7). 
Participants may discontinue study intervention at any time for any reason or be discontinued from the 
study intervention at the discretion of the investigator should any untoward effect occur.  In addition, a 
participant may be discontinued from study intervention by the investigator or the Sponsor if study 
intervention is inappropriate, the study plan is violated, or for administrative and/or other safety reasons.   
A participant must be discontinued from study treatment but continue to be monitored in the study for 
any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to discontinue study 
intervention 
• After prolonged study intervention interruption that prohibits restarting study intervention if 
agreed upon with the Sponsor 
• Radiographic disease progression outlined in Section 6.1.4. 

 
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• Any progression or recurrence of malignancy, or any occurrence of another malignancy that 
requires active treatment 
• Any study intervention-related toxicity specified as a reason for permanent discontinuation as 
defined in the guidelines for dose modification due to AEs in Section 5.2.4. 
• The participant has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment. 
• The participant has a confirmed positive serum pregnancy test 
 
5.7 Participant withdrawal From Study 
A participant must be withdrawn from the study if the participant or the participant’s legally acceptable 
representative withdraws consent from the study. 
If a participant withdraws from the study, they will no longer receive study intervention or be followed 
at scheduled protocol visits. 
Specified details regarding procedures to be performed at the time of withdrawal from the study are 
outlined in Section 6.1.6.1. 
5.8 
Participant Replacement Strategy: Patients who cannot join the combination of the study and 
deem ineligible to move from the lead-in phase to the combination therapy phase of the study will 
be replaced by other participants.  
5.9 
Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health 
hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, adequate notification will be provided so 
that appropriate adjustments to participant treatment can be made. 

 
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6.0 TRIAL ASSESSMENTS AND PROCEDURES 
6.1 Trial Procedures 
• Study procedures and their timing are summarized in The Schedule of Activities, Section 2.2.   
• Adherence to the study design requirements, including those specified in the Schedule of Activities 
is essential and required for study conduct. 
• The investigator is responsible for ensuring that procedures are conducted by appropriately 
qualified (by education, training, and experience) staff. 
• All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria 
• Additional evaluations/testing may be deemed necessary by the investigator, the Sponsor and/or 
Merck for reasons related to participant safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations may require that 
additional informed consent be obtained from the participant. In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of ICF may be utilized for screening or baseline purposes provided 
the procedure met the protocol-specified criteria and were performed within the time frame defined 
in the SoA. 
• All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
 
6.1.1 Administrative and General Procedures 
6.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential participant or each participant’s 
legally acceptable representative prior to participating in a clinical trial. If there are changes to a 
participant’s status during the study (e.g. health requirements) the investigator must ensure appropriate 
consent is in place. 
 
 

 
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6.1.1.2 General Informed Consent 
Consent must be documented by the participant’s dated signature or by the participant’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of the 
person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the participant before participation in 
the trial. 
The initial informed consent form, any subsequent revised written informed consent form and any 
written information provided to the participant must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The participant or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
participant’s willingness to continue participation in the trial.  The communication of this information 
will be provided and documented via a revised consent form or addendum to the original consent form 
that captures the participant’s dated signature or by the participant’s legally acceptable representative’s 
dated signature. 
Specifics about a trial and the trial population will be added to the consent form template at the protocol 
level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and 
Sponsor requirements. 
If the investigator recommends continuation of study intervention beyond disease progression, the 
participant or his/her legally acceptable representative will be asked to sign consent. 
There is a potential for enrollment of cognitively impaired subjects, whose disease may directly benefit 
from trial procedures that would be unavailable outside the research context. Risks to subjects are 
reasonable in relation to anticipated benefits. Available systemic therapies are limited and not curative. 
The relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented 
by available alternative approaches. 
This trial is not prohibited by law. Subjects will be particularly closely monitored per stated protocol 
procedures and assessment plans and will be withdrawn if they appear to be unduly distressed or 
unable to follow protocol requirements. 
These subjects will be informed about the research to the extent compatible with the subject’s 
understanding. The consent document includes a signature line for a Legally Authorized 
Representative (LAR). If capable, the subject will sign and personally date the written informed 
consent. 
 

 
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6.1.1.3 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure 
that the participant qualifies for the trial.  
6.1.1.4 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history will 
include all active conditions, and any condition diagnosed within the prior 10 years that are considered 
to be clinically important by the Investigator.  Details regarding the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as medical history.   
If a medical condition is diagnosed at the time of screening due to the physical examination, laboratory 
tests, radiologic assessment, other assessment, and/or a combination of these evaluations, the medical 
condition is to be recorded as a baseline condition along with the participant’s other medical history 
unless due to any protocol-specified intervention (eg, procedure, washout or run-in treatment including 
placebo run-in). 
 
6.1.1.5 Prior and Concomitant Medications Review 
6.1.1.5.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol-
specified washout requirement, and record prior medication taken by the participant within 28 days 
before starting the trial.  Treatment for the disease for which the participant has enrolled in this study 
will be recorded separately and not listed as a prior medication.  
6.1.1.5.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant during 
the trial.  In addition, new medication started during the Second Course should be recorded. All 
medications related to reportable SAEs and ECIs should be recorded as defined in Section 6.2. 
6.1.1.6 Disease Details and Treatments 
6.1.1.6.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status.  
6.1.1.6.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 

 
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6.1.1.6.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the 
last dose of trial treatment.  If a participant initiates a new anti-cancer therapy within 30 days after 
the last dose of trial treatment, the 30-day Safety Follow-up visit must occur before the first dose of 
the new therapy.  Once new anti-cancer therapy has been initiated the participant will move into 
survival follow-up.  
6.1.1.7 Assignment of Screening Number 
6.1.1.8 Assignment of Randomization Number 
6.1.1.9 Trial Compliance (Medication/Diet/Activity/Other) 
6.1.2 Clinical Procedures/Assessments 
6.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-up period 
according to NCI CTCAE Version 5.0 (see Appendix 2).  Toxicities will be characterized in terms 
regarding seriousness, causality, toxicity grading, and action taken with regard to trial treatment.  
Please refer to section 6.2 for detailed information regarding the assessment and recording of AEs.   
6.1.2.2 Physical Exam 
A complete physical examination will be conducted by an investigator or medically qualified designee 
(consistent with local requirements) as per institutional standard [specify if there are specific 
assessments that must be conducted as a minimum] [systems/evaluations]. Height and weight will also 
be measured and recorded. 
A brief directed physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard [specify if there are specific 
assessments that must be conducted as a minimum]. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
6.1.2.3 
Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the screening 
period.  Clinically significant abnormal findings should be recorded as medical history.  The time 
points for full physical exams are described in Section 2.4.  After the first dose of study intervention, 
new clinically significant abnormal findings should be recorded as AEs.   

 
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Investigators should pay special attention to clinical signs related to previous serious illnesses. 
6.1.2.4 Directed Physical Exam 
For cycles that do not require a full physical exam per the Section 2.2, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated prior to study intervention 
administration.  New clinically significant abnormal findings should be recorded as AEs. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
6.1.2.5 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the administration of 
each dose of trial treatment and at treatment discontinuation as specified in the Schedule of Activities 
(Section 2.2).  Vital signs should include temperature, pulse, respiratory rate, weight and blood 
pressure.  Height will be measured at screening only. 
6.1.2.6 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix 1) at screening, prior 
to the administration of each dose of trial treatment and discontinuation of trial treatment as 
specified in the Schedule of Activities (Section 2.2). 
 
6.1.2.7 
Electrocardiograms 
A single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in the SoA (see Section 2.2) using an ECG 
machine that automatically calculates the HR and measures PR, QRS, QT, and [QTc] intervals.  
6.1.2.8 
Elevated Transaminases With Treated HBV or HCV 
Participants who were treated for HBV or HCV, enrolled in the study, and present with elevated 
transaminases 
according 
to 
the 
criteria 
below 
should 
be 
evaluated 
for 
viral 
hepatitis exacerbation/reactivation. 
• If baseline AST/ALT <2×ULN and an increase of AST/ALT ≥5×ULN 
• If baseline AST/ALT ≥2×ULN and an increase of AST/ALT >3 × baseline level 
• AST/ALT ≥2×ULN and an increase of AST/ALT >3 × baseline level 
Viral load testing and additional hepatitis serologies should be included as required. 
 

 
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6.1.3 Clinical Safety Laboratory Assessments 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for the timing 
and frequency. 
• The investigator or medically qualified designee (consistent with local requirements) must 
review the laboratory report, document this review, and record any clinically relevant changes 
occurring during the study in the AE section of the CRF. The laboratory reports must be filed 
with the source documents. Clinically significant abnormal laboratory findings are those which 
are not associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant's condition. 
• All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted in 
accordance with the SoA. 
• If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are considered 
clinically significant by the investigator (e.g., SAE or AE or dose modification), then the results 
must be recorded in the appropriate CRF (e.g., SLAB). 
• For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every attempt 
should be made to perform repeat assessments until the values return to normal or baseline or if 
a new baseline is established as determined by the investigator. 
Details regarding specific laboratory procedures/assessments to be performed in this study are provided 
below. Refer to the Study Flow Chart (Section 2.2) for the timing of laboratory assessments. 
6.1.3.2 
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2. 
 
6.1.3.3 
Pregnancy Testing 
All women who are being considered for participation in the study, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours or the first dose of study 
intervention. If a urine test is positive or not evaluable, a serum test will be required. Participants 
must be excluded/discontinued from the study in the event of a positive test result. Repeated 
pregnancy test (such as monthly testing) may be conducted if required by local regulation. 
 

 
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6.1.4 Tumor Imaging and Assessment of Disease 
Tumor imaging is strongly preferred to be acquired by computed tomography (CT).  MRI imaging as 
well as FDG-PET CT are alternative modalities per PI discretion.  For the abdomen and pelvis, 
contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated contrast 
is contraindicated, or when local practice mandates it.  MRI is the strongly preferred modality for 
imaging the brain.  The same imaging technique regarding modality, ideally the same scanner, and the 
use of contrast should be used in a participant throughout the study to optimize the reproducibility of 
the assessment of existing and new tumor burden and improve the accuracy of the assessment of 
response or progression based on imaging. 
 
Expedited confirmation of measurable disease based on RECIST 1.1 at Screening should be used 
to determine participant eligibility.  Confirmation that the participant’s imaging shows at least 1 
lesion that is appropriate for selection as a target lesion per RECIST 1.1 is highly recommended 
prior to participation [randomization/allocation].   
When the Investigator identifies radiographic progression per RECIST 1.1, efforts should be 
made to verify radiologic PD. Treatment should continue until PD has been verified.  Regardless 
of whether PD is verified, if the Investigator considers the participant has progressed, but elects 
to implement iRECIST, the Investigator will assess for confirmation of progression by iRECIST 
at subsequent time points.   
6.1.4.1   Initial Tumor Imaging 
Initial tumor imaging at Screening must be performed within 28 days prior to the date of MT 
treatment.  The site study team must review screening images to confirm the participant has 
measurable disease per RECIST 1.1.  
Tumor imaging performed as part of routine clinical management is acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28-days prior to the date of 
treatment.  
6.1.4.2   Tumor Imaging During the Study 
For patients who start with lead-in phase, the first on-study imaging assessment should be performed at 
the onset of the combination therapy phase (C1D1 +/- 7 days) and then every 12 weeks (+/-7 days). 
Response assessment by cross-sectional imaging such as CT, MRI, or PET-CT as per standard of care for 
each patient. PET/CTs may be substituted for CT or MRI at baseline and re-staging, if in the opinion of 
the treating physician.  
 Patients who were on mitotane prior to consenting will not need lead-in phase and will go directly to 
combination therapy and the screening phase imaging will be considered the baseline for future tumor 
measurement.   

 
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Objective response should be confirmed by a repeat imaging assessment.  Tumor imaging to confirm PR 
or CR should be performed at least 4 weeks after the first indication of a response is observed.  Participants 
will then return to regular scheduled imaging every 12weeks, starting with the next scheduled imaging 
time point.  Participants who receive additional imaging for confirmation do not need to undergo the next 
scheduled tumor imaging if it is less than 4 weeks later; tumor imaging may resume at the subsequent 
scheduled imaging time point.   
Per iRECIST (Section 6.1.4.6), disease progression should be confirmed by the site 4 to 8 weeks after 
first radiologic evidence of PD in clinically stable participants.  Participants who have unconfirmed 
disease progression may continue on treatment at the discretion of the investigator until progression 
is confirmed by the site provided they have met the conditions detailed in Section 6.1.4.6.  Participants 
who receive confirmatory imaging do not need to undergo the next scheduled tumor imaging if it is 
less than 4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point, 
if clinically stable.  Participants who have confirmed disease progression by iRECIST, as assessed 
by the site, will discontinue study treatment.  Exceptions are detailed in Section 6.1.4.6. 
6.1.4.3   End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the time of 
treatment discontinuation (±4-week window).  If previous imaging was obtained within 4 weeks prior 
to the date of discontinuation, then imaging at treatment discontinuation is not mandatory.  In 
participants who discontinue study treatment due to documented disease progression and the 
investigator elects not to implement iRECIST, this is the final required tumor imaging. 
For participants who discontinue study treatment without documented disease progression, every 
effort should be made to continue monitoring their disease status by tumor imaging using the same 
imaging schedule used while on treatment (every 12 weeks ±14 days) to monitor disease status until 
the start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of consent, 
or the end of the study, whichever occurs first. 
6.1.4.4   Second Course (Retreatment) Tumor Imaging 
N/A 
6.1.4.5   RECIST 1.1 Assessment of Disease 
RECIST 1.1 will be used as the primary measure for assessment of tumor response, date of disease 
progression, and as a basis for all protocol guidelines related to disease status (eg, discontinuation of 
study treatment).  Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per 
organ, the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically 
relevant to enable a broader sampling of tumor burden.  

 
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6.1.4.6    iRECIST Assessment of Disease 
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen with 
immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor response and 
progression and make treatment decisions. When clinically stable, participants should not be 
discontinued until progression is confirmed by the investigator, working with local radiology, 
according to the rules outlined in Appendix 4. This allowance to continue treatment despite initial 
radiologic disease progression takes into account the observation that some participants can have a 
transient tumor flare in the first few months after the start of immunotherapy, and then experience 
subsequent disease response. This data will be captured in the clinical database.  
Clinical stability is defined as the following: 
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status 
• No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care  
Any participant deemed clinically unstable should be discontinued from study intervention at central 
verification of site-assessed first radiologic evidence of disease progression and is not required to 
have repeat tumor imaging for confirmation of disease progression by iRECIST.  
If the investigator decides to continue treatment, the participant may continue to receive study 
intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm disease 
progression by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR. 
If repeat imaging does not confirm disease progression per iRECIST, as assessed by the investigator, 
and the participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If disease progression is confirmed, participants will be discontinued from 
study intervention.  
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 4, study 
intervention should be discontinued; however, if the participant is achieving a clinically meaningful 
benefit, an exception to continue study intervention may be considered following consultation with 
the Sponsor. In this case, if study intervention is continued, tumor imaging should continue to be 
performed following the intervals as outlined in Section 6 and submitted to the iCRO.  
A description of the adaptations and iRECIST process is provided in Appendix 4.  A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided in Table 
8 and illustrated as a flowchart in Figures 1 and 2. 
 

 
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Table 8 Imaging and Treatment After First Radiologic Evidence of Progressive Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of disease 
progression by 
RECIST 1.1 per 
investigator assessment 
[For those studies 
in which PFS is 
the 
primary 
endpoint, 
add 
this: Submit the 
imaging to BICR 
for verification] 
Repeat imaging 
at 4 to 8 weeks to 
confirm disease 
progression 
May continue study 
treatment at the 
assessment of the 
investigator and 
after the 
participant’s consent 
[For those studies in 
which PFS is the 
primary 
endpoint, 
add this: Submit the 
imaging to BICR for 
verification] 
Repeat imaging at 4 
to 8 weeks to 
confirm disease 
progression per 
investigator’s 
discretion only. 
Discontinue treatment 
First radiologic 
evidence of disease 
progression by 
RECIST 1.1  
Repeat imaging 
at 4 to 8 weeks to 
confirm disease 
progression. 
May continue study 
intervention at the 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST. 
Repeat imaging at 4 
to 8 weeks to 
confirm disease 
progression per 
investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor imaging 
confirms disease 
progression (iCPD) by 
iRECIST per 
investigator 
assessment. 
No additional 
imaging required. 
Discontinue 
treatment (exception 
is possible upon 
consultation with 
Sponsor). 
No additional 
imaging required. 
Not applicable 
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator 
assessment. 
Repeat imaging 
at 4 to 8 weeks to 
confirm disease 
progression. May 
occur at next 
regularly 
scheduled 
imaging visit. 
Continue study 
intervention at the 
investigator’s 
discretion. 
Repeat imaging at 4 
to 8 weeks to 
confirm disease 
progression per 
investigator’s 
discretion only. 
Discontinue treatment 
Repeat tumor imaging 
shows iSD, iPR, or iCR 
by iRECIST per 
investigator 
assessment. 
Continue 
regularly 
scheduled 
imaging 
assessments. 
Continue study 
intervention at the 
investigator’s 
discretion. 
Continue regularly 
scheduled imaging 
assessments. 
May restart study 
intervention if 
condition has improved 
and/or clinically stable 
per investigator’s 
discretion. Next tumor 
imaging should occur 
according to the regular 
imaging schedule. 

 
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Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of disease 
progression by 
RECIST 1.1 per 
investigator assessment 
[For those studies 
in which PFS is 
the 
primary 
endpoint, 
add 
this: Submit the 
imaging to BICR 
for verification] 
Repeat imaging 
at 4 to 8 weeks to 
confirm disease 
progression 
May continue study 
treatment at the 
assessment of the 
investigator and 
after the 
participant’s consent 
[For those studies in 
which PFS is the 
primary 
endpoint, 
add this: Submit the 
imaging to BICR for 
verification] 
Repeat imaging at 4 
to 8 weeks to 
confirm disease 
progression per 
investigator’s 
discretion only. 
Discontinue treatment 
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable disease; 
iUPD=iRECIST unconfirmed progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1; 
VOP=verification of progression 
[For studies in which PFS is the primary endpoint, add the following: Note: If progression has been centrally verified, 
further management is by the site, based on iRECIST. Any further imaging should still be submitted to the iCRO, but 
no rapid review will occur. If RECIST 1.1 disease progression has not been centrally verified, the site should continue 
treatment. Whether or not treatment continues, imaging should be collected and submitted to the iCRO with VOP 
request until RECIST 1.1 progression is verified by BICR.] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 1: Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator 
 

 
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6.1.5 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Per SoA 
6.1.6  Other Procedures 
6.1.6.1 Discontinuation and withdrawal 
Participants who discontinue study intervention prior to completion of the treatment period should be 
encouraged to continue to be followed for all remaining study visits as outlined in the SoA and Section 
6.2. 
Participants who withdraw from the study should be encouraged to complete all applicable activities 
scheduled for the final study visit at the time of withdrawal. Any AEs that are present at the time of 
withdrawal should be followed in accordance with the safety requirements outlined in Section 6.2. 
6.1.6.2 Blinding/Unblinding: N/A 
6.1.7 Visit Requirements 
Visit requirements are outlined in Section 2.2 – Schedule of Activities.   Specific procedure-related 
details are provided above in Section 6.1 - Trial Procedures. 

 
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6.1.7.1 Screening 
6.1.7.1.1 Screening Period: 28 days prior to the initiation of MT therapy. Patients who have been 
on MT therapy can proceed to PEM therapy when completing 28 days of MT therapy  
6.1.7.2 
Treatment Period: Daily oral MT therapy to follow acceptable standards of care 
for mitotane therapy including concomitant steroid replacement and periodic MT levels 
check. PEM will be given 400 mg IV on D1 (+/- 5 days) in 6 weeks cycles for total of 18 
cycles.  
Post-Treatment Visits:  All patients who discontinue treatment without objective disease progression will 
be followed up with tumor assessment every 12 weeks (±14 days) or as determined by the principal 
investigator or designee) until disease progression or the start of a different anti-cancer therapy. Survival 
follow-up via phone call, medical record review, or visit with physician will occur every 3 months for 2 
years once they are off-study treatment or until patient death, withdrawal of consent, patient is lost to 
follow-up, or study termination, whichever occurs first. 
6.1.7.3 
 
6.1.7.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last 
dose of study intervention or before the initiation of a new anti-cancer treatment, whichever comes 
first.  Participants who are eligible for retreatment/crossover with pembrolizumab (as described in 
Section 5.2.2) may have up to two safety follow-up visits, one after the Initial Treatment Period 
and one after the Second Course Treatment. 
6.1.7.3.2 Efficacy Follow-up Visits 
All patients who discontinue treatment without objective disease progression will be followed up with 
tumor assessment every 12 weeks (±14 days) or as determined by the principal investigator or designee) 
until disease progression or the start of a different anti-cancer therapy. Survival follow-up via phone call, 
medical record review, or visit with physician will occur every 3 months for 2 years once they are off-
study treatment or until patient death, withdrawal of consent, patient is lost to follow-up, or study 
termination, whichever occurs first. 
 
6.1.7.3.3 Survival Follow-up Contacts 
Participant survival follow-up status will be assessed approximately every 12 weeks to assess for 
survival status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
The first survival follow-up assessment should be scheduled as described below: 

 
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• For participants who discontinue treatment intervention and who will not enter the Efficacy 
Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks after the 
discontinuation visit and/or safety follow-up visit (whichever is last). 
For participants who completed assessments in the Efficacy Follow-up Phase, the first survival 
follow-up contact will be scheduled 12 weeks after the last efficacy assessment follow-up visit has 
been performed. 
6.1.7.3.4 Post Study 
Participants will be required to return to clinic approximately within 30 days after the last dose of study 
intervention for the poststudy visit.  If the poststudy visit occurs less then 14 days after the last dose of 
study intervention, a subsequent follow-up telephone call should be made at 30 days post the last dose of 
study intervention to determine of any AEs have occurred since the poststudy clinic visit.   
 
6.2 Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and assessing causality 
of AE and SAE and the procedures for completing and transmitting AE, SAE, and other reportable safety 
event reports can be found in Appendix 5.   
Adverse events, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting events that 
meet the definition of an AE or SAE as well as other reportable safety events. Investigators remain 
responsible for following up AEs, SAEs, and other reportable safety events for outcome. 
The investigator, who is a qualified physician, will assess events that meet the definition of an AE or 
SAE as well as other reportable safety events with respect to seriousness, intensity/toxicity and 
causality.Time Period and Frequency for Collecting AE, SAE, and Other Reportable Safety Event 
Information 
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed but before 
intervention allocation/randomization must be reported by the investigator if the participant is receiving 
placebo run-in or other run-in treatment, if the event cause the participant to be excluded from the study, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, or a procedure. 
• All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator. 

 
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• All AEs meeting serious criteria, from the time of intervention allocation/randomization through 
90 days following cessation of study intervention or 30 days following cessation of study 
intervention if the participant initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator. 
• All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation/randomization through the time required to eliminate systemic exposure after 
cessation of study intervention as described in Section 5.11, or 30 days after cessation of study 
intervention if the participant initiates new anticancer therapy must be reported by the 
investigator. Additionally, any SAE brought to the attention of an investigator at any time 
outside of the time period specified above must be reported immediately to Merck if the event is 
considered drug-related. 
 
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events in former 
study participants. However, if the investigator learns of any SAE, including a death, at any time after a 
participant has been discharged from the study, and he/she considers the event to be reasonably related 
to the study intervention or study participation, the investigator must promptly notify Merck. 
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and reported to 
Merck within the time frames as indicated in Table . 
Exception: A positive pregnancy test at the time of initial screening is not a reportable event unless the 
participant has received study intervention. 

 
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Table 9 Reporting Time Periods and Time Frames for Adverse Events and Other Reportable Safety 
Events 
Type of Event 
Reporting Time 
Period: 
Consent to 
Randomization/ 
Allocation 
Reporting Time 
Period: 
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period 
Reporting Time Period: 
After the Protocol-
specified Follow-up 
Period 
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Merck: 
 
 
 
 
 
Serious Adverse Event 
(SAE) including Cancer 
and Overdose 
Report if: 
- due to protocol-
specified 
intervention 
- causes exclusion 
- participant is 
receiving placebo 
run-in or other run-
in treatment 
Report all 
Report if: 
- drug/vaccine related. 
(Follow ongoing to 
outcome) 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of receipt of 
information 
Pregnancy/Lactation 
Exposure 
Report if: 
 
-  participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in) 
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event. 
Report all 
Previously reported – 
Follow to 
completion/termination; 
report outcome 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of receipt of 
information 
Event of Clinical 
Interest (require 
regulatory reporting) 
Report if: 
- due to 
intervention 
- causes exclusion 
Report 
- potential drug-
induced liver 
injury (DILI) 
- require regulatory 
reporting 
Not required 
Within 2 
business days 
but no longer 
than 3 
calendar days 
of receipt of 
information 
 
 
 
 
 
 

 
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6.1.2 Method of Detecting AEs, SAEs, and Other Reportable Safety Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other reportable safety 
events. Open-ended and nonleading verbal questioning of the participant is the preferred method to 
inquire about AE occurrence. 
6.1.3 Follow-up of AE, SAE, and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each participant at 
subsequent visits/contacts. All AEs, SAEs, and other reportable safety events including pregnancy and 
exposure during breastfeeding, events of clinical interest (ECIs), cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost to follow-
up. In addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
allocated or randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 5. 
6.1.4 Sponsor Responsibility for Reporting Adverse Events  
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable country specific regulatory requirements, global laws and regulations.  
6.1.5 Pregnancy and Exposure During Breastfeeding 
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any pregnancy or 
infant exposure during breastfeeding in a participant (spontaneously reported to the investigator or their 
designee) that occurs during the study are reportable to the Sponsor. 
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Any pregnancy complication will be reported as an AE or SAE. 
The medical reason (example: maternal health or fetal disease) for an elective termination of a pregnancy 
will be reported as an AE or SAE. Prenatal testing showing fetus will be born with severe 
abnormalities/congenital anomalies that leads to an elective termination of a pregnancy will be reported 
as an SAE for the fetus. 
Pregnancy outcomes of ectopic pregnancy, 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 
6.1.6 Events of Clinical Interest (ECIs) 
Selected nonserious and SAEs are also known as ECIs and must be reported to Merck.  

 
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Events of clinical interest for this study include:  
1. 
An overdose of pembrolizumab that is not associated with clinical symptoms or abnormal 
laboratory results. For purposes of this study, an overdose of pembrolizumab will be defined as 
any dose of 1,000 mg or greater.  No specific information is available on the treatment of 
overdose of pembrolizumab. In the event of overdose, the participant should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if clinically 
indicated.   
2. 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal 
and an elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of 
normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the upper 
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.  
 
7.0 STATISTICAL ANALYSIS PLAN 
We will simultaneously monitor efficacy and toxicity using the Bayesian optimal phase 2 (BOP2) design 
(Zhou, Lee and Yuan, 2017). Specifically, let 𝑛𝑛 denote the interim sample size, and 𝑁𝑁 denote the 
maximum sample size. Let 𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒 and 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡 denote the binary efficacy and toxicity endpoints, with 𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒=
1 and 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡= 1 indicating that patients experience efficacy and toxicity, respectively. We assume that 
the joint distribution of (𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒, 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡) follows a multinomial distribution with four elementary outcomes: 
(𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒, 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡) = (1, 1), (1, 0), (0, 1) and (0, 0). Let 𝐩𝐩= (𝑃𝑃11, 𝑃𝑃10, 𝑃𝑃01, 𝑃𝑃00) denote the probabilities of 
observing the four outcomes, and let 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 𝑃𝑃𝑃𝑃(𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒= 1), 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡= 𝑃𝑃𝑃𝑃(𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡= 1) and 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒=
𝑃𝑃𝑃𝑃(𝑌𝑌𝑒𝑒𝑒𝑒𝑒𝑒= 1, 𝑌𝑌𝑡𝑡𝑡𝑡𝑡𝑡= 1). When efficacy and toxicity endpoints are monitored separately, the joint 
distribution reduced to marginal distribution of efficacy and marginal distribution of toxicity, 
respectively. For trial monitoring and decisions, extreme toxicities (TOX) will be defined as 
any grade 3 or higher adverse event that is possibly, probably, or related to therapy 
received on this protocol. Any grade 3 or higher adverse event that is potentially treatable with steroids 
or hormonal replacement will only count as an extreme toxicity if it does not improve to grade 1 or 
better within 2 weeks of therapy.  
The treatment is deemed unacceptable if 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒≤0.23 or 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡> 0.5. Thus, we will stop enrolling patients 
and claim that the treatment is unacceptable if 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒> 0.23|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆ቀ𝑛𝑛
𝑁𝑁ቁ
𝛼𝛼
, 

 
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or 
𝑃𝑃𝑃𝑃(𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡≤0.5|𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑) < 𝜆𝜆ቀ𝑛𝑛
𝑁𝑁ቁ
𝛼𝛼/3
, 
where 𝜆𝜆=0.5 and 𝛼𝛼=1 are design parameters optimized to maximize the study power, i.e., probability of 
correctly concluding an efficacious and safe treatment as acceptable when 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 0.3, 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡= 0.3 and 
𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 0.18, while controlling that the probability of incorrectly claiming an inefficacious and toxic 
treatment, i.e., type I error, with 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒= 0.23, 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡= 0.5 and 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒= 0.15, to 9.5%. Note that in the 
safety stopping rule, the original publication of the design used the probability cutoff 𝜆𝜆(𝑛𝑛/𝑁𝑁)𝛼𝛼, here the 
attenuation factor 3 is added (i.e., 𝛼𝛼/3) to obtain stricter interim stopping boundaries to enhance safety. 
 
For the purposes of interim monitoring, toxicities and responses will be monitored for 24 weeks post start 
of the combination therapy. 
This optimization is performed assuming a vague Dirichlet prior 𝐷𝐷𝐷𝐷𝐷𝐷(0.15,0.08,0.35,0.42) for 𝐩𝐩. The 
prior is chosen such that it corresponds to a prior effective sample size of 1 patient, and the prior estimates 
of 𝑝𝑝𝑒𝑒𝑒𝑒𝑒𝑒 and 𝑝𝑝𝑡𝑡𝑡𝑡𝑡𝑡 match the values specified when the treatment is unacceptable. The above decision rule 
leads to the following optimal stopping boundaries: 
Table 1: Optimized stopping boundaries 
# patients treated 
Stop if # response <= 
OR # toxicity 
>= 
10 
0 
6 
20 
3 
11 
35 
7 
18 
50 
11 
25 
When the total number of patients reaches the maximum sample size of 50, we conclude that the treatment 
is acceptable if the number of responses are greater than 11, and the number of toxicities are less than 25; 
otherwise we conclude that the treatment is unacceptable. The go/no-go criteria in Table 1 are non-
binding. 
Below are the operating characteristics of the design based on 10000 simulations using the BOP2 web 
application (BOP2 V1.4.7.0), which is available at http://www.trialdesign.org. 
Table 2: Operating characteristics 
Scenari
o 
Pr(Ef
f) 
Pr(Tox
) 
Pr(Eff & 
Tox) 
Early Stopping 
(%) 
Claim Acceptable 
(%) 
Average Sample 
Size 
1 
0.23 
0.5 
0.15 
83.15 
9.47 
23.0 
2 
0.30 
0.3 
0.18 
24.46 
71.38 
42.9 
 

 
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ORR will be summarized with a 95% confidence interval (Clopper-Pearson exact method). 
Analysis of Secondary Endpoints: OS and PFS will be analyzed using Kaplan-Meier survival curves. T-
tests and dot plots will be used to associated mitotane levels (specify time of measurement) with overall 
response. Adverse events will be summarized with frequencies tables. Highest grade adverse event will 
be determined for each subject and the count of all adverse events and related adverse events will be 
computed.  
8.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
8.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and 
ensure appropriate supply, storage, handling, distribution and usage of investigational product in 
accordance with the protocol and any applicable laws and regulations. 
Pembrolizumab will be provided by Merck as summarized in Table 10. 
Table 10 Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
8.2 Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
8.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or designee are 
not blinded to treatment. Drug identity (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
8.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified 
on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 

 
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8.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received from Merck 
or designee, the amount dispensed to and returned by the participants and the amount remaining at the 
conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational product 
will be destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange 
for disposal of all empty containers, provided that procedures for proper disposal have been established 
according to applicable federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. 
 
9.0 ADMINISTRATIVE AND REGULATORY DETAILS 
 
 
 
10.0 REFERENCES 
At the end of protocol  

 
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11.0 APPENDICES 
Appendix 1: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 11 will be performed [by the central laboratory] [by the local laboratory]. 
• [Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make either a study intervention decision or 
response evaluation, the results must be entered into the CRF.] 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 5.1 of 
the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by the 
investigator or required by local regulations. 
Table 11 Protocol-required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Chemistry 
BUN 
Potassium 
AST/SGOT 
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
ULN) 
 
Albumin 
Bicarbonate 
Chloride 
Phosphorous 
 
Creatinine 
Sodium 
ALT/SGPT 
Total Protein 
 
Glucose [Indicate if 
fasting, or 
nonfasting] 
Calcium 
Alkaline 
phosphatase 
 
Routine 
Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte 
esterase] by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy 
Testing 
• 
[Highly sensitive serum or urine] hCG pregnancy test (as needed for WOCBP) 
Other Screening 
Tests 
• 
FSH (as needed in WONCBP only) 
• 
[Serum or urine] [alcohol and drug screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) if applicable] 
• 
 [Serology [(HIV antibody, HBsAg, and hepatitis C virus antibody)] [or specify other 
tests] [if applicable] 
 

 
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ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; FSH=follicle-stimulating 
hormone; hCG=human chorionic gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; 
RBC=red blood cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; 
ULN=upper limit of normal; WOCBP=women of childbearing potential; WONCBP=women of nonchildbearing potential 
 
 
 
The investigator (or medically qualified designee) must document their review of each laboratory safety 
report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Appendix 3: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s medical records, 
medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with two FSH measurements in the postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one of the non-
hormonal highly effective contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status 
before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if they agree to 
one of the following during the protocol defined time frame in section 5.11:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long 
term and persistent basis) and agree to remain abstinent 

 
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● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% per year as 
described in Table 12 when having penile-vaginal intercourse with a woman of childbearing potential 
who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration. 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception that has a low user dependency consistently and correctly as described 
in Table 12 during the protocol-defined time frame in Section 5.11. 

 
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Table 12 Highly Effective Contraceptive Methods That Have Low User Dependency 
 
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant a, b 
● Intrauterine hormone-releasing system (IUS) b 
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the 
sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.  
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive implants are limited to those which inhibit ovulation. 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the treatment 
period and for at least [190 days, corresponding to time needed to eliminate study treatment plus 30 
days for study treatments with genotoxic potential] after the last dose of study treatment.   
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a highly 
effective method of contraception consistently and correctly as described in Table 13 during the 
protocol-defined time frame in Section 5.11.  
 
Table 13 Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  

 
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Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing) hormonal contraception b, c 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b, c 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  
 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least [190 days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential] after the last dose of study treatment. 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
 
Female Participants: 

 
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Female participants of childbearing potential are eligible to participate if they agree to use one of the 
contraception methods described in Table 14 consistently and correctly during the protocol-defined time 
frame in Section 5.11. 
Table 14  Contraceptive Methods 
Acceptable Contraceptive Methods   
Failure rate of >1% per year when used consistently and correctly.  
● Male or female condom with or without spermicide 
● Cervical cap, diaphragm or sponge with spermicide 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b, c  
● Intrauterine hormone-releasing system (IUS) b  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies. 
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and 
correctly).  

 
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b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at 
least 190 days, corresponding to time needed to eliminate study treatment plus 30 days for study 
treatments with genotoxic potential] after the last dose of study treatment . 
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.  
 
Pregnancy Testing 
Female Participant: Pregnancy test, serum or urine at baseline, urine prior to every cycle for women of 
child-bearing potential; All WOCBP must have a negative serum or urine pregnancy test within 72 hours 
prior to start of pembrolizumab. 
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or when pregnancy 
is otherwise suspected. 

 
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Appendix 4:  Description of the iRECIST Process for Assessment of Disease Progression 
Assessment at Screening and Prior to RECIST 1.1 Progression 
Until radiographic progression based on RECIST 1.1, there is no distinct iRECIST assessment. 
Assessment and Decision at RECIST 1.1 Progression 
In participants who show evidence of radiological PD by RECIST 1.1 the Investigator will decide whether 
to continue a participant on study treatment until repeat imaging 4 to 8 weeks later is obtained (using 
iRECIST for participant management (see Table 8 and Figures 1 and 2).  This decision by the Investigator 
should be based on the participant’s overall clinical condition. 
Clinical stability is defined as the following:  
• Absence of symptoms and signs indicating clinically significant progression of disease 
• No decline in ECOG performance status  
• No requirements for intensified management, including increased analgesia, radiation, or other 
palliative care 
Any participant deemed clinically unstable should be discontinued from study treatment at site-assessed 
first radiologic evidence of PD and is not required to have repeat tumor imaging for confirmation of PD 
by iRECIST. 
If the Investigator decides to continue treatment, the participant may continue to receive study treatment 
and the tumor assessment should be repeated 4 to 8 weeks later to confirm PD by iRECIST, per 
Investigator assessment.   
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, including: 
• Increase in the sum of diameters of target lesion(s) identified at baseline to ≥ 20% and ≥ 5 mm 
from nadir 
o Please note: the iRECIST publication uses the terminology “sum of measurements”, but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology. 
• Unequivocal progression of non-target lesion(s) identified at baseline 
• Development of new lesion(s) 
iRECIST defines new response categories, including iUPD (unconfirmed progressive disease) and iCPD 
(confirmed progressive disease).  For purposes of iRECIST assessment, the first visit showing progression 
according to RECIST 1.1 will be assigned a visit (overall) response of iUPD, regardless of which factors 
caused the progression. 

 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be assessed as usual. 
New lesions will be classified as measurable or non-measurable, using the same size thresholds and rules 
as for baseline lesion assessment in RECIST 1.1.  From measurable new lesions, up to 5 lesions total (up 
to 2 per organ), may be selected as New Lesions – Target.  The sum of diameters of these lesions will be 
calculated and kept distinct from the sum of diameters for target lesions at baseline.  All other new lesions 
will be followed qualitatively as New Lesions – Non-target. 
Assessment at the Confirmatory Imaging 
On the confirmatory imaging, the participant will be classified as progression confirmed (with an overall 
response of iCPD), or as showing persistent unconfirmed progression (with an overall response of iUPD), 
or as showing disease stability or response (iSD/iPR/iCR). 
Confirmation of Progression 
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the following 
occurs: 
• Any of the factors that were the basis for the initial iUPD show worsening 
o For target lesions, worsening is a further increase in the sum of diameters of ≥ 5 mm, compared 
to any prior iUPD time point 
o For non-target lesions, worsening is any significant growth in lesions overall, compared to a 
prior iUPD time point; this does not have to meet the “unequivocal” standard of RECIST 1.1 
o For new lesions, worsening is any of these: 
 An increase in the new lesion sum of diameters by ≥ 5 mm from a prior iUPD time point  
 Visible growth of new non-target lesions  
 The appearance of additional new lesions 
• Any new factor appears that would have triggered PD by RECIST 1.1 
Persistent iUPD 
Progression is considered not confirmed, and the overall response remains iUPD, if: 
• None of the progression-confirming factors identified above occurs AND 
• The target lesion sum of diameters (initial target lesions) remains above the initial PD threshold 
(by RECIST 1.1) 
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the scan on which iUPD is 
seen.  This may correspond to the next visit in the original visit schedule.  The assessment of the 

 
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subsequent confirmation scan proceeds in an identical manner, with possible outcomes of iCPD, iUPD, 
and iSD/iPR/iCR. 
Resolution of iUPD 
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if: 
• None of the progression-confirming factors identified above occurs, AND 
• The target lesion sum of diameters (initial target lesions) is not above the initial PD threshold.  
The response is classified as iSD or iPR (depending on the sum of diameters of the target lesions), or iCR 
if all lesions resolve. 
In this case, the initial iUPD is considered to be pseudo-progression, and the level of suspicion for 
progression is “reset”.  This means that the next visit that shows radiographic progression, whenever it 
occurs, is again classified as iUPD by iRECIST, and the confirmation process is repeated before a response 
of iCPD can be assigned. 
Management Following the Confirmatory Imaging 
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the participant 
continues to be clinically stable, study treatment may continue and follow the regular imaging schedule.  
If PD is confirmed, participants will be discontinued from study treatment. 
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but the 
participant is achieving a clinically meaningful benefit, an exception to continue study treatment may be 
considered.  In this case, if study treatment is continued, tumor imaging should continue to be performed 
following the intervals as outlined in Section 6. 
Detection of Progression at Visits After Pseudo-progression Resolves 
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated by any of the 
following events: 
• Target lesions 
o Sum of diameters reaches the PD threshold (≥ 20% and ≥ 5 mm increase from nadir) either for 
the first time, or after resolution of previous pseudo-progression.  The nadir is always the 
smallest sum of diameters seen during the entire trial, either before or after an instance of 
pseudo-progression. 
• Non-target lesions 
o If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD. 

 
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o If non-target lesions had shown previous unequivocal progression, and this progression has not 
resolved, iUPD results from any significant further growth of non-target lesions, taken as a 
whole. 
• New lesions 
o New lesions appear for the first time 
o Additional new lesions appear 
o Previously identified new target lesions show an increase of ≥ 5 mm in the new lesion sum of 
diameters, from the nadir value of that sum 
o Previously identified non-target lesions show any significant growth 
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD evaluation 
process (see Assessment at the Confirmatory Imaging above) is repeated.  Progression must be confirmed 
before iCPD can occur. 
The decision process is identical to the iUPD confirmation process for the initial PD, except in one respect. 
If new lesions occurred at a prior instance of iUPD, and at the confirmatory scan the burden of new lesions 
has increased from its smallest value (for new target lesions, their sum of diameters is ≥5 mm increased 
from its nadir), then iUPD cannot resolve to iSD or iPR. It will remain iUPD until either a decrease in the 
new lesion burden allows resolution to iSD or iPR, or until a confirmatory factor causes iCPD. 
Additional details about iRECIST are provided in the iRECIST publication (Seymour et al. 2017).  
 

 
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Appendix 5: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting 
11.1.1 Definition of AE 
AE definition 
• An AE is any untoward medical occurrence in a clinical study participant, temporally associated 
with the use of study intervention, whether or not considered related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of a study intervention. 
• NOTE: For purposes of AE definition, study intervention (also referred to as Merck product) 
includes any pharmaceutical product, biological product, vaccine, diagnostic agent, medical 
device, combination product, or protocol specified procedure whether investigational or marketed 
(including placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by Merck for human use in this study. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though it may 
have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention or a 
concomitant medication. 
• For all reports of overdose (whether accidental or intentional) with an associated AE, the AE term 
should reflect the clinical symptoms or abnormal test result. An overdose without any associated 
clinical symptoms or abnormal laboratory results is reported using the terminology “accidental or 
intentional overdose without adverse effect.” 
      

 
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Events NOT meeting the AE definition 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
• Surgery planned prior to informed consent to treat a pre-existing condition that has not worsened. 
 
11.1.2 Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are 
met. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• The term “life-threatening” in the definition of “serious” refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• Hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an 
elective procedure to treat a pre-existing condition that has not worsened is not an SAE. A pre-
existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and 
is documented in the participant’s medical history. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) that may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 

 
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e. Is a congenital anomaly/birth defect 
• In offspring of participant taking the product regardless of time to diagnosis. 
f. Other important medical events 
• Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the participant or may require 
medical or surgical intervention to prevent 1 of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization, or development of drug dependency or drug abuse. 
11.1.3 Additional Events Reported in the Same Manner as SAE 
Additional events that require reporting in the same manner as SAE 
In addition to the above criteria, AEs meeting either of the below criteria, although not serious per ICH 
definition, are reportable to Merck in the same time frame as SAEs to meet certain local requirements. 
Therefore, these events are considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose of pembrolizumab 
11.1.4 Recording AE and SAE 
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation (eg, 
hospital progress notes, laboratory, and diagnostics reports) related to the event. 
• The investigator will record all relevant AE/SAE information on the AE CRFs/worksheets at each 
examination. 
• There may be instances when copies of medical records for certain cases are requested by the Merck. 
In this case, all participant identifiers, with the exception of the participant number, will be blinded 
on the copies of the medical records before submission to the Merck. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. In such cases, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 

 
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Assessment of intensity/toxicity 
• An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, not when it is rated as severe. 
1. 
The investigator will make an assessment of intensity for each AE and SAE (and other reportable 
safety event) according to the NCI Common Terminology for Adverse Events (CTCAE), version 
5. Any AE that changes CTCAE grade over the course of a given episode will have each change 
of grade recorded on the AE CRFs/worksheets. 
• Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL). 
• Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
• Grade 4: Life threatening consequences; urgent intervention indicated. 
• Grade 5: Death related to AE. 
Assessment of causality 
1. 
Did Merck product cause the AE? 
2. 
The determination of the likelihood that Merck product caused the AE will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source 
document or worksheet that supports the causality noted on the AE form, ensures that a medically 
qualified assessment of causality was done. This initialed document must be retained for the 
required regulatory time frame. The criteria below are intended as reference guidelines to assist 
the investigator in assessing the likelihood of a relationship between the test product and the AE 
based upon the available information. 
3. 
The following components are to be used to assess the relationship between Merck’s product 
and the AE; the greater the correlation with the components and their respective elements (in 
number and/or intensity), the more likely Merck product caused the AE: 
• Exposure: Is there evidence that the participant was actually exposed to Merck product such 
as: reliable history, acceptable compliance assessment (pill count, diary, etc.), expected 
pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
• Time Course: Did the AE follow in a reasonable temporal sequence from administration of 
Merck product? Is the time of onset of the AE compatible with a drug-induced effect (applies 
to studies with investigational medicinal product)? 

 
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• Likely Cause: Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors. 
• Dechallenge: Was Merck product discontinued or dose/exposure/frequency reduced? 
• If yes, did the AE resolve or improve? 
• If yes, this is a positive dechallenge. 
• If no, this is a negative dechallenge. 
• (Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; 
(2) the AE resolved/improved despite continuation of the Merck product; (3) the study is a 
single-dose drug study; or (4) Merck product(s) is/are only used 1 time.) 
• Rechallenge: Was the participant re-exposed to Merck product in this study? 
• If yes, did the AE recur or worsen? 
• If yes, this is a positive rechallenge. 
• If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, 
or (2) the study is a single-dose drug study; or (3) Merck product(s) is/are used only 1 time.) 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND MAY HAVE 
BEEN CAUSED BY MERCK PRODUCT, OR IF RE-EXPOSURE TO MERCK’S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE INIRB/IEC. 
4. 
Consistency with study intervention profile: Is the clinical/pathological presentation of the 
AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
5. 
The assessment of relationship will be reported on the case report forms/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
6. 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative 
of Merck product relationship). 

 
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• Yes, there is a reasonable possibility of Merck product relationship: 
• There is evidence of exposure to the Merck product. The temporal sequence of the AE onset 
relative to the administration of Merck product is reasonable. The AE is more likely explained 
by Merck product than by another cause. 
• No, there is not a reasonable possibility of Merck product relationship: 
• Participant did not receive the Merck product OR temporal sequence of the AE onset relative 
to administration of the Merck product is not reasonable OR the AE is more likely explained 
by another cause than the Merck product. (Also entered for a participant with overdose without 
an associated AE.) 
7. 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
8. 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Merck. However, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to Merck. 
9. 
The investigator may change his/her opinion of causality in light of follow-up information and 
send an SAE follow-up report with the updated causality assessment. 
10. 
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements. 
11. 
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent of 
the combination. In general, causality attribution should be assigned to the combination regimen 
(ie, to all agents in the regimen). However, causality attribution may be assigned to a single agent 
if in the investigator’s opinion, there is sufficient data to support full attribution of the AE to the 
single agent. 
Follow-up of AE and SAE 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals.  
• New or updated information will be recorded in the CRF.  

 
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• The investigator will submit any updated SAE data to Merck within 2 business days but no longer 
than 3 calendar days of receipt of the information. 
11.1.5 Reporting of AEs, SAEs, and Other Reportable Safety Events to the Merck 
SAE reports and any other relevant safety information are to be forwarded to the Merck Global 
Safety facsimile number:  +1-215-661-6229 
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 215-661-6229) at the time of submission to FDA. 
 
 
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